A Bioworld speciAl report The NexT GeNeraTioN: BioWorld ...into other parts of the body, so we may...

A Bioworld speciAl report

The NexT GeNeraTioN: BioWorld looks aT 65 iNNovaTive NeW CompaNies

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aavlife series a: $12m for Friedreich’s ataxia gene therapy program ........................................................................................ 5

agilis Biotherapeutics launches with $8m, intrexon deal ............................................................................................................ 7

money in hand, alcobra focuses ‘attention’ on adhd ................................................................................................................. 9

alizé pharma seeks to realize goals through asset-based model ............................................................................................... 11

alphamab converts Cro platform into drug development engine ............................................................................................. 13

start-up amcure raises $7m to target Cd44v6 in cancer ............................................................................................................ 15

Two-pronged amyndas targets complement-based anti-inflammatories ......................................................................................................16

antriabio’s basal insulin dream takes flight ................................................................................................................................. 18

arcturus shoots for ‘lUNar’ landing in treating rare diseases ................................................................................................... 19

av Therapeutics tackles next-gen prostate cancer therapy ......................................................................................................... 21

Berg pharma plying ‘conversation’ within cells to create drugs .................................................................................................. 22

Carsgen’s China-led series a to fund clinical trials of Car-T candidate ..................................................................................... 24

myos, Cloud collaborate to ‘muscle in’ on new therapeutic category ......................................................................................... 26

Corbus prepares to put anti-inflammatory drug to the test ........................................................................................................ 28

recent start-up Cour lands former pfizer r&d chief as chairman .................................................................................................... 30

‘Crispr’ dough: Genome-editing start-up raises $25m in series a ............................................................................................... 31

raise the ‘Curtana’ for start-up with $7.6m grant for GBm therapy ............................................................................................ 33

domainex makes the leap from discovery to drug pipeline ......................................................................................................... 35

Big data for small molecules; exscientia inks first pharma deal ................................................................................................. 37

Fibrotech launches diabetic nephropathy study, partnering talks .............................................................................................. 39

Genmab exploring world of rabbits in mab discovery deal ......................................................................................................... 40

Genoa seeks ‘breath of fresh air’ in ipF with inhaled pirfenidone................................................................................................ 41

Glionova gets $6m in series a for new approach in cancer .......................................................................................................... 43

imevax gets $10m in series a for H. pylori vaccine ........................................................................................................................ 45

immunovaccine reports success protecting animals from ebola ................................................................................................ 46

Novartis, atlas fund Crispr-Cas9 venture intellia in $15m series a .......................................................................................... 48

kindex brewing diabetes drug with hops-derived humulone; $5m series a ............................................................................... 51

Beyond child’s play: legochem’s platform to expedite drug discovery ....................................................................................... 52

longevity’s hybridtides not just ‘me-too’ peptides .................................................................................................................................. 54

lTi taps lysosomal experts, model for parkinson’s work .............................................................................................................. 56

lumos seeking to light the way with drug for ultra-rare CTd...................................................................................................... 58

18-month-old mabspace aims to fast track FoBs in China for cancer, Ckd ............................................................................... 60

Uk’s magnus launches with $25m round, ‘real understanding of disease’ ...............................................................................................62

TaBle oF CoNTeNTs


mount Tam Biotech to explore Buck institute compound in sle ................................................................................................ 63

Nightstarx gene therapy may help restore vision to choroideremia patients ...................................................................................... 65

Novan seeks to unleash power of nitric oxide in ‘tunable’ drugs ................................................................................................. 67

start-up ocugen eyes new opthalmology opportunities ............................................................................................................. 69

round two for former pharmasset execs with hBv start-up oncore ........................................................................................ 70

osteoqc mines Canadian talent to build new bone disease venture........................................................................................... 72

series a round sets otologic hearing-loss pill on pathway to clinic ............................................................................................ 73

like a canoe, protein can ‘portage’ cargo across cells ................................................................................................................. 75

protelica steering its own path to develop next-gen protein drugs ............................................................................................ 77

passion for science is paying off in prothelia partnership ............................................................................................................ 79

rani set to start trials of insulin-delivering capsule next year ..................................................................................................... 81

‘Cure, not care’ is the mantra for Japan’s regimmune ................................................................................................................ 83

replicel marches ahead with cell therapy trials........................................................................................................................... 85

reviral’s series a provides runway to move rsv candidate into the clinic .................................................................................. 87

rigontec gets $12m for rNa-based immunotherapies ................................................................................................................ 88

Finding its ‘niche’: start-up scholar rock targeting growth factors ........................................................................................... 89

scioderm seeks fast track with breakthrough drug for rare skin disorder ..................................................................................... 91

serenus Biotherapeutics looks to tap africa’s underdeveloped market ...................................................................................... 93

acute, chronic pain therapy in ‘site’ for Janssen labs spinout .................................................................................................... 95

more than so-so progress for sotio in cancer immunotherapy .................................................................................................... 97

Tip of the ‘spero’: roche, start-up target new antimicrobial pathway ....................................................................................... 99

synaffix closes series a round for adC platform .......................................................................................................................... 101

a-T, G-C . . . and more? synthorx launched on new dNa base pair tech ................................................................................... 103

Terravab seeks a ‘whole world’ solution to subduing mrsa ....................................................................................................... 104

pain in the brain? Trigemina seeking to break the barrier ........................................................................................................... 106

Tunitas fusion proteins take double aim at allergic disease ........................................................................................................ 108

versatile aCTr: platform garners $12m in series a for Unum Therapeutics ............................................................................... 110

Third rock’s voyager blasting off with $45m for CNs gene therapy ........................................................................................... 112

vyome adds $8m to advance pipeline against skin conditions ................................................................................................... 114

xeris rethinks delivery technology to improve hypoglycemia treatment .................................................................................... 116

Biotech veteran Coles returns to fold with start-up Yumanity .................................................................................................... 118

Zai has arrived; inks deal with sanofi for preclinical Copd drugs ............................................................................................... 120


AAVLife SerieS A: $12M for friedreich’S AtAxiA gene therApy progrAMBy Randy Osborne, Staff Writer

about 13 years ago, when amber salzman’s son and two nephews were diagnosed with adrenoleukodystrophy (ald), a genetic brain disorder, she didn’t know much about rare diseases at all. That’s changed for the Ceo of paris-based aavlife, which – with $12 million in series a money – is taking aim at another: Friedreich’s ataxia (Frda).

Though one nephew died, salzman’s son today is a healthy adolescent and the other nephew is a sophomore at stanford University, thanks to gene therapy sought by salzman, then an r&d executive at london-based Glaxosmithkline plc.

Working the rare disease field, “you feel it much more closely than when you’re working in some of the large diseases,” salzman said. patients may soon feel the results of aavlife’s efforts in Frda, as the company specifically targets the cardiovascular effects of the disease.

“We’re going directly into the heart,” she said. “it does drip into other parts of the body, so we may get lucky and see an impact” on neurological as well as cardiac symptoms, but “most likely, you have to put the vector in the spine and/or parts of the brain. We just need to do a little more work before we feel comfortable saying we’re ready to go into humans” and try for neurological improvements. The cardiac research is expected to enter the clinic next year.

“if you look at the strategies that have taken place before gene therapy, they’ve kind of tried to mop up the mess of not having enough frataxin, whereas we’re going in and up-regulating the amount of frataxin that’s being expressed rather than try to fix the downstream problem,” salzman told BioWorld Today.

Frda symptoms usually appear early in life, between the ages of 5 and 15, though they may be delayed until adulthood. First comes the loss of control of body movements (ataxia), often starting with difficulty in walking, then spreading to the upper body, with nervous system damage often accompanied by heart problems.

“When we went to pitch this [program] to raise the funds, there were some investors who said, ‘Cardio? Who cares about cardio?’’ salzman recalled. “i said, ‘Well, don’t talk to me, talk to the patients. They’ll tell you who cares about cardio.’ There has been so much focus on the neuro, but if you talk to the leading people in the field, they’ll say they kept describing it as

a neurological disorder, but then found that more than half of their patients were dying because of heart failure.”

versant ventures led aavlife’s financing round with participation from inserm Transfert initiative, a French seed investment firm linked to the French National institute of health and medical research.

The company’s approach was detailed recently in Nature Medicine. researchers found that deleting the frataxin gene (mutated in Frda) in mice caused the rodents’ hearts to degenerate, as those in human patients do. delivery of a normal frataxin gene by way of adeno-associated virus (aav, from which the company derives the first part of its name) restored normal function.

one of the co-authors of the Nature Medicine paper and a co-founder of aavlife is ronald Crystal, chairman of genetic medicine and professor of internal medicine at Weill Cornell medical College in New York.

“There’s always a caveat with mouse studies,” allowed Crystal, who has been doing gene therapy for more than 20 years. “on the other hand, the thing that was so striking to me about this is that you can not only pre-treat and prevent the cardiac manifestations in this knockout mouse, but after the cardiac failure has ensued, you can actually reverse it. it’s very unusual for a gene therapy application to see that.”

rare diseases ‘iN voGUe’

improving the cardiac aspect of Frda would “markedly expand life spans,” he said. “We’ve had experience doing [gene therapy] with angiogenesis in the past.” although the neurology piece represents “a much bigger challenge, that doesn’t mean it’s not doable, and we’re working on that.” he noted that his lab has a neurological gene therapy program in Batten disease, the lysosomal storage disorder that strikes children ages 3 to 4 and kills them by ages 10 to 12. aav gene therapy has been delivered directly to the brains of 12 children, Crystal told BioWorld Today. “We know a lot about its characteristics and safety.” in Frda, published papers suggest that animal doses for neurological benefit may be too high to replicate in humans without serious side effects.

Ceo salzman said the phase i/ii heart study likely will enroll 10 to 12 patients. “if this really works, it’s totally possible to do another study after that, and register on [a trial with]


another 30 patients.” endpoints are tricky but not impossible, and Crystal is helping to design them. “i think [the trial] has a real chance of working,” he said. Treadmill measures for cardiac function are out of the question, because patients have neurologic disease and are confined to wheelchairs.

“We can use upper-extremity exercise” as well as imaging, which checks the mass of the left ventricle, which enlarges in Frda, Crystal said. “We have a number of parameters that we can use. We’re also planning a natural history study, together with the Friedreich’s ataxia association, to be able to make the decision as to what parameter would be the best as the primary [one] for the clinical trial.”

salzman said rare diseases are “in vogue,” thanks to smaller trials and less cost. Frda may draw particular interest, since about 5,000 patients exist in the U.s. and 10,000 in europe – large numbers for a rare disease. Cortellis Competitive intelligence lists a dozen Frda programs in development, sponsored by companies or nonprofit research organizations. recent newsmakers include Cambridge, mass.-based voyager Therapeutics inc., which in February 2014 raised $45 million in a series a round for its aav gene therapy approach in Frda and other central nervous system disorders. a synthetic biology company in New York developing first-in-class dNa-based therapeutics, agilis Biotherapeutics llC is working on Frda through an exclusive channel collaboration with intrexon Corp., of Germantown, md. (see BioWorld Today, Jan. 2, 2014, and Feb. 12, 2014.)

ald, which got salzman into rare diseases in the first place,

became the focus of Cambridge, mass.-based Bluebird Bio inc., public as of the summer of 2013’s $101 million initial offering. (see BioWorld Today, June 20, 2013.)

While casting for treatments that might help her son and nephew fight ald, salzman crossed paths with French neurologist patrick aubourg. “he was thinking, ‘i’ve been working on this damn disease for 20, 25 years, and we’re not making progress. i want to go the gene therapy route as well,’” she said. “When i met him in paris, we pooled resources and thoughts about how we were going to take it forward.” aubourg’s published success with four afflicted boys led to Third rock ventures’ interest, along with Genzyme ventures, and Bluebird was on its way.

aubourg is also a co-founder of aavlife, along with salzman, Crystal, and two other French scientists, hélène puccio and pierre Bougnères. Begun in late 2013, aavlife has just begun to add employees. Though the first efforts will involve cardiac consequences of Frda, salzman has bigger plans with regard to the neurological fallout of the disease, and maintains for it the same outlook as she held with ald. “parents [of Frda-stricken children] say, ‘look i’d like you to cure everything. But please, i don’t want my child dying in their 20s because of heart failure,’” salzman said. “Not that the neuro component is not a big deal. it is a big deal. You have people at the bench science level saying we don’t know enough to go forward. We’re not going to know everything. But what’s the minimum we need to know to be responsible about going forward?” //

– BioWorld Today, april 16, 2014


AgiLiS BiotherApeuticS LAuncheS with $8M, intrexon deALBy Marie Powers, Staff Writer

as 2013 ticked away, intrexon Corp. extended a string of biotech deals by inking an exclusive channel collaboration (eCC) with agilis Biotherapeutics llC, which simultaneously launched with an $8 million financing.

in april 2013, ampliphi Biosciences Corp., of richmond, va., inked an eCC with intrexon, of Germantown, md., to develop bacteriophage-containing human therapeutics across three programs. as part of that deal, ampliphi received an exclusive, worldwide license to apply intrexon’s expertise and technology toward the standardized production of wild type phages and to design and produce genetically modified bacteriophages. (see BioWorld Today, dec. 17, 2013.)

in september 2013, intrexon increased its stake in exton, pa.-based Fibrocell science inc. The companies inked an r&d collaboration in october 2012 with the goal of controlling cellular functions while developing a next generation of genetically and nongenetically modified autologous fibroblasts and autologous dermal cells. (see BioWorld Today, sept. 27, 2013.)

in december 2013, intrexon’s $26 million takeover of san diego-based medistem inc. added endometrial regenerative cells, derived from menstrual blood, to its bag of tricks to use with its integrated synthetic biology platforms, enhancing the potential for cell-based therapeutic candidates across a range of conditions. (see BioWorld Today, dec. 23, 2013.)

intrexon also inked a deal with ovascience inc., of Cambridge, mass., to accelerate development of the company’s ovature technology platform, designed as a next-generation approach to in vitro fertilization, and the companies established a joint venture to combine their technology platforms for new applications in human and animal health.

a synthetic biology company developing first-in-class dNa-based therapeutics, New York-based agilis initially will focus on a treatment for Friedreich’s ataxia (Frda) through the eCC with intrexon. The companies have an option to expand their relationship by adding another rare genetic disease to the eCC.

in fact, George Zorich, Ceo of agilis, gave credit for the company’s launch to intrexon – specifically, to chairman and Ceo randal J. kirk – and to founding investor Griffin securities. Falcon Fund and stadium Capital management llC also were

lead investors in the round.

Zorich began his career at eli lilly and Co., advancing through several other pharmas before landing in 1997 as president at General injectables and vaccines inc., where kirk was Ceo. The two remained friends after the marketer of vaccines and other injectables was acquired in 1999 by henry schein inc. Zorich went on to sabex Usa, a specialty injectable company, and then to Bioniche pharma holdings ltd. – both acquired by big pharmas during his tenure. kirk turned to Zorich when the concept for agilis began to percolate about a year ago.

agilis and intrexon will take a dNa-based approach to develop therapeutics targeting the underlying disease mechanisms of Frda. The neurodegenerative disease is caused by a defect in the FxN gene that results in limited production of the protein frataxin, which functions in the mitochondria of the cell. progression of the disease causes nervous system damage, movement disorders and early death from cardiac malfunction.

agilis will use intrexon’s Ultravector platform and rheoswitch Therapeutic system (rTs) to develop gene therapies and genetically modified cell therapies that address both the neurological and cardiovascular pathologies of Frda. rTs is an inducible gene switch technology that regulates the expression of therapeutic proteins or bioactive rNa in a dose-dependent fashion.

The companies hope to develop therapies that repair or replace the broken gene in Frda and enable increased production of frataxin. The ability to combine gene correction with therapeutic modulators in a multigenic approach emerged from rapid advances in synthetic biology, according to Zorich.

“We’re at the right place and the right time to produce a protein and actually target the delivery, via vectors, to the heart, central nervous system – wherever it needs to go – based on the right collaborations,” he told BioWorld Today. “This approach definitely was not realistic a decade ago, but it’s where the future of exciting therapies of the 21st century is going to go.”

Frda was selected as the initial indication because agilis and intrexon are convinced that frataxin “is a correctable protein fix,” Zorich added. “The timing is right.”

The initial $8 million investment will take agilis “pretty far down the road” into drug development, an investigational new


drug application and initial human trials, Zorich said. With the company pursuing rare diseases, studies “won’t require 2,000 patients,” he pointed out.

For a rare disease, Frda also offers an intriguing commercial potential. Friedrich’s is the most common hereditary ataxia, with an estimated 5,000 to 10,000 patients in the U.s. and no Fda-approved treatments that address the cause of the disease.

Zorich is the only full-time employee of agilis, which initially is relying on a network of advisors and consultants as well as intrexon resources. long term, agilis’ business strategy will stay “fluid and dynamic,” Zorich indicated, adding, “we could

develop the horsepower to take these products to market, but we also have to look at other options, including out-licensing, as appropriate.”

Ultimately, the partnership with intrexon could result in “a tremendous amount” of products based on cutting-edge synthetic biology.

“There’s so much mystery around this technology,” Zorich said. although many U.s. universities, including his alma mater, the University of Wisconsin, have not yet embraced synthetic biology, “this will be the go-forward strategy for many health care and biological products,” he maintained. //

– BioWorld Today, Jan. 2, 2014


Money in hAnd, ALcoBrA focuSeS ‘Attention’ on AdhdBy Marie Powers, Staff Writer

alcobra ltd. didn’t set out to address attention deficit hyperactivity disorder (adhd), an indication with a number of approved drugs – including ritalin (methylphenidate, Novartis aG), Concerta (a different formulation of methylphenidate, Johnson & Johnson) and adderall xr (d-amphetamine, shire plc) – as well as spectacular failures. instead, the company was formed in 2008 by several israeli entrepreneurs to pursue a drug that would induce rapid sobriety for social drinkers by quickly reducing blood alcohol levels – thus, the mashup of “alcohol” and “sobriety” in its name.

But a funny thing happened as its compound, mG01Ci, an extended-release oral nonstimulant formulation of metadoxine, moved through clinical trials. in a phase i study, the drug did not rapidly eliminate alcohol from the bloodstream; participants still were legally intoxicated, explained Yaron daniely, Ceo of the Tel aviv-based company. Unexpectedly, however, individuals who took the drug had a rapid and dramatic restoration of cognitive function – despite high alcohol blood levels – compared to those on placebo, measured on attention tasks such as driving in a simulator and memory tests.

With those findings in hand, in 2010, the company turned its attention to improving cognitive function, initially in adhd. a phase i study of mG01C1 in adhd confirmed initial signs of efficacy in the adhd population.

in 2011, alcobra conducted a randomized, double-blind, placebo-controlled, multicenter phase iia safety and efficacy study that enrolled 120 patients. The study protocol was designed with input from key opinion leaders in the U.s., daniely said, with an eye to discussions with the Fda about a phase ii or even a phase iii.

Top-line results showed the drug met the primary efficacy outcome, demonstrating a significant improvement on the Conners’ adult adhd rating scale-investigator rated Total adhd symptoms score (Caars-iNv) compared to placebo (p < 0.03).

according to Thomson reuters Cortellis Clinical Trials intelligence, full results on an intent-to-treat analysis, reported in december 2012, showed patients treated with mG01Ci had statistically significant improvement in Caars-iNv total adhd symptoms score (p = 0.02), higher rate of response

(>/= 25 percent [p = 0.03] or >/= 40 percent [p = 0.04] improvement) on the Caars-iNv total adhd symptoms score and improvement in Tova score (p = 0.02) and aaQol score (p = 0.01) compared to placebo. improvement in adhd symptoms (scored by Caars-iNv) was significantly different in patients treated with mG01Ci compared to placebo as early as two weeks following initiation of treatment.

safety findings, also reported in december 2012, showed mG01Ci was generally well tolerated. The most commonly observed adverse events, compared to placebo, were nausea (17 percent vs. zero), fatigue (31 percent vs. 27 percent) and headaches (29 percent vs. 39 percent).

essentially, the findings “showed very clearly that the drug was effective in treating the cognitive dysfunction in adhd, that the drug onset was very rapid and that response rates were very high,” daniely said. Tolerability, he added, “was in a league of its own” compared to approved adhd drugs, with no impact on appetite, mood or sleep and – importantly – no changes in cardiovascular function.

Based on the strong data, alcobra went public in may 2013, raising $25 million at $8 per share and gaining a Nasdaq listing as adhd. The company subsequently raised $33 million in a follow-on offering of 2 million shares, priced at $16.50 apiece, in october 2013. The same month, the stock hit a 52-week high of $26.96 but subsequently fell back, along with much of the market, closing Feb. 6, 2014, at $19.95.

Failures in the adhd space have included the blowup of Targacept inc.’s TC-5619 and multiple misses by Cephalon inc. (see BioWorld Today, aug. 11, 2006, and sept. 18, 2012.)

and others are trying to build a better mousetrap in adhd. For example, Neurovance inc., of Cambridge, mass., has a phase iia pilot study testing eB-1020 sr in adults with adhd, Theravance inc. spinout Theravance Biopharma, of south san Francisco, has a monoamine reuptake inhibitor program in phase ii, and highland Therapeutics inc., of Toronto, recently reported positive interim phase i/ii results from an ongoing study of hld-200, a formulation of methylphenidate, in the indication.

alcobra is unswayed by the competition. most drugs approved in adhd are scheduled substances with a raft of side effects, and the mechanisms of action are nonspecific, daniely pointed out. The only nonstimulant approved in adhd, the


norepinephrine reuptake inhibitor strattera (atomoxetine, eli lilly and Co.), takes nearly 10 weeks to show effectiveness and comes with boxed warnings. in contrast, alcobra’s drug is not a stimulant, is target-specific it “and works from day one, which is a huge advantage in managing this disorder,” he added.

With feedback from the Fda in hand, alcobra expects to launch the phase iii in adhd in February 2014. The design mimics that of the phase ii, with plans to enroll 300 patients at multiple centers in the U.s. and israel. Top-line data are expected to report in the second half of 2014.

The company also is poised to begin a phase ii pediatric study of mG01Ci in the second quarter, also likely reporting data before year-end.

in the second quarter, alcobra also plans to move into a second indication with a phase ii study of mG01Ci in cognitive function associated with Fragile x syndrome – an indication that was granted Fda orphan drug designation – in adolescents and adults. eventually, the company may pursue additional cognitive disorders related to schizophrenia, alzheimer’s disease, Tourette’s syndrome and mood disorders.

“We’ve seen in a preclinical model [of Fragile x] a very significant improvement, so we’re very eager to try to reproduce the cognitive improvements that we’ve seen in adhd in this orphan space, which doesn’t have any products approved, to

date,” daniely told BioWorld Today.

in January 2014, alcobra reported those findings in Fmr1 knockout mice, a validated animal model of Fragile x, showing that normalization of certain overactivated biological markers was evident in the blood and brains of test mice following treatment with metadoxine. The findings suggested the possibility of using that effect as a screening tool to identify patients who are more likely to respond to the treatment and to monitor their response over time. improved cognitive and social functions were associated with reduction of blood levels of overactivated akt and extracellular signal-related kinase in the test mice.

With only eight employees, alcobra runs a lean operation, so cash from the initial public offering and follow-on are expected to provide sufficient financing to see the company through the next few years, giving the company sufficient runway to bring its only asset to approval both in adhd and Fragile x, according to daniely.

“We believe the risk in executing our programs for the next 12 months and getting to the point where we have positive phase iii data has been significantly narrowed by what we’ve done this far,” he said. “our intent is to plow on, get this drug through phase iii, get the efficacy and safety data and then evaluate our strategic options.” //

– BioWorld Today, Feb. 7, 2014


ALizé phArMA SeekS to reALize goALS through ASSet-BASed ModeLBy Marie Powers, Staff Writer

alizé pharma sas has a diverse and seemingly incongruous portfolio that includes an unacylated ghrelin analog (UaG) aimed at prader-Willi syndrome and type 2 diabetes, a pegylated recombinant l-asparaginase to treat acute lymphoblastic leukemia (all) and a rare disease program with an as-yet undisclosed target. But that doesn’t mean the programs compete with each other. instead, each is housed in a separate development company – each with its own scientific experts – in alizé’s asset-based business model.

The concept is attracting interest and funding – approximately €13.3 million (Us$16.6 million) from a syndicate of private and institutional investors since the lyon, France-based biotech was founded in 2007. Now, clinical data are starting to roll in.

in december 2014, alizé pharma reported positive findings for its UaG, aZp-531, from two phase i studies. a double-blind, single ascending dose study in healthy volunteers assessed the effect of six doses of aZp-531 vs. placebo in 44 healthy volunteers, while a double-blind, 14-day multiple ascending dose phase ib study examined the effect of four doses of aZp-531 compared to placebo in 32 overweight or obese subjects who were otherwise healthy.

Findings showed repeated administration of aZp-531 for 14 days was well tolerated at all doses, with once-daily subcutaneous administration at the higher doses tested resulting in 24-hour exposure to aZp-531. reductions in blood glucose levels occurred in overweight and obese subjects – particularly those with elevated post-prandial glucose levels at baseline. The effects increased over time of treatment and were associated with unchanged insulin levels, supporting an insulin-sensitizing mechanism of action.

additionally, after 14 days of treatment, reduced body weight was observed in the overweight and obese subjects treated with aZp-531 but not those in the placebo group.

The company said the data suggested a good safety profile, pharmacokinetics consistent with once-daily dosing and positive effects on glucose control and weight – consistent with data from preclinical animal models and supporting a differentiated profile for aZp-531 in metabolic indications. alizé plans to report detailed findings at undisclosed scientific and medical conferences in 2015.

in the meantime, the company initiated a multiple ascending dose, double-blind, placebo-controlled phase ib study in type 2 diabetes to assess the safety, pharmacokinetics and pharmacodynamic response of three doses of the drug administered over 14 days. The study plans to enroll 36 patients with uncontrolled type 2 diabetes treated with metformin, with results expected in the second half of 2015.

alizé also is moving forward with partnering discussions for the aZp-531 program, according to Thierry abribat, manager of TaB Consulting and president of alizé pharma. abribat, a veteran of sanofi-recherche and Canada’s Theratechnologies inc., formed alizé with colleagues from opi sa, after that venture was sold to newly launched eusa pharma inc., of oxford, Uk, in 2007. eusa also picked up opi’s pipeline, which included leukotak, an anti-Cd25 monoclonal antibody in phase ii development as a second-line treatment in acute graft-vs.-host disease, and Nelsyn, an orphan drug candidate for lambert-eaton syndrome, a condition that affects a subset of multiple sclerosis patients. (see BioWorld Today, march 2, 2007.)

at the time of the acquisition, opi also had a preclinical anti-il-6 antibody aimed at inflammatory disease and a library of antibodies targeting rare diseases. alizé picked up those assets and began to collaborate on lead aZp-531 program with the erasmus medical Center in rotterdam and the University of Turin. alizé – the name is a French term alluding to a trade wind – has amassed a portfolio of 37 pending and granted patents protecting its UaGs and their therapeutic applications.

“Back in 2007, the idea was for us to create a rather different business model than the classical biotech company,” abribat told BioWorld Today. “Basically, this is what we call today the asset-based model. We acquire early stage assets – typically at the late discovery stage – from academics, pharma or biotech companies. We put them in a different corporate entity and develop them, typically to phase ii, at which time we either try to license out or sell the company.”

The business approach lowers alizé’s risk to investigational new drug-enabling work and early clinical development, without the cost of large late-stage studies, and allows the parent to consider a wide range of assets rather than focusing on narrow therapeutic indications or platforms.


The second entity, alizé pharma ii sas, is focusing on the development of pegcrisantaspase (asparec/JZp416), the pegylated recombinant l-asparaginase program in all, which is partnered with Jazz pharmaceuticals plc, of dublin, and has moved into phase ii/iii development.

earlier in december 2014, alizé pharma iii sas was formed to acquire exclusive global rights to develop and commercialize a family of peptides with bone anabolic properties. The peptides are derived from a fragment of a physiological protein, insulin-like growth factor binding protein-2, or iGFBp-2. in vitro and in vivo studies suggested the peptides can induce bone formation by stimulating osteoblast differentiation and inhibiting osteoclast differentiation.

The iGFBp-2 technology was invented by david Clemmons, chief of the division of endocrinology and metabolism in the school of medicine at the University of North Carolina (UNC) at Chapel hill, and Clifford rosen, director of clinical and translational research and a senior staff scientist at maine

medical Center’s research institute in portland.

The respective universities own the patent on the iGFBp-2 peptides, which originally was licensed to New paradigm Therapeutics inc. (NpT), a UNC spin-off founded by Clemmons. NpT granted an exclusive sublicense to alizé, and both companies will collaborate on the development of a therapy targeting bone diseases, with alizé paying NpT a predetermined percentage of licensing or divestment revenues.

The company’s investors include the French public investment bank Bpifrance, via its innobio fund, along with octalfa, sham innovation santé, Cema and Tab Consulting.

“We have been able to establish that the model works,” abribat said, by taking an asset through acquisition, development and outlicensing and moving into additional cycles. “our goal by 2015 is to have three to four assets in development at any given time.” //

– BioWorld Today, dec. 11, 2014


ALphAMAB conVertS cro pLAtforM into drug deVeLopMent engineBy Marie Powers, Staff Writer

suzhou alphamab Co. ltd. is among the new generation of Chinese biopharmas moving rapidly along the evolutionary curve from contract research activities such as high-throughput screening, analytical biology and process development to the construction of a pipeline of biosimilars and, most recently, the development of novel compounds directed at cancer, autoimmune and infectious diseases.

like most Chinese biopharmas, alphamab is rich in talent, boasting approximately 100 employees – more than half of them holding advanced degrees. The firm, founded in 2008 and based in the suzhou industrial park, has its own laboratory and Gmp facility, with large-scale in-house production capability for recombinant monoclonal antibodies (mabs). The company has collaborations with multiple academic institutions in the U.s. and China.

alphamab initially used its platform technologies to generate cash flow while its scientists concentrated on drug development, explained Ceo Ting xu.

“many companies can do screening, but we have three separate platforms in-house,” xu told BioWorld Today.

The distinction is important for alphamab, explained xiaoxiao Wang, the company’s associate director of early development. many of China’s small biotechs focus on just one aspect of drug development, limiting their ability to screen out, validate or sequence mabs at the earliest stages of discovery, when deciding which programs to advance is paramount to a company’s long-term success.

alphamab’s charge repulsion improved bispecific, or CriB, platform also is a differentiator. CriB provides a stable scaffold to generate bispecific antibody mimics that target different epitopes in a single drug. in short, the company can use a single cell to produce two antibodies, offering the potential to generate two-drug combinations while lowering the overall cost of drug development.

“We are the only company in the world doing this,” xu maintained.

The company’s biosimilars pipeline contains its most advanced candidates, with investigational new drug applications (iNds) filed for three of them and two already licensed to undisclosed

companies. They include kN-007, a biosimilar of the factor viia product Novoseven (eptacog alfa, Novo Nordisk a/s) to treat hemophilia; kN-002, a biosimilar of humira (adalimumab, abbvie inc.) for autoimmune indications; and kN-004, a biosimilar of avastin (roche aG/Genentech inc.) to treat cancer.

ChiNa’s Biopharma iNdUsTrY ‘moviNG To The NexT sTaGe’

although alphamab’s internal drug development activities originally focused on mabs, half of the candidates in its pipeline now are proteins, xu said. lead compound kN-003, developed in cooperation with researchers at the University of Chicago, is an anti-hBsag mab that showed neutralization activity against hepatitis B virus (hBv), both in vitro and in vivo, according to Cortellis Competitive intelligence.

alphamab’s goal is to replace serum-origin hepatitis B immunoglobulins to prevent relapse in liver transplant patients and transmission of hBv from mother to infant and to provide treatment in chronic hBv.

alphamab also is advancing kN-015, a follicle-stimulating hormone (Fsh) receptor agonist to treat female infertility, through preclinical studies. although recombinant Fsh was widely used in assisted reproductive technology and in-vitro fertilization, the company pointed out, multiple injections were required due to the short half-life of those drugs. alphamab’s modified Fsh technology increases the drug’s half-life by a factor of 10, allowing for a single dose of each treatment.

Candidates earlier in the pipeline include a humanized mab against raNkl to treat cancer bone metastases and a therapeutic protein designed to inhibit multiple isotopes of veGF, piGF and pdGF that could be used to treat multiple solid tumors as well as wet age-related macular degeneration.

alphamab has filed two iNds on its internal candidates with the CFda and expects its first iNd approval this year, enabling the company to advance its lead asset into a phase i trial in australia, according to xu. ironically, China’s biotechs often look outside their borders for a speedier and more assured path through early clinical trials.

“in China, we have to wait for approval from the CFda to move along,” sometimes resulting in unforeseen delays, xu pointed


out. speed is of the essence for biotechs seeking to serve the vast Chinese market, since “the whole biopharmaceutical industry in China is moving to the next stage,” he added.

alphamab identifies six to eight drug candidates each year and moves one or two along the development pathway on its own, according to xu. The company now has some 30 active projects, most of them innovative therapeutics.

access to capital is a major limiting factor. an initial angel financing round in July 2011 generated approximately ¥125 million (Us$20 million) for the company, accelerating its drug development timetable. all told, alphamab has raised approximately ¥220 million.

however, “in China, finding venture capital is still not that easy,” xu acknowledged. “There is money floating around, but there are no great exit strategies, like in the U.s.”

part of the issue is China’s cultural dependence on cultivating long-term relationships to engender mutual trust. although that’s a worthy goal, the pace of partnering is sometimes

too slow to keep up with changing dynamics in biopharma development. That’s one reason alphamab participated in the Chinabio partnering Forum in suzhou in may, where xu had the opportunity to mingle with big pharma representatives, venture capitalists and biotechs from the U.s. and europe.

Changes are coming, xu observed, noting that venture funds in China are supporting clinical-stage candidates and certain Chinese pharmas are starting to establish funds for early stage biotechs. “small biotechs in China are getting to the stage where they are doing cutting-edge research,” he said. “We’re at the level to be able to license out our assets to companies in the U.s. and other countries. We’re also getting to the stage where we can in-license assets for the Chinese market, which is exploding.”

Turning back to alphamab’s future, xu predicted, “our first few compounds will be commercialized in China. Then we’ll move into global development.” //

– BioWorld Today, July 14, 2014


StArt-up AMcure rAiSeS $7M to tArget cd44V6 in cAncerBy Cormac Sheridan, Staff Writer

German start-up amcure Gmbh raised €5 million (Us$6.7 million) in a series a round to take forward a preclinical drug development program in cancer based on targeting a variant of the Cd44 receptor, called Cd44v6, which is implicated in both angiogenesis and metastasis.

The company currently is completing lead optimization and will shortly select a peptide-based candidate drug molecule to take into preclinical development. “it’s a linear peptide, which has really surprising effects on metastasis, especially, but also on angiogenesis,” matthias klaften, Ceo of eggenstein-leopoldshafen-based amcure, told BioWorld Today. The program is expected to move into the clinic in early 2016.

The company has generated proof-of-concept data in several animal models of cancer, including pancreatic cancer, breast cancer and colon cancer. “We saw an effect on the primary tumor, an anti-angiogenic effect, which was quite strong,” he said. The company also tested the drug in a metastatic model. “We were able to completely prevent this primary tumor from metastasizing.”

The company was spun out of the karlsruhe institute of Technology (kiT), where véronique orian-rousseau leads a long-term research effort focused on the involvement of Cd44v6 in cancer biology. Cd44, an adhesion molecule that binds hyaluronic acid and is involved in cell adhesion and cell-matrix interactions, generates multiple variants through alternative splicing.

one of those, Cd44v6, includes exon 6, which encodes a co-receptor active for different receptor tyrosine kinases involved in cancer signaling, including c-met and vascular endothelial growth factor receptor 2 (veGFr2). “By blocking this co-receptor function we are able to interfere with different receptor signaling pathways,” klaften said.

a previous drug development effort, based on an earlier era of the same research program, reached the clinic under Boehringer ingelheim Gmbh, of ingelheim, Germany. it licensed intellectual property from the kiT, which fed into the development of an antibody-drug conjugate (adC), bivatuzumab mertansine, which targeted Cd44v6.

Clinical development was terminated, however, following the emergence of serious skin reactions, including one fatal case of toxic epidermal necrolysis, in a phase i trial. “most of these mertansine-linked adCs failed actually,” klaften said. The data are reported in the oct. 15, 2006, issue of Clinical Cancer Research, in a paper, titled “a phase i dose escalation study with anti-Cd44v6 Bivatuzumab mertansine in patients with incurable squamous Cell Carcinoma of the head and Neck or esophagus.”

That program was based on the exploitation of Cd44v6 purely as a targeting molecule, rather than a biological target, as its involvement in receptor signaling was not then understood. “From the research done by Boehringer ingelheim, we know it is cancer-specific,” klaften said. Cd44v6 is highly overexpressed in pancreatic and head and neck cancers.

peptide-based drugs have long been prized for their specificity and potency, but they make poor drugs because of their vulnerability to degradation by proteases. several firms are developing methods to improve their pharmaceutical properties by introducing structural modifications, such as stapling. part of amcure’s lead optimization process involves modifiation as well, but it has not disclosed any specifics. “We have more or less our own way of doing it,” klaften said.

lBBW venture Capital led the recent funding round. other participants included kfW, mBG mittelstaendische Beteiligungsgesellschaft Baden-Wuerttemberg, s-kap Beteiligungen pforzheim, Biom aG and private investors. //



two-pronged AMyndAS tArgetS coMpLeMent-BASed Anti-infLAMMAtorieSBy Marie Powers, Staff Writer

researcher John lambris has devoted his career of more than 30 years to exploring the human complement system. his lab at the University of pennsylvania, where lambris serves as professor of research medicine in the department of pathology and laboratory medicine, was among the first in the world to map the critical sites on the human C3 protein that are responsible for its many functions and to define its complex binding dynamics to various C3 natural ligands. These included complement receptors and regulators as well as bacterial and viral proteins. in addition, lambris and colleagues revealed the involvement of complement in clinical conditions ranging from cancer to transplantation to sepsis.

Those efforts are culminating in the development of complement-based anti-inflammatory therapeutics through the discovery of a small-size complement inhibitor called compstatin, which has exhibited consistent efficacy in a series of disease models.

The U-penn technology first was licensed in 2006 to the start-up potentia pharmaceuticals inc., which attempted to validate complement inhibition as an approach to treating age-related macular degeneration (amd). The company raised $5 million in a series a round in 2007 and followed that with a $12 million series B round in 2008. (see BioWorld Today, sept. 12, 2008.)

after a successful phase i study, louisville, ky.-based potentia inked a licensing and option deal granting alcon research ltd., a subsidiary of emeryville, Calif.-based alcon inc., rights to develop its complement inhibitor, poT-4, in amd in return for an undisclosed up-front payment and an agreement to acquire shares of potentia on the achievement of certain development milestones.

alcon completed a phase ii study of poT-4 in 49 patients with exudative amd in april 2012 before terminating a second phase ii and halting the program later that year for what was termed a management decision, according to Cortellis Clinical Trials intelligence.

in the meantime, lambris continued to refine the technology at U-penn and add to the patent estate. The efforts yielded more potent compstatin analogues with improved pharmacokinetic properties and the development of a platform for peptide-based drug design that integrates both rational and in silico approaches.

earlier in 2014, lambris formed sister companies, amyndas pharmaceuticals sa in Glyfada, Greece, and amyndas pharmaceuticals inc. in philadelphia, in an effort to broaden the therapeutic benefit of the second-generation compstatin analogues. The closely held companies are working in tandem to move the new generation compstatin analogues into additional indications, starting with transplantation and paroxysmal nocturnal hemoglobinuria (pNh) and potentially including periodontal diseases, hemodialysis, ischemia and reperfusion injuries.

lambris’ U-penn lab previously demonstrated a strong crosstalk between complement and other defense systems in health and disease. Under normal conditions, pathogens can trigger any of three complement pathways – classical, lectin and alternative – that converge at the central C3 protein of the complement cascade, he explained. activation of C3 eventually results in cell lysis, the removal of pathogens through phagocytosis and the alert to other immune system cells to help fight the infection. in a series of in vivo studies, lambris and colleagues showed complement also is involved in immune surveillance, housekeeping functions and a number of developmental processes, including liver and limb regeneration, hematopoietic development and stem cell engraftment.

The downside, of course, is that the complement system also can be activated as a consequence of trauma or injury or in various autoimmune diseases, causing inflammation and cellular destruction.

‘We Feel We’ve doNe someThiNG verY UNiQUe here’

amyndas – the name is derived from the homeric word for “defender” – has met with the swedish medical products agency as it seeks to advance a new generation of compstatins, which have shown 20,000-fold improvements in binding affinity to human C3, enhanced inhibitory potency and an extended circulating in vivo half-life in monkeys, compared with earlier analogues.

The company participates in a consortium of european universities and U-penn that was awarded a european Union seventh Framework programme (Fp7) grant of approximately $8 million. The company supplemented that funding with a


loan from a major european bank and grants from several disease-focused foundations.

That funding is sufficient to support the company of six employees and advance the technology into toxicology studies, now under way, and into a phase i study in europe in 2014 that will examine the effect of new-generation compstatin analogues in tempering the immune response that causes the rejection of kidney transplants. if all goes well, a phase iia trial could begin in 2015, lambris said.

“We will try to do this without taking venture capital at this stage,” he said. “if we do take vC money, we’ll expand the indications, but that’s not the focus now.”

eventually, amyndas wants to test the technology in pNh and, potentially, atypical hemolytic uremic syndrome. alexion pharmaceuticals inc.’s soliris (eculizumab) is approved in both orphan indications. The monoclonal antibody binds to C5, a protein toward the end of the cascade that promotes cell lysis and inflammation. (see BioWorld Today, march 19, 2007, and sept. 26, 2011.)

But soliris is expensive – approximately $400,000 per patient per year – and shows only limited effect in a considerable number of patients, lambris said.

“in pNh, it’s clear that about 30 percent of the patients are not responding to the therapy,” he told BioWorld Today. For example,

he said, some Japanese patients have a mutation that prevents the therapy from working as designed. inhibiting upstream at C3 instead of C5 could increase the number of pNh responders.

additionally, since new-generation compstatin analogues, such as the company’s lead candidate amY-101, bind tightly to C3 and have a long half-life, the drug could be self-administered subcutaneously every 12 hours, giving patients better control and dramatically reducing the need for clinic visits.

Because amY-101 is a peptide, another advantage is that manufacturing costs are expected to be much lower – an estimated $15 per gram of compound – than for antibodies such as soliris, he said.

in addition to amY-101, amyndas is developing compounds to target complement inhibition on cell surfaces by compsorbin, a 14 amino acid cyclic peptide that binds to complement factor h and inhibits biomaterial and cell induced complement activation.

long term, the company will seek to partner with a big pharma to move its pipeline to commercialization.

“We feel we’ve done something very unique here,” lambris said. “our goal is to bring something to the clinic while protecting the technology. i spent 30 years of my life developing the technology. Now it’s time to take the technology to the next stage and help the patients.” //



AntriABio’S BASAL inSuLin dreAM tAkeS fLightBy Michael Fitzhugh, Staff Writer

seven big trailers owned by antriabio inc. sit parked in Boulder, Colo., holding the keys to a dream deferred: inside is the equipment pr pharmaceuticals inc. (prp) once used to manufacture microparticles for its experimental sustained-release formulation of basal insulin, insular. outside are the rough realities that drove it into Chapter 11 bankruptcy in 2008.

Nevan elam, Ceo and chairman of antriabio, is now carrying the nearly crushed dream ahead. Backed by a new $10 million private placement and a well-developed microsphere insulin formulation, antriabio expects to take its lead program, aB101, into phase i/iia testing by mid-2015, elam told BioWorld Today. Follow-on testing will advance the program further toward elam’s ultimate goal of taking a piece of the $10 billion basal insulin market now dominated by products such as the once-daily lantus (insulin glargine, sanofi sa) and levemir (insulin detemir, Novo Nordisk a/s).

“Those are safe and effective drugs, but in order to achieve an extended-release profile for 24 hours, they utilize a very complex process involving the alteration of the molecular structure of insulin to create an analogue,” elam said. aB101’s formulation achieves the potential of a once-per-week profile using human recombinant insulin instead, something elam said is a fundamental difference. “We believe that it would be very difficult to achieve this type of extended release with an analogue,” he said.

elam’s grasp of the commercial risks of developing a diabetes therapy is likely better than most. his familiarity with prp began during his time as head of the pulmonary Business Unit of Nektar Therapeutics inc. as he and his team plowed ahead on its inhaled insulin program, exubra, Nektar’s board challenged elam to build a metabolic disease franchise.

as he scoured the market for programs with which he could build the franchise, elam found Fort Collins, Colo.-based prp. The science appeared good from a distance. Then, when he looked more closely, it looked great, he said. many road trips between Nektar’s san Carlos headquarters and Fort Collins ensued as the due diligence progressed.

“The key discovery made at prp was where to pegylate the insulin molecule to change the solubility of insulin so that insulin could be blended evenly in either oil or water-based solutions,” elam noted. “We are able to achieve a once-per-week release profile by mixing

the pegylated insulin in a solvent with a common polymer, plGa, to produce uniform microspheres.”

as Nekar’s confidence in prp grew, confidence in exubra was falling. in october 2007, elam got a call from pfizer, the company’s partner on exubra. They wanted to meet and the news was not good; they were pulling the plug on exubra.

“Nektar had to do some soul searching,” he said. as part of that process, elam suggested the company sell its pulmonary business to a big pharma. in september 2008, he struck a deal with Novartis to sell most of Nektar’s pulmonary delivery assets to Novartis aG for $115 million. (see BioWorld Today, oct. 22, 2008.)

prp was out of a deal and, with the financial crisis in full swing, investors had little appetite for rescuing the company from bankruptcy. as its Chapter 11 filing transitioned into a Chapter 7 dissolution case, prp’s intellectual property went up for sale. eventually, elam was able to buy the rights in late 2012, fulfilling antriabio’s main mission: to shape the technology into a success, as aB101.

as many as 60 percent of type 2 diabetics only take oral medicines, such as metformin. some of those patients should be on insulin, but don’t want shots. “having a once-a-week therapy could open the gate for some of those patients to utilize basal insulin replacement therapy earlier,” elam said.

For now, the five-person company is busy building its own strength. sankaram mantripragada, prp’s former vice president of r&d, joined the company as its chief scientific officer in February 2014, the same month elam joined. and the company is working on a reverse stock split that will help move its oTC shares (oTCQB: aNTB) toward a planned up-listing onto Nasdaq later in 2014. on april 23, 2014, the company announced the formation of its scientific advisory board. it is now also ready to do early toxicity testing in two animal species during the fourth quarter, after which it expects to move into a combined phase i/iia trial in mid-2015.

elam said the company has “a very rare opportunity to leap-frog the standard of care.” if he’s right and aB101 succeeds, antriabio will owe prp’s bankruptcy estate $40 million in milestone payments, but that would be a small price to pay, he said, relative to the reward to be gained if aB101’s promise and the equipment in those trailers help the company manufacture a big win. //



ArcturuS ShootS for ‘LunAr’ LAnding in treAting rAre diSeASeSBy Marie Powers, Staff Writer

Founded two years ago, arcturus Therapeutics inc. started from ground zero as a Johnson & Johnson innovation tenant, with no assets, technology or pipeline in hand. That situation changed quickly. in June 2013, the san diego-based company raised $1.3 million in seed funding from high net worth investors from the U.s. and Canada. Four months later, the company tapped most of those investors again and added interests from Japan in a $5 million series a round.

Now, arcturus is shooting for the moon with lead compounds lUNar-101 and lUNar-102. The rNa therapies are targeting the treatment of rare diseases using the company’s lipid-enabled and unlocked nucleic acid modified rNa, or lUNar, delivery technology platform.

Co-founders Joseph payne, president and Ceo, and padmanabh Chivukula, chief scientific officer and chief operations officer, came from oceanside, Calif., office of Nitto denko Technical Corp., based in osaka, Japan, where the veterans of nanoparticle technology helped to deliver an rNa interference (rNai)-based drug aimed at treating fibrosis in the liver and other organs to the clinic.

“pad and i thought rNai medicines would be even better suited for rare diseases, so we decided to jump ship, leverage our expertise and start a new company,” payne told BioWorld Today.

Nanoparticle technology also represents the backbone of arcturus’ platform. lUNar uses a Gmp-ready microfluidic formulation process to yield particles smaller than 80 nm that are biodegradable and biocompatible with a low polydispersity index. The formulation process is scalable, and the resulting particles have demonstrated stability, safety and potency in multiple animal species.

arcturus elected to buy a second technology, in 2013 acquiring the patented portfolio of unlocked nucleobase analog (UNa) intellectual property from marina Biotech inc., of Bothell, Wash., to use in its rNai work. Terms of the deal were not disclosed, but payne cited the use of UNas in rNai to silence aberrant gene expression as a promising approach to treat disease. The flexible nature of UNa reduces the binding affinity between two strands of an rNai drug and gives unique characteristics to its gene silencing abilities, he pointed out.

“Unlocked nucleic acids are flexible,” payne explained. “most

nucleic acids are rigid, but by introducing flexibility into a rigid rNa medicine, you capture very important and significant pharmaceutical benefits.”

although the development of rNa therapies is a hot area, having two core technologies – lUNar and UNa – gives arcturus a distinct advantage over most rNa companies, many of which rely on solo platforms, he said.

“UNa makes rNa better,” payne pointed out, adding that the combination even attracted two of the company’s competitors as licensees. Tekmira pharmaceuticals Corp., of vancouver, British Columbia, is using the UNa technology to pursue hepatitis B therapies, while arrowhead research Corp., of pasadena, Calif., is pursuing a rare disease that affects multiple organs.

arCTUrUs’ ChemisTrY is The keY

The allele selectivity of arcturus’ UNa technology offers another advantage: more than 100-fold selectivity, or 99 percent knockdown of a disease allele from one parent with no knockdown of the healthy allele from the other parent, according to payne.

“every single one of our competitors knock down both alleles at the same time,” he maintained. “We have that capability, too, because some diseases require that profile, but our chemistry unlocks the door to treat autosomal dominant diseases.”

although a group of 117 autosomal dominant diseases comprises the best known therapeutic targets, arcturus’ chemistry profile allows it to pursue a much bigger universe of roughly 3,400 autosomal dominant diseases, payne said.

in January 2014, at the Biotech showcase in san Francisco held simultaneously with the J.p. morgan healthcare Conference, arcturus began to strut its stuff, introducing the flagship lUNar-101 program. The rNai therapeutic is targeting transthyretin (TTr) to treat familial amyloid cardiomyopathy, or FaC. preclinical findings in a non-human primate study showed greater than 75 percent knockdown of serum TTr protein levels after 10 days, with the effect sustained over three weeks. No adverse events (ae), including no injection site reactions, were observed using the lUNar delivery technology.

The company also reported that no aes were observed at the highest doses (30 mg/kg total; administered three times at 10 mg/kg over 15 days) in a multiple dose rat


toxicology study. serum levels of alanine aminotransferase and aspartate aminotransferase were determined after intravenous administration, and no changes were observed in these liver enzymes.

lUNar-102 uses the same platform technologies to selectively silence the variant TTr allele v30m to treat familial amyloid polyneuropathy, or Fap.

arcturus kept up the pace all year, reporting data from preclinical studies in seven of the past nine months. in october 2014, the company presented a poster at the annual meeting of the oligonucleotide Therapeutics society in san diego showing that lUNar-101 demonstrated a 90 percent reduction in TTr at day 10 and continued reduction of 91 percent at day 20 in non-human primates (n = 3, up to 94 percent) after a single low dose of 0.3 mg/kg.

and in November 2014, arcturus reported at international mrNa health Conference in Cambridge, mass., that lUNar delivery of synthetic human erythropoietin messenger rNa in non-human primates generated 1000-fold increase of erythropoietin protein with a single low dose (0.3 mg/kg). No safety issues were observed, suggesting lUNar delivery of messenger rNa was well tolerated.

The company also reported that delivery of chemically modified

messenger rNa in lUNar resulted in rapid expression of protein, within two hours, that persisted for greater than 24 hours.

The next step is to advance lUNar-101 into a human trial, expected to begin next year and report data in 2016, with the goal of demonstrating safety, tolerability and biological proof of concept. The company completed its pre-investigational new drug application meeting with the Fda “and gained alignment” with the agency on its clinical plan, payne said.

“as our pipeline progresses, we’re going to validate our lUNar delivery technology and allele selectivity, while our partners are going to further validate UNa in humans,” he predicted. “We’re in really good shape for a very young company.”

arcturus also is in the midst of raising what payne described as “a substantial round” that will involve the company’s insiders as well as new investors. That financing is expected to close by year-end.

With 13 employees and a recent move into its own space in the former home of pfizer labs, arcturus wants “to establish and build a very prominent and significant company in san diego,” payne said. small wonder that arcturus’ name harkens to the brightest star in the northern hemisphere. For now, the sky seems the limit. //

– BioWorld Today, Nov. 20, 2014


AV therApeuticS tAckLeS next-gen proStAte cAncer therApyBy Catherine Shaffer, Staff Writer

av Therapeutics inc. decloaked in late december 2013 by merging with a public shell company. it is developing a chemotherapy candidate, capridine, that has been shown in preclinical models to have activity against prostate and colon cancer, with plans to launch phase i trials in the second quarter of 2014.

“We’ve had financing from a group of individuals – four major investors in our company,” av Ceo abraham mittleman told BioWorld Today. “We’re looking for partners. We’ve had some inquiry by one of the larger pharmaceutical companies,” he said, adding that av expected to meet with that company after the holiday to discuss potential terms.

The New York-based company’s early funding totals more than $6 million, and includes contributions by the National institutes of health and the department of defense.

av, also known as advanced vaccine Therapeutics, was founded about 10 years ago, according to mittleman, with a project to develop cancer vaccines, focusing on finding out how to break immune tolerance. initially, av’s research focused on developing synthetic peptides using chaperone protein complexes.

prostate cancer is the most common type of cancer affecting men in the U.s., with annual expenditures exceeding $15 billion. Current standard chemotherapies have limited efficacy for metastatic disease, and are associated with severe bone marrow toxicity and poor tolerance.

dendreon Corp.’s provenge (sipuleucel-T) was approved in 2010 for metastatic hormone refractory prostate cancer, but its sales have been consistently disappointing since then. av said that provenge is “expensive and has minimal efficacy,” leaving the door open for other competitors in the prostate cancer marketplace.

Capridine is a nitro-acridine drug with documented activity against prostate, colon and other cancers, according to av. it is active against hormone-dependent and hormone-independent prostate cancer xenografts. animal studies suggest a broad therapeutic dose range.

av’s development plan for capridine includes Gmp drug manufacture and formulation, stability testing, toxicity testing, pharmacokinetic and pharmacodynamics studies, investigational

new drug application and phase i/ii trials.

av’s second most-advanced product is the pros-vax synthetic peptide vaccine, which mimics cancer proteins and recruits the patient’s immune response to multiple cancer-specific proteins. av said preclinical studies for pros-vax are complete, and it contended the vaccine may eliminate micrometastatic and residual disease, preventing recurrence.

“We’re at the moment where Gmp production is starting,” mittleman said. “We hope to be in humans in nine months.”

mittleman said that pros-vax is interesting because it’s a synthetic peptide that is not patient-specific. That is in contrast to provenge, which is a complex multistep treatment involving removal of blood by apheresis, processing and then reinfusing the patient. “it’s very expensive, with limited benefits,” mittleman said.

av is positioning pros-vax for the early stages of the disease, after surgery and radiation.

in terms of composition of the vaccine, mittleman said that the company has been looking at two separate peptides, and “both were effective.” pointing out that some current vaccines such as pneumonia vaccine, contain 20 different proteins, he said, “We’re going to be testing the hypothesis of multiple vs. single peptides and see what happens with recurrence.”

another question to be answered for pros-vax is schedule of administration, whether it should be a once-monthly therapy, or something more like once every six months.

The market for av’s two products totals about $1 billion for the drug and $300 million for secondary prevention of prostate cancer in the U.s. alone, according to av. Company executives contended that capridine may be applicable as an adjunct to existing chemotherapy regimens to reduce toxicity and increase efficacy against cancer.

There are plans to develop capridine internally through phase i/ii testing before bringing in a partner, depending on available capital.

av Therapeutics (oTCQB:avTh) just started trading on Jan. 2 and closed Jan. 8, 2014, at 60 cents. //



Berg phArMA pLying ‘conVerSAtion’ within ceLLS to creAte drugSBy Marie Powers, Staff Writer

in the eight years since Berg pharma llC was co-founded by billionaire businessman, venture capitalist and real estate mogul Carl Berg, scientist Niven r. Narain, who serves as the company’s president and chief technology officer, and Berg llC managing director and investor mitch Gray, the company has quietly amassed an enormous portfolio of early stage drug candidates and diagnostics across multiple indications, with the largest concentration in cancer. Using Berg’s interrogative biology drug discovery platform, the Boston-based biotech is starting to move those assets forward.

Berg pharma – the company’s co-founder and namesake also serves as chairman – is using its enabling technologies to incorporate changes in drug development farther upstream, at the discovery level, rather than tweaking molecules later in the process, according to Narain. in traditional drug development, damaging side effects may not appear until late in clinical development or even after approval and marketing, he pointed out.

“What we did was develop a platform that gets back to fundamental biology,” Narain said.

human tissue samples are the starting materials for Berg’s drug discovery platform – in cancer, which is “not a neat disease,” samples from a variety of types of cancer patients.

“We go much deeper than the genome,” Narain explained. “We feel the genome is the template of the human system, but the gene produces rNa, which produces proteins and metabolites and lipids. Berg’s created the technologies that drive a much more robust understanding of the conversation within the cellular process.”

Berg seeks to use that “conversation” within the cells to understand how metabolic alterations relate to the onset of disease. The biological platform is agnostic, Narain said, so the company doesn’t start its drug discovery process with any bias.

“it’s all data-driven,” he told BioWorld Today. “We take the human tissue samples, we run them through the instrument-based platforms and we subject the data to a Bayesian artificial intelligence system.”

Berg’s health care analytics approach is designed to identify the pressure points that govern the breakdown of healthy biological

processes, leading to disease. The company then develops therapeutic candidates based on organic compounds found in the human body that “normalize” the disease microenvironment.

“Where others call that a drug target, Berg actually uses that as the drug,” Narain explained. “all of our drugs are based on internal proteins and peptides.” The approach precludes the need for screening of chemical libraries or use of synthetic compounds, dramatically compressing the drug development timetable and reducing or altogether eliminating the risk of toxicity.

“What we’re doing is essentially using the body’s own machinery to fix itself,” he said.

‘We’ve BUilT The pipeliNe iN a verY dYNamiC maNNer’

Berg’s lead program is cancer candidate Bpm 31510, which has been formulated in a topical cream for skin cancer and intravenously for solid tumors, potentially including pancreatic, triple-negative breast, liver and brain cancer. Bpm 31510 targets the metabolism of cancer cells by reversing the Warburg phenotype. The endogenous small molecule, which resides in mitochondria, restores oxidative phosphorylation and confers re-capitulation of the BCl-2 protein family potential to induce cell death, a process cancer evades.

The Fda recently approved the company’s plans to begin a phase iib trial of Bpm 31510 in skin cancer. in the meantime, Berg is expanding a phase ib study into four arms, comparing Bpm 31510 alone against a variety of combinations and controls. The program will make use of Berg’s artificial intelligence to characterize a molecular and metabolic footprint for each patient, based on multiple tissue samples, enabling investigators to compare responders and non-responders. one arm of the trial will evaluate the effect of mitochondrial priming – therapy with Bpm 31510 followed by chemotherapy.

in diabetes, the company has two lead molecules that act through an insulin-independent mechanism. The internal proteins, designed to drive glucose into skeletal muscle and decrease localized inflammation, are preparing to enter investigational new drug-enabling studies.

Berg has four additional diabetes targets that are entering early validation studies and other early stage assets that may


be expanded into neurology indications, such as parkinson’s disease and alzheimer’s disease.

of course, Berg enjoys the luxury of exploration without counting the pennies. The company is privately held and self-funded – mostly by Carl Berg. But even with 200 employees, the company’s burn rate is lower than some of its peers, Narain insisted.

“We’ve spent a significant amount of capital but nowhere near what a comparator company would have spent,” he said. “Because our process is data-driven, we do things differently. We’ve built the pipeline in a very dynamic manner.”

The company is seeking to build and scale based on the big pharma model but also plans to partner or license its assets following proof-of-concept studies.

“We want to discover and develop, then look to big pharma for what they do very well, which is late-stage clinical development, sales and marketing,” Narain said.

Berg is more interested in co-development deals than out-

licensing, he added. The company’s desire to keep “skin in the game” for a lower up-front and higher back-end royalties “sends a message that we believe in our technologies,” Narain said.

The public markets aren’t completely off the table, either – perhaps, even, for a piece of the company.

“We’re getting a lot of free advice from various outfits right now,” Narain admitted.

Ultimately, Berg’s drug development process is a hallmark of the personalized medicine movement, designed to provide patient-specific treatment options that lead to optimal clinical outcomes.

“We envision our company as a sustainable model for changing the health care system,” Narain said. “We’re showing that if you can stratify patients and build drugs based on understanding patient biology through their phenotype, that’s going to lead to a better health care reimbursement model and also provide our country with more funds to create innovative medicines.” //



cArSgen’S chinA-Led SerieS A to fund cLinicAL triALS of cAr-t cAndidAteBy Cornelia Zou, Staff Writer

hoNG koNG – Carsgen, a Chinese developer of cancer therapies, announced its completion of an undisclosed series a financing led by China-based health care private equity fund BvCF management ltd. The proceeds will be used to initiate the clinical trials of Carsgen’s lead therapeutic asset.

The biotech company focuses on the development of chimeric antigen receptors T-cell (Car-T) immunotherapy to treat various cancers such as liver, lung, stomach and brain cancers.

“Carsgen is the first company to start a clinical study in human liver cancer with its proprietary technology platform,” said rachel Zhao, principal at shanghai-based BvCF. While Car-T cell treatment is accepted as the most potential cell immunotherapy, testing has focused more on hematologic rather than solid tumor targets.

“With our investment, the company would be able to build its cell treatment lab and start to recruit patients for its first pilot trial in liver cancer; the latter part would be the main purpose of the proceeds,” Zhao added.

Carsgen will collaborate on the clinical trial with the shanghai Cancer institute and shanghai renji hospital, with whom it has cooperated before. The company plans to initiate clinical studies with the fund for its lead therapeutic, kJgpc3-001, a glypican-3 (GpC3)-directed Car-T cell therapy for liver cancer. kJgpc3-001 takes T cells extracted from the patient, genetically modifies them to express a chimeric antigen receptor for glypican-3 and then returns them to the body to attack the cancer cells. GpC3 is often overexpressed in liver cancers, or hepatocellular carcinoma (hCC). preclinical studies have shown that kJgpc3-001 is able to kill hCC cells.

“hCC is the fifth most common cancer and the third most common cause of cancer mortality worldwide,” said li Zonghai, Ceo of Carsgen. “The vast majority of liver cancer patients live in China and, unfortunately, it remains underdiagnosed and inadequately treated, with a very high rate of death within the first five years of diagnosis. Carsgen’s game-changing Car-T approach offers new hope for hCC patients.”

The World health organization reported 745,000 cases of liver cancer cases around the world in 2012. liver resection surgery is by far the most effective treatment for hCC, but tumor recurrence is very high. and the five-year survival rate

is only 10 percent. however, most hCC patients are diagnosed at late stage, so potentially curative therapies, including chemotherapy, are often ineffective. The medical need for new therapies to treat the prevalent disease remains unmet.

“The leadership team [of Carsgen] has a strong background in cancer biology, cancer immunology and antibody development, as well as clinic cellular therapy technology and has assembled a strong proprietary position in Car-T cell therapy specifically,” said Yang Zhi, founder and managing partner of BvCF. “additionally, Carsgen has established a great working relationship with several prominent hospitals in shanghai, including renji hospital, the first Western medicine hospital in shanghai.”

While Carsgen is planning its initial clinical trials for kJgpc3-001, it is advancing its Car-T therapies for lung and brain cancers at the same time.

Further details of the investment were not disclosed. But “the company plans to raise another round with milestones in the trial,” said Zhao.

“We only invest in companies that are at the early growth stage – not start-up companies but companies that have been there a little while,” Yang told BioWorld Today in a previous interview. “What i value in health care companies are teams, products that differentiate them from others and relatively mature technologies.”

BvCF has invested in close to 20 biotech or health care companies such as sinobiopharma inc., Nod pharmaceuticals inc. and allgens Co. and already has exited from investments into some large domestic biotech companies such as Citic pharmaceuticals Co. and vaccine maker ealong Biotech, which was acquired by simcere pharmaceutical Co. ltd. in 2009.

The sponsors of BvCF are mainly strategic investors, which include pharmaceutical companies, institutional investors and foundations.

in april 2014, BvCF, previously known as Bioveda, secured its third fund, BvCF iii Fund lp, to invest $188 million in pharmaceuticals, medical technology, health care services and biotech companies in China. (see BioWorld Today, april 18, 2014.)

Besides Carsgen, some of the other investments of BvCF’s newly completed BvCF iii Fund include companies such as gene tech company Beijing Biocytogen Co. and U.s. company


micurx pharmaceuticals inc., which focuses on antibiotics.

The previous dollar-fund BvCF raised, Bioveda China Fund ii, closed at $90 million in 2008. BvCF also has an rmB-

denominated fund of ¥300 million (Us$48 million) and is planning a second and larger one. //



MyoS, cLoud coLLABorAte to ‘MuScLe in’ on new therApeutic cAtegoryBy Marie Powers, Staff Writer

myos Corp., which is taking a bifurcated approach in developing products to improve muscle mass, increase mobility and reduce frailty, is going to the “cloud” through a research and development agreement with newco Cloud pharmaceuticals inc. although terms were not disclosed, the partners will focus on identifying and advancing candidates that inhibit targets in the myostatin regulatory pathway and inflammatory mediators associated with sarcopenia and cachexia.

myos – Greek for “muscle” – will retain rights to the design and structure of any small molecules developed for the muscle health treatment market. Cloud, which is seeking to accelerate early stage drug discovery using cloud computing technology for the synthesis and design of small molecules, will focus its collaborative efforts on furin regulation and Janus kinase 3 (Jak3) inhibition, with rights to move forward with Jak3 work in indications outside muscle health, according to Ceo ed addison.

Furin is a prototypical proprotein convertase that processes latent precursor proteins into their biologically active forms. Furin convertase plays a central role in the processing of myostatin to its biologically active form, serving as a potentially important target for development of therapeutic candidates. Jak3 functions in signal transduction and is thought to be a factor in complex biochemical pathways central to inflammation.

Candidates created as part of the research relationship will be the first small molecules for myos as potential therapies to treat age-related muscle loss, or sarcopenia, in addition to cachexia, a wasting syndrome that can occur in patients with cancer, aids, congestive heart failure, multiple sclerosis and other chronic illnesses.

The companies hope to report on initial target testing with furin convertase by the end of next year and to identify a candidate to move into an investigational new drug application within 24 months, according to peter levy, chief operating officer of myos, based in Cedar knolls, N.J. meanwhile, myos will continue to assess and identify additional small-molecule candidates for design and evaluation by Cloud, based in research Triangle park, N.C.

myos was attracted by Cloud’s use of high-performance

computational methodologies to make rational drug design decisions, according to Bob hariri, executive chairman of myos.

“We’re at a very unique time where the toolsets available to scientists are increasing at a rate beyond moore’s law,” hariri told BioWorld Today. “if you use a computer as a computational tool to screen, for example, binding domains on a target, you’ll find there are 50 or 100 candidate molecules out there already, and there are dramatically more synthetic opportunities available to come up with candidates that would work.”

That type of systemized approach, he said, is far superior to the “serendipity” associated with traditional drug discovery.

“at myos, the team has been looking at some important regulatory pathways, where there’s a lot known about specific receptor-mediated events and specific cell-signaling events,” he said. “it seemed like a logical place to connect that drug design capability to a company seeking to better understand how to manipulate and control the processes that are behind the growth and retention of muscle mass.”

‘a verY poWerFUl reveNUe- GeNeraTiNG eNGiNe’

The deal actually came together after kenneth sorensen, managing director of array Capital management and a member of Cloud’s board, introduced addison to hariri, who previously founded anthrogenesis Corp., which was acquired by summit, N.J.-based Celgene Corp. in 2002 for $45 million. hariri then led the Celgene Cellular Therapeutics unit. (see BioWorld Today, Nov. 15, 2002.)

addison is a serial entrepreneur in the software space. Cloud, which changed its name in June 2014 from Teradiscoveries, focuses on in silico design of new drugs based on structure-based target information.

“We’re not limited to kinases,” addison told BioWorld Today. “We can deal with allosteric proteins and flexible proteins.”

Both companies are relative newcomers to drug development. myos, which previously operated as atlas Therapeutics Corp., was founded to explore the mechanics of the muscle system, which controls vast processes in the human body yet “no major pharmaceutical company had ever created a focused discovery or development effort to identify ways to maximize the performance of the organ and control some of the processes


which degrade the system, either as a result of aging or disease,” hariri said.

The company has a commercial product based on the over-the-counter (oTC) supplement fortetropin (mYo-T12), a natural myostatin inhibitor, that is marketed as myo-x. one of the company’s goals is to capitalize on data generated from development of its nutritional supplement – also designed to increase lean muscle mass and stimulate muscle healing – to move into drug design.

in June 2014, myos also inked a three-year master service agreement with researchers from rutgers University to expand the company’s basic science platform for further development of fortetropin and other product formulations.

Ultimately, myos is banking on both arms of the company to yield blockbuster products, with its oTC dietary nutraceuticals helping to support the longer-term drug development operation.

“The two actually buttress and enable one another” for “a very powerful revenue-generating engine,” hariri explained.

partner Cloud’s inverse design platform, developed by Chief scientific officer shahar keinan while at duke University, is used to discover novel compounds by exploring “virtual” chemical space. “our experiments have shown that over 80 percent of the molecules we find are not in the patent literature and have never been synthesized but are very, very

good,” addison said.

a strategic relationship with microsoft Corp. in 2012 to extend the reach of its drug discovery process helped to accelerate its platform and design six drugs in silico.

The company has come on strong in the past six months, addison said, attracting two biotech and two pharmas to partner with pipeline candidates and garnering several government grants. Cloud is in the process of raising a series B round, expected to close in the third quarter, with a goal of raising $20 million. From there, the company hopes to be self-sustaining by partnering aggressively, with each agreement containing an opportunity to “earn a piece” of the commercialized drugs.

in the deal with myos, Cloud will design and optimize the therapeutic candidates in muscle inflammation and atrophy, while myos will conduct much of the ensuing preclinical development for the Jak3 sarcopenia program. The companies will have a similar structure for the furin program.

“With the core competency that we have and with myos having strength in biochemistry and preclinical development, it seemed to make a good partnership,” addison said.

“We see this as a multiyear, long-term partnership,” he added. “it’s not going to end just with those two projects.” //



corBuS prepAreS to put Anti- infLAMMAtory drug to the teStBy Michael Fitzhugh, Staff Writer

Just six months after revealing a $10.3 million private placement to back development of a once-shelved therapy, Corbus pharmaceuticals holdings inc. is preparing to submit an investigational new drug application to jump straight into a phase iia trial of its sole program, an anti-inflammatory therapy it calls resunab.

The Norwood, mass.-based company, formed at the beginning of 2014 to advance what it viewed as an undervalued asset, is moving fast. Following its private placement, Corbus joined the oTC market in october 2014 and is quickly building momentum through a concerted investor outreach campaign for a planned first-quarter jump to the Nasdaq.

With preclinical and phase i data establishing resunab’s safety already in hand, the company is working toward filing an investigational new drug application to test resunab as a treatment for diffuse scleroderma (ds) in the first quarter of 2015 ahead of a planned phase ii study in the first half of next year. another 75-patient phase ii study in cystic fibrosis (CF) is planned for the same time frame. Corbus expects to wrap up both studies around mid-2016. With smooth sailing, an approval would come as early as 2018.

resunab, or ajulemic acid, began life as a potential oral treatment for neuropathic pain, invented by sumner Burstein at University of massachusetts medical school. Burstein licensed it first to atlantic pharmaceuticals inc. and then to indevus pharmaceuticals inc., which established the drug’s safety in a 121-patient phase i trial and its analgesic effects in a phase iia.

But following indevus’ review of the preclinical and clinical data in pain relief, it decided to drop the program. The analgesic effect was too short, wearing off between three and eight hours post-dose. They returned rights, and a 23-volume dossier of clinical data, to Burstein.

reviewing the data with mark Tepper, a veteran of Bristol-myers squibb Co. and emd serono who had once been a student in his biochemistry class years earlier, the men found the drug still showed promise. Through activation of CB2 receptors on immune cells, it appeared to trigger a natural inflammatory resolution pathway, stimulating the production of anti-inflammatory mediators and thereby reducing levels of pro-inflammatory mediators and cytokines.

Furthermore, resunab exhibited none of the serious adverse side effects that are associated with routinely used anti-inflammatory drugs: the gastrointestinal side effects of non-steroidal anti-inflammatory drugs (Nsaids) and the metabolic side effects of corticosteroids.

To move the drug ahead, Tepper bought it from Burstein and formed JB Therapeutics inc. which, through a reverse acquisition and recapitalization in march 2014, became Corbus.

standard therapies for regulating inflammation, such as steroids or common Nsaids try to stop the pro-inflammatory cascade. “it’s complex, because there’s a lot of redundancies, you get a lot of side effects, all because you’re trying to jam the pro-inflammatory mediators. resunab seeks instead to switch off inflammation altogether,” Corbus Ceo Yuval Cohen told BioWorld Today.

Cohen, co-founder and former Ceo of anti-inflammatory drug specialist Celsus Therapeutics plc, took that company public and then left it in march 2014 with the idea of taking six months off. Just about a week later, a mutual friend introduced him to Tepper.

seeing how much work had already been done and the size of the potential opportunity, he couldn’t resist getting involved.

“The nice thing about this story is we know so much about it. We know it’s safe in animals. We know it’s safe in humans. The one question remaining is, when you give it to a patient, what actually changes?” said Cohen.

The company has a little insight into that already. Tests of the drug in cell samples taken directly from ds patients have shown it reduces to normal levels of TGF-beta, which is over-expressed in ds patients and drives their fibrosis. The trials ahead will clarify resunab’s future further.

“if we can capture these diseases where inflammation and fibrosis go hand in hand and recapitulate some of the anti-inflammatory and anti-inflammatory effects we’ve seen in animal studies, then i think we’ll have a real winner on our hands,” said Cohen.

Corbus’ development of a CB2 agonist puts it in good company alongside abbvie inc., Glenmark pharma ltd., eli lilly and Co., and astrazeneca plc. But Cohen said it’s the only company in the crowd targeting inflammation and that it’s fielding the only


candidate with no central nervous system effects.

in the CF space, he expects it will have an additional advantage by escaping the genetic constraints faced by other therapies which rely on the delta F508 mutation of CF, such as kalydeco (ivacaftor, vertex pharmaceuticals inc.), or other mutations that circumscribe their target treatment groups. as an anti-inflammatory drug that’s mutation agnostic and indifferent to the flora in potential patients’ lungs, Cohen said, he expects it to be both relatively easy to recruit patients for trials and, ultimately, easier to achieve broad market penetration for resunab.

With just six employees, the company has no plans to manufacture or market resunab on its own should it succeed. Cohen said the company’s vision at the moment is to find the

right partner for it.

The company is focused on developing resunab as a pill now, but may also look at an alternate formulation that would allow for topical usage, an option that would allow it to move into the ophthalmology and dermatology markets, said Cohen.

Corbus is also “actively interested” in in-licensing assets it can position for rare, life-threatening inflammatory diseases, Cohen said.

Corbus trades as CrBp on the oTC market under the name of its parent, Corbus pharmaceutical holdings inc. shares closed flat at $3 on Nov. 21, 2014. //



recent StArt-up cour LAndS forMer pfizer r&d chief AS chAirMAnBy Michael Fitzhugh, Staff Writer

Cour pharmaceutical development Co. inc., a small company developing nanotechnology-based immunotherapies for acute inflammation and autoimmune disease, has appointed pfizer r&d veteran Catherine mackey as chairman of its board.

Founded in 2012, the elmhurst, ill.-based Northwestern University spinout is still preclinical. But it already has two yet-to-be-named big pharma collaborators in place and anticipates adding a third by the end of 2014, Cour Ceo and president, John puisis, told BioWorld Today.

Cour’s immune-modifying nanoparticles (imps), based on work done at the University of sydney and Northwestern University, are derived from biodegradable polymer polylactic-co-glycolic-acid (plGa) and have the potential to address a variety of inflammatory conditions.

The negatively charged particles bind to the positively charged marCo receptor of monocytes, directing them to the spleen for destruction through apoptosis, thus diminishing inflammation. inflammatory monocytes are prevented from entering sites of injury or inflammation, reducing tissue damage and accelerating repair and recovery.

The company’s tolerizing immune-modifying nanoparticles (Timps) also employ plGa nanoparticles, but load them with antigen-specific proteins that induce immune tolerance. in the case of specially programmed Timps, the modified particles can be used to deliver toleragenic signals to antigen-presenting cells, resulting in long-term immune tolerance.

at the heart of the technology are proprietary modifications to the nanoparticles that determine the immune target and mechanism of action, while the particle itself biodegrades and is then cleared by the body.

so far, Cour has filed patents to encapsulate hundreds of epitopes that modulate cell response. The highly specific Timps are at the

core of its pharma partnerships in type 1 diabetes, celiac disease and a third yet-to-be-named autoimmune disorder. it’s diabetes partner has an exclusive option on its investigational Timp, while its celiac partner has an exclusive evaluation option.

supported by the stable foundation of its partnerships, Cour plans to advance its internal imps in several cardiovascular indications, including acute myocardial infarction, acute encephalitis syndrome and, once lead optimization is complete, ischemic stroke and inflammatory bowel disease.

so far, puisis said, the company has raised enough seed capital to fund its needs. “our goal is to see how these collaborations play out and determine our capital needs going forward,” he said. as the company further explores applications for its platform and tackles the strategic thinking necessary to build a stable foundation, it was just the right time to bring mackey on board, he said.

mackey, an experienced corporate director, brings 30 years of operating experience in the biopharma and agricultural industries. she served as senior vice president of worldwide r&d and site director for la Jolla laboratories between 2001 and 2009 and has advised a number of other start-ups.

“When i looked at Cour and compared it to other start-ups, they have an enormous amount of data, an impressive patent portfolio, and have only taken nondilutive funding,” mackey noted. “They’ve built a very solid foundation. as a platform, it’s not a one-trick pony.”

indeed, Cour, which gained its name after company co-founders voted over dinner to incorporate the ideas of courage and heart, may have many tricks ahead. “There are many discoveries yet to be made,” puisis said. “We’re still identifying immune pathways we want to explore further, and there are lot of opportunities left to be realized there.” //

– BioWorld Today, may 22, 2014


‘criSpr’ dough: genoMe-editing StArt-up rAiSeS $25M in SerieS ABy Cormac Sheridan, Staff Writer

Crispr Therapeutics aG, a start-up formed by the co-inventor of the Crispr/Cas9 genome-editing technology, closed a $25 million series a round that will fund the translation of this hugely popular approach from the academic lab to the clinic.

emmanuelle Charpentier, who holds positions at hanover medical school in Germany and at Umeå University in sweden, published seminal papers in Nature in 2011 and in Science in 2012 that have spawned rapid, widespread adoption of the Crispr/Cas9 system for genetic manipulation of countless model organisms.

Joining her as scientific founders is a multidisciplinary line-up of american scientists, including: 2006 Nobel laureate and rNai pioneer Craig mello, of the University of massachusetts medical school, in Worcester, mass.; rNa delivery expert daniel anderson, of massachusetts institute of Technology; stem cell scientist Chad Cowan of harvard University; and gene therapy and genome-editing expert matthew porteus, of stanford medical school.

despite its strong american flavor, the company is headquartered in Basel, switzerland, although its main operational base will be in london. “We decided to go to europe, one of the reasons being that europe has a really strong network in gene therapy,” Ceo rodger Novak told BioWorld Today. Novak was previously a co-founder of vienna-based Nabriva Therapeutics Gmbh, an anti-infectives spinout from sandoz Gmbh, and he later headed up paris-based sanofi Group’s global anti-infectives r&d group.

The funding, which has come solely from Basel-based versant ventures, is earmarked for preclinical and possibly early clinical development of therapies in as-yet-undisclosed indications. “The $25 million will be exclusively used to fund two to three programs in the area of Crispr/Cas, to bring them to the iNd or CTa [clinical trial application] stage,” Novak said. The cash could extend to a first-in-man study, which would, by default, be a phase ii trial. “You can’t do it in healthy volunteers,” he said.

Given the novelty of the technology, Crispr Therapeutics aims to reduce some of the technical and clinical risk by focusing initially on indications that do not require systemic delivery. Cell therapies, including stem cell therapies, that involve ex vivo genome editing and therapies for ophthalmology indications

are candidates for further study, but the company has not yet pinned down the conditions it will focus on first.

“We are being very careful about which are the indications to go after first, to give us a high likelihood of success. We don’t want to promise the world,” Tom Woiwode, partner at versant ventures, told BioWorld Today. The slow progress at translating sirNa-based therapeutics into products offers a cautionary precedent. There is, however, a key difference between the two technologies. “sirNa is an inherently transient modification,” he said. in contrast, Crispr/Cas9 alters its target dNa locus permanently.

academic scientists have been attracted by the Crispr/Cas9 system’s ease of use and low cost in comparison with other genome-editing technologies, such as zinc finger nucleases and transcription activator-like effector nucleases (TaleNs), both of which rely on complex dNa-protein interactions. “very soon it will be a little bit like pCr,” Charpentier told BioWorld Today. “it’s a very democratic tool.”

The technology is derived from a form of microbial immunity that relies on hypervariable genetic loci, called clustered regularly interspaced short palindromic repeats (Crispr). Those store dNa snippets from invading plasmids and bacteriophage, which are transcribed and processed into rNa molecules, called Crispr (cr) rNas. Those guide a Cas9 nuclease to the complementary site on invasive plasmids or phage, where they catalyze double-stranded dNa breaks and enable further modifications to be introduced.

Charpentier, her research collaborator Jennifer doudna, of the University of California, Berkeley, and co-workers, described in the aug. 17, 2012, issue of Science the key step in the development of the technology, the production of a chimeric rNa molecule, comprising a mature crrNa and its trans-activating crrNa (tacrrNa) counterpart, with which it ordinarily forms a two-rNa structure. reprogramming that guide rNa (grNa) molecule enables users to direct the Cas9 activity to any genetic locus of interest.

doudna is among the founders of a rival firm, Cambridge-based editas medicine, which raised $43 million in 2013. “There’s room for a couple of players,” Novak said. “i do expect one or two other players to come into the game.” (see BioWorld Today, Nov. 25, 2013.)


earlier this month, the Broad institute of harvard and miT claimed to have received the first U.s. patent grant on Crispr/Cas9 technology, arising out of the work of another editas co-founder, Feng Zhang. Crispr Therapeutics’ patent applications are still being processed. Because of sweden’s ip rules, Charpentier has personal ownership of her inventions. “We not only believe it – it’s a fact that we remain uniquely positioned as the only company with access to the foundational ip for use in human therapeutics,” she said.

moving the Crispr/Cas9 system from academic labs into human patients requires further refinements of the technology to minimize the risk of off-target effects, to improve the

efficiency of Crispr/Cas9 uptake, and to iron out issues relating to chemistry, manufacturing and control (CmC).

“For some of the applications, we’re not years away from reducing it to practice,” Novak said. an outstanding task remains the development of additional functional genetox assays, to assess the safety of specific therapies. “You need to make sure your off-target activity is so low your risk-benefit ratio is on the side of the benefit.” human trials may not be far off. “assuming we have a pretty straightforward ride, with some effort and a little bit of luck, you could see the first clinical trial in maybe three years’ time,” he said. //



rAiSe the ‘curtAnA’ for StArt-up with $7.6M grAnt for gBM therApyBy Marie Powers, Staff Writer

a year after its official launch, Curtana pharmaceuticals inc. stepped onstage holding a $7.6 million product development grant from the Cancer prevention and research institute of Texas (CpriT) to fund its lead cancer therapy program, which is targeting the oliG2 transcription factor (TF) – initially in glioblastoma multiforme (GBm). Though still preclinical, the san diego-based company, which is relocating to austin in conjunction with the grant, hopes to take a leading role in applying small-molecule therapeutics to brain cancer.

oliG2 is critical in tumorigenesis and regulates the survival and expansion of GBm, explained Greg stein, Curtana’s co-founder and Ceo. although the TF is not typically active in normal brain tissue and is not found in normal tissues outside the central nervous system, it is highly expressed in diffuse gliomas and nearly all glioma cancer stem cells (CsCs) that are positive for the Cd133 stem cell marker.

TFs are promising targets for drug intervention, but the development of specific TF inhibitors has proved difficult due to expansive protein-protein interfaces and the absence of hydrophobic pockets. Using a combined pharmacophore-based small-molecule design, scientific co-founder and advisor santosh kesari identified several candidate compounds that demonstrated selective oliG2 pathway inhibition and in vitro anti-GBm potency in biochemical, cell-based and reporter assays.

Because overexpression of oliG2 drives tumorigenesis and promotes resistance to chemotherapy and radiation therapy, Curtana’s first-in-class small-molecule therapeutics are targeting CsCs in the central nervous system. The oliG2 inhibitors are thought to be the only adjuvant treatment for nearly all gliomas, including high-grade glioblastomas, that specifically targets the CsCs while also acting as a potent radiosensitizer, according to stein.

“i wasn’t looking for GBm automatically, but i liked the value proposition,” he told BioWorld Today.

a board-certified emergency medicine physician, stein previously co-founded and served as vice president of operations and medical affairs at sova pharmaceuticals inc., another san diego-area preclinical biotech, which is developing therapeutics to treat inflammatory and neuropathic pain by

modulating cystathionine-γ-lyase, or Cse, an enzymatic target involved in the production of the gasotransmitter h2s. prior to that, he was involved in several other biotech start-ups.

The formation of Curtana was serendipitous. While at sova, stein stumbled across literature suggesting the company’s technology approach – though focused on a different target – could have utility in GBm. he looked for a local expert and found kesari, who had been working in the field for almost a decade.

kesari is director of the Neuro-oncology program, the Neurotoxicity Treatment Center and the Translational Neuro-oncology laboratories at moores Cancer Center and a professor of neurosciences at the University of California san diego (UCsd) school of medicine. he previously served as assistant professor of neurology at the dana-Farber Cancer institute and Brigham and Women’s hospital.

“santosh is the most passionate researcher i’ve worked with,” stein said. “he really wants to see a cure for brain cancer, and he’s bent over backwards in making himself and his personnel available.”

Though, as a physician, stein had seen death, he also had been deeply affected by the loss of a close friend to brain cancer.

The two decided to form a company around kesari’s technology and, in september 2013, inked an exclusive worldwide license with UCsd.

‘WilliNG To Take risk oN earlier- sTaGe opporTUNiTies’

Funding was the next challenge. in mid-2013, CpriT was preparing to review grants again after a moratorium in 2012 as the agency brought in a new Ceo and took measures to strengthen its governance and accountability. in december 2013, CpriT formally issued nine requests for applications for grant awards. The agency received nearly 600 applications, and Curtana was one of two recipients of new company product development grants totaling $13.6 million. in all, CpriT awarded $107 million, including 15 grants through its prevention program and 84 grants through its research program.

“CpriT really recognizes that translational gap, or valley of death,” stein said. “They’re willing to take the risk on these


earlier-stage opportunities, which, for the most part, traditional venture has not been funding.”

Curtana’s grant, designed to provide two-thirds of the company’s operational funding over the next three years, is expected to advance its research platform through preclinical development, including toxicology and other requisite chemistry studies, to the submission of an investigational new drug (iNd) application.

“We’ll go out and raise a minimum of $3.8 million in matching funds, and probably more than that, so we’ll be well funded into the clinic,” stein said.

kesari will remain in san diego and oversee the company’s scientific progress as head of its scientific advisory board, but the company’s senior management will move to Texas, where stein expects to set up a lab and work with local scientists as part of the CpriT grant requirements. he expects to have about a dozen employees under Curtana’s roof by the time the iNd is filed.

The company’s name was selected “to be easily recognizable” without some of the letters and syllables that dominate biotech monikers, stein said. But Curtana also refers to a ceremonial sword, and stein likes the notion of targeting and striking down GBm.

“our goal is to create value and get a drug to patients as soon as possible,” stein said. For the time being, he won’t close any potential collaboration or partnering doors to make that happen, though he harbors the notion of taking a product through to registration and commercialization.

although a bevy of biotechs – agenus inc., angiochem inc., Celldex Therapeutics inc., delmar pharmaceuticals inc., GW pharmaceuticals plc and stemline Therapeutics inc., among them – is pursuing GBm, progress has been slow, in many cases, and actual treatment has evolved little over the last two decades, while patients with the aggressive cancer still face a median survival of less than 15 months. (see BioWorld Today, aug. 13, 2013, June 2, 2014, and July 2, 2014.)

stein said he believes Curtana’s platform differentiates the company from conventional therapeutic approaches in GBm, which often include surgery, chemotherapy and radiation that target the tumor bulk but have limited effect on the CsCs that drive tumor growth and recurrence.

“oliG2 is a unique target,” he said, “and because it’s only overexpressed in the cancer, we see an opportunity for a highly effective, targeted therapeutic.” //

– BioWorld Today, aug. 22, 2014


doMAinex MAkeS the LeAp froM diScoVery to drug pipeLineBy Marie Powers, Staff Writer

established a dozen years ago, domainex ltd. is familiar to drug developers – especially in the Uk, where the company spun out of University College london – as a contract research organization.

initially, domainex operated in partnership with sister organization NCe discovery, with the two entities sharing a similar shareholder base.

That relationship changed in 2006, when the companies were combined “to give a more critical mass” and to bring the chemistry and advanced biology assets at NCe discovery into the domainex fold, explained Ceo eddy littler.

“in some ways, that’s where the company that we have today really started,” said littler, who joined domainex shortly after the merger.

although Cambridge-based domainex continues to provide contract research services, the integration of NCe discovery also served as “the trigger point” to launch an internal pipeline.

“i’m a big believer that a lot of companies succeed or fail in biotech on the very early decisions they made about which targets to choose,” littler told BioWorld Today. “We spent quite a lot of time on that process.”

Banking on its experience in drug discovery, domainex examined targets “that were known by the pharma community but regarded as being challenging,” littler explained. The company refined the process to focus on programs whose specific problems could be solved by applying its platform, known as combinatorial domain hunting (Cdh). The technology is designed to clone and express difficult genes and to produce protein at the requisite levels by screening all possible protein constructs, in rapid fashion.

domainex started with a group of targets that included the closely related pro-inflammatory kinases TaNk-binding kinase 1 (TBk1) and ikappaB kinase epsilon (ikkε). in July 2014, the company reported that its lead program, encompassing small-molecule inhibitors of TBk1/ikkε, demonstrated a more potent effect in a model of chronic obstructive pulmonary disease (Copd) than the pde4 inhibitor daliresp (roflumilast, Forest laboratories inc.) or a p38 inhibitor. The domainex compound showed at least three times the effectiveness of roflumilast

“and was many more times effective than the p38 inhibitor” in reducing the cigarette smoke-induced influx of inflammatory cells, particularly neutrophils, into the lung, littler said.

daliresp was approved by the Fda in 2011 to reduce the risk of Copd exacerbations in patients with severe Copd associated with chronic bronchitis and a history of such flare-ups. Forest labs, now part of actavis plc, had licensed the drug – marketed as daxas in the european Union and Canada – from privately held Nycomed Gmbh, of Zurich, switzerland, in a deal potentially worth more than $500 million. (see BioWorld Today, aug. 11, 2009, and march 2, 2011.)

domainex is exploring the TBk1/ikkε inhibitors in a number of inflammatory disease models, including rheumatoid arthritis, lupus and psoriasis, and said they also have applications in a range of cancers, including colorectal, breast and lung cancers. domainex has filed multiple patents on the lead series to treat Copd and on the use of TBk1 in cancer.

“Copd is a huge medical need and a very attractive marketplace, so we chose that as our first disease model,” littler pointed out.

The company’s real coup was to solve the problem of oral bioavailability for the drug class. “We spent about a year solving that problem, and it was probably the worst one i’ve ever seen,” littler said. “But we got there. We had to. We’re a small biotech company, and that was our program. We had to be successful, or the company would have failed.”

orGaNiZaTioNal ChaNGe BesT approaChed From a posiTioN oF sTreNGTh

in the process of working on the TBk1/ikkε inhibitors, domainex discovered targets involved in epigenetic gene regulation known as lysine methyltransferase, or kmTs. scientific evidence suggests those enzymes play a significant role in many diseases, littler said, with a number of the enzymes known to have relevance in mechanisms of carcinogenesis. Using its Cdh technology, the company subsequently cloned and expressed a number of kmT enzymes, with the design of inhibitors representing the second program in its pipeline.

“it’s a very hot area, and we have some novel chemistry in that area that looks very much like drug-like molecules,” littler said,


describing the company’s molecules as “very, very clean.”

Findings on the TBk1/ikkε inhibitors won domainex a £1.4 million (Us$2.4 million) Biomedical Catalyst award from the Uk’s Technology strategy Board to advance the program into phase i studies. The company also secured early funding from the Bloomsbury Bioseed Fund and two small rounds from longbow Capital. revenues from its drug discovery services, which represent about 70 percent of the company’s operations, make it less focused on fundraising than most small biotechs.

“The service business has been quite successful and is profitable,” littler said, noting that domainex expects to expand from 32 to approximately 40 employees by year-end. “our priority now is to take the service business forward and grow it organically or through some sort of m&a to increase the critical mass of the technologies.”

littler, whose résumé includes tenure at Wellcome research laboratories and Glaxo Wellcome plc – now part of Glaxosmithkline plc, of london – as well as sweden’s medivir aB, maintained that just as most biotechs are more efficient organizations than large pharmas, most life science service organizations are similarly more efficient than biotechs.

“You’re working for a client, and the relationship is usually fairly straightforward,” he observed. “They give you cash, and you deliver the goods on time, as they expect. That relationship drives you to be extremely efficient, and that efficiency spins

over directly to the approach to internal programs.”

The company’s ongoing service work with pharmas – including more than 40 collaborations, to date, on its Cdh platform – has served as a springboard to its pipeline by increasing the company’s understanding of a variety of targets while providing opportunities to discuss its internal projects with clients. The hybrid approach “is a very effective model, both on a technical level and from a commercial standpoint,” littler said.

By year-end, domainex expects to establish a separate intellectual property company (ipCo) that will serve as a repository for its patents and enable its internal drug pipeline to move forward with its own set of goals, targets, budgets and timelines. at that point, domainex will seek to raise additional funding.

“That work is getting off the ground,” littler said. “By the end of the year, we’ll have established the ipCo and we hope to be in discussions with a couple of investors about taking these projects through to clinical proof of concept.”

organizational change is best approached from a position of strength, he added. With the company’s service business running smoothly and its nascent drug pipeline now at an inflection point, “that’s the right time to make these changes and move the company forward,” littler said. //

– BioWorld Today, oct. 3, 2014


Big dAtA for SMALL MoLecuLeS; exScientiA inkS firSt phArMA deALBy Nuala Moran, Staff Writer

loNdoN – dundee University spinout exscientia ltd. has signed a $4.8 million drug discovery deal with sunovion pharmaceuticals inc. to design bi-specific small molecules for treating psychiatric disorders.

“We will be applying the bi-specific philosophy of the antibody space to design small molecules for engaging multiple targets,” said andrew hopkins, founder and Ceo.

exscientia claims it is the first company to develop a systematic way of designing small molecules with bi-specific target profiles, in effect mimicking the iterative process employed by chemists, on a much larger scale, at a much faster rate.

The name exscientia, latin for “from knowledge,” embodies the company’s approach of applying the power of big data to an existing knowledge base, but also generating new understanding in the process. hopkins uses the analogy of music, where eight notes can generate infinite variety. “We can take a small field of targets and change the traditional way of approaching them,” he told BioWorld Today.

“We are exploiting the wealth of information that is already available, which provides a huge number of opportunities. We can find chemical matter for more challenging product profiles,” hopkins said.

it is not merely a case of automating an existing manual process, however. The roots of exscientia’s technology platform go back to pfizer inc.’s Uk laboratories in sandwich, kent, where hopkins and colleagues carried out research to develop a big data approach to drug design.

The sequencing of the human genome was supposed to deliver multiple new drug targets. however, the pharmaceutical industry struggled to marshal that new resource, with one particular issue being that there was no centralized repository of what gene targets were addressed by existing drugs, coupled with limited understanding of how to modulate disease targets embodied in dNa sequences.

in 2002 hopkins coined the term “the druggable genome,” pointing to the requirement to build understanding of how many disease targets are embedded in the genome. That led to the July 2006 publication in Nature Biotechnology of

“Global mapping of pharmacological space,” which identified human targets for which drugs had been discovered to date.

The work laid the foundations for new, more predictive approaches to drug discovery and the rational design of compounds with multitarget profiles, which hopkins has taken forward since taking up a chair in medicinal informatics at dundee University in 2007.

Those advances in polypharmacology led to the formation of exscientia in september 2012. “We were lucky because we immediately did deals with two top 10 pharma companies,” hopkins said.

The company employs some of the leading experts in medicinal chemistry, bioinformatics and drug design, including former researchers at inpharmatica ltd., one of the first knowledge-based in-silico drug discovery companies, and other ex-pfizer researchers, including andy Bell, co-inventor of viagra (sildenafil) and vfend (voriconazole). Bell joined exscientia as chief chemist in april 2014.

since its formation, exscientia has signed other partnerships, but sumitomo dainippon pharma ltd.’s subsidiary sunovion, of marlborough mass., is the first pharma partner to be named.

The partnership with sunovion brings a further enhancement to exscientia’s polypharmacology expertise, introducing the use of large-scale phenotypic screening, a method for assessing a compound’s ability to modulate a biological pathway, as opposed to showing it can engage specific targets. “rather than looking at binding, we can measure the behavioral response,” hopkins said.

While the algorithmic platform can design in ligands to multiple targets, with the aim of increasing efficacy, it can also design out the ability to lock on to “anti-targets” that are known to introduce the risk of side effects or toxicity. The basis of that is the capability exscientia has to look for all possible targets a chemical may have in the proteome, using in silico screens. “a key thing our approach does is to take account of off-target effects a priori,” hopkins said.

in parallel with its research collaborations, exscientia has started to develop an in-house portfolio, beginning with a bi-specific molecule that is designed to be a treatment for diabetes.


The pharma industry collaborations mean exscientia has been cash-positive from the beginning. “Now we are interested in expanding, in particular, growing our own programs, but

we won’t take any in-house projects forward without raising capital,” hopkins said. //



fiBrotech LAuncheS diABetic nephropAthy Study, pArtnering tALkSBy Nuala Moran, Staff Writer

loNdoN – Fibrotech Therapeutics pty has begun dosing in the phase ib trial of its lead molecule FT011 in treating diabetic nephropathy and is now involved in “intensive discussions” to partner the small-molecule antifibrotic.

The melbourne, australia-based company announced the start of phase ib as it released phase i data showing FT011 was safe and well tolerated at doses of up to 1,000 mcg. “it’s essentially a very clean drug with excellent safety,” said darren kelly, Ceo of Fibrotech and co-discoverer of FT011.

its oral bioavailability and clean profile will put FT011 in a strong position vis-a-vis other fibrosis treatments that are in development, kelly said, citing intermune inc.’s esbriet (pirfenidone). The orphan drug treatment for idiopathic pulmonary fibrosis (ipF) was approved in europe in 2011, and is due for resubmission to the Fda later this year after receiving a non-approvable letter in 2010. “i think we have shown a very different safety profile [for FT011], and given this, it will be attractive to broaden into other indications. ipF is an orphan indication where you don’t need such a clean tox package,” kelly told BioWorld Today.

FT011 is one of 250 antifibrotic compounds that Fibrotech has discovered. kelly said he wants to partner this lead program to enable the company to expand its efforts to other indications. “an in-depth partnering or acquisition could add breadth. This is important because fibrosis is a frequent form of kidney disease, but also a feature of so many other diseases,” he said.

in march 2014, kelly was busy pressing the flesh at the Bioeurope spring meeting in Turin, italy, where he reported having “a very successful time.” kelly added, “There are intensive discussions currently with several of the leading pharma companies and larger biotechs.”

although FT011 is only just through initial development, kelly said he believes there is now an appetite in pharma for in-licensing early stage assets. Fibrotech already has scoped the phase ii trial of FT011, with the provisional design calling for the drug to be tested in 150 patients over 12 months.

FT011 is an analogue of an off-patent drug, tranilast (rizaben), an antifibrotic, which is approved for the treatment of asthma, atopic dermatitis and allergic rhinitis in Japan. Fibrotech has

synthesized more than 120 analogues, many of which are new chemical entities and which the company said have improved antifibrotic effects compared to the parent molecule.

The compounds were co-discovered by kelly, a professor at the University of melbourne, who spun out Fibrotech in 2006. in common with other antifibrotic drugs that are in development, including Genzyme inc.’s fresolimumab and eli lilly and Co.’s lY2382770, which are both in early phases of development, FT011 targets TGF-beta, which is a key driver of fibrosis. Fibrotech said FT011 potently attenuates TGF-beta-induced collagen synthesis in cellular assays.

in preclinical studies, FT011 was shown to be orally bioavailable, with no toxicity up to doses of 2,000 mcg/kg/day in rats. The drug significantly inhibited progression of renal fibrosis and decline in renal function in rat models of diabetic nephropathy, and it showed activity when tranilast had no effect at the same dose.

kelly is extremely familiar with the diabetic ren-2 rat model, having developed it in 1998. since then it has been widely used for preclinical testing in diabetic nephropathy, where Fibrotech claims it has shown “exceptional predicitive power” of both positive and negative clinical trial outcomes.

in addition to diabetic nephropathy, Fibrotech has demonstrated FT011 inhibits progression of cardiac fibrosis following myocardial infarction, slows diabetic cardiomyopathy and also delays the onset of retinopathy caused by diabetes. once it has partnered or sold FT011, the company has ambitions to expand beyond late-stage nephropathy to the earlier stages of the disease, and into other fibrosis indications. “The next objectives are lung fibrosis and cardiac fibrosis,” kelly said.

To date, Fibrotech has been funded by private australian investors. it also has received a rapid access to interventional development (raid) grant through the U.s. National institute of health’s National institute of diabetes and digestive kidney diseases.

The company has sufficient funding to complete the phase ib FT011 trial but said it would need to raise a$15 million to a$20 million (Us$13.7 million to $18.2 million) for the phase ii study. //

– BioWorld Today, march 24, 2014


genMAB expLoring worLd of rABBitS in MAB diScoVery deALBy Cormac Sheridan, Staff Writer

Genmab a/s has made an eye-catching move into rabbit-based antibody discovery by entering a multitarget deal with mab discovery Gmbh, a company founded by a group of big pharma scientists.

Given Genmab’s deep roots in the use of transgenic mice for antibody discovery – the Copenhagen, denmark-based company originally was spun out of medarex inc. (now part of New York-based Bristol-myers squibb Co.), which had previously acquired the pioneer in that area, san Jose, Calif.-based Genpharm international inc. – the agreement is a significant validation not only for mab discovery but for the wider space of rabbit-based antibody discovery.

several firms have emerged in recent years to declaim the advantages of rabbit-derived antibodies, which, they maintain, eliminate many of the headaches associated with optimizing molecules derived from more conventional routes such as transgenic mice or phage display. Those include Numab aG, of Wädenswil; switzerland, apexigen inc., of Burlingame, Calif., which obtains its technology from sister firm epitomics, inc., also of Burlingame; and Therapeutic human polyclonals inc., which roche aG acquired in 2007. (see BioWorld Today, april 3, 2007, aug. 27, 2010, and oct. 30, 2013.)

“There is a general observation that technologies that have been in use for years get to their limits,” stephan Fischer, Ceo and co-founder of Neuried, Germany-based mab discovery, told BioWorld Today. The natural antibody repertoire of the rabbit is highly diverse, and rabbit species also have many other “developmentability” attributes. “They produce antibodies with a very high affinity and potency up front – there is no need to do in vitro lead optimization or any other engineering exercise that takes a lot of time and needs a lot of investment,” he said. “This is what you get in the rabbit B-cell supernatant right away.”

Fischer, previously head of biologicals r&d at Basel, switzerland-based roche, formed mab discovery in 2010, along with andreas Tschirky, another roche r&d veteran, with the help of $25 million investment from Wilmington N.C.-based Cro ppd inc.

The company has used that cash to put in place a highly automated discovery platform, which employs fluorescence-activated cell sorting (FaCs) to isolate antibody-producing B-cells from the serum of immunized rabbits. Between 25,000 and 50,000 B-cell clones are then grown in microtiter plates, using culture conditions designed to optimize antibody production, so that the resulting molecules can be evaluated in high-throughput cell-based assays and in silico. The lead candidates are humanized using standard approaches and fused to human Fc domains. The highly integrated system is based on know-how rather than on any single piece of proprietary technology. “There is no blocking ip,” Fischer said.

although the process introduces a time saving of several months, its main value lies in the quality of the outcome, Fischer said. The mab discovery process yields between 50 and 150 hits, which can be further evaluated and optimized, whereas a more conventional process typically uncovers a handful of molecules. “This, in our opinion, is a mechanism that translates into a better chance of success downstream,” he said.

mab discovery also has entered research collaborations with several large pharma companies, including ingelheim, Germany-based Boehringer ingelheim Gmbh. “in all the cases we’ve tested so far, we’ve been very successful at finding active molecules in the end stage,” Fischer said.

details of the Genmab deal have been kept under wraps, but given the danish firm’s scientific strength in antibody-related technologies, the collaboration may be the strongest test yet of the thesis that rabbits can – immunologically speaking – go where mice cannot. “That is what they want to find out, if that is the case,” Fischer said.

meanwhile, Genmab’s core antibody discovery and development business, based on the Ultimab platform that originated in medarex, continues to make progress. on march 27, 2014, the company logged a $22 million milestone from its partner Johnson & Johnson arising out of the progress of its anti-Cd38 antibody daratumumab, in a phase ii trial in multiple myeloma. //



genoA SeekS ‘BreAth of freSh Air’ in ipf with inhALed pirfenidoneBy Marie Powers, Staff Writer

mark surber, president and Ceo of Genoa pharmaceuticals inc., has witnessed firsthand the devastation wrought by idiopathic pulmonary fibrosis (ipF), a lung disease linked both to genetic and environmental factors that results in progressive lung scarring. surber’s father and grandfather both died from the disease, and other family members are susceptible.

although surber is reluctant to “stand on the shoulders” of family members to explain his passion about the indication, “i have a very personal interest to advance the science and resulting therapies,” he admitted, noting that he’s seen the distress of ipF patients struggling to breathe in an indication that is estimated to kill as many individuals in the U.s. as breast cancer but has no Fda-approved drugs.

Genoa’s team came together in 2010 with the goal of re-purposing promising drugs for inhaled delivery. surber, a co-founder, was the inventor of the patent estate surrounding Gp-101 (aerosol pirfenidone), a formulation for direct inhalation delivery to the lungs. he also had experience with start-ups as the first employee at aires pharmaceuticals inc., of san diego, where he was project lead and inventor of aironite, an aerosol medicine to treat pulmonary hypertension. aires positioned itself as an acquisition target in a 2010 option with Novartis aG as part of a $20 million series B, but the big pharma never moved and aires was picked up in 2014 by mast Therapeutics inc. in an all-stock deal. (see BioWorld Today, Nov. 15, 2010.)

surber also was an early employee at san diego-based mpex pharmaceuticals inc., where he served as project lead and inventor of aeroquin, an aerosol formulation of levofloxacin designed to treat cystic fibrosis. aptalis pharma inc. (then axcan holdings inc.), of mont-saint-hilaire, Quebec, snagged mpex in april 2011 for an undisclosed up-front payment and a series of milestones.

Genoa, also in san diego, harkens to a sailing term describing the type of large jib that overlaps a sailboat’s main sail, providing a “breath of fresh air” to manipulate the craft and enhance the sailing experience, surber explained. in short, that’s the premise of Gp-101, which is designed to enhance the efficacy of pirfenidone – approved in europe and Canada in ipF as the oral agent esbriet (intermune inc.) – without the

side effects that prompted an Fda complete response letter to intermune in 2010. (see BioWorld Today, may 5, 2010.)

Germany’s Boehringer ingelheim Gmbh also is advancing the tyrosine kinase inhibitor nintedanib in ipF. Both compounds have shown efficacy in their clinical programs, which have not been compared head to head, but are hampered by troublesome side effects, including gastrointestinal symptoms and rash. (see BioWorld Today, may 20, 2014.)

GeNoa FolloWs ‘The mosT expedieNT paThWaY’ To markeT

preclinical studies by Genoa suggested that small, inhaled doses of Gp-101 were superior to oral pirfenidone in delivering medication to the lungs to treat ipF but that the effect was short-lived. earlier this year, however, Genoa and collaborators at mcmaster University showed that short-lived lung levels are all that’s required for maximum pirfenidone activity to improve ipF treatment. Characterization of the aerosol pirfenidone mechanism suggested the drug inhibits a single, upstream pro-fibrotic target with strong influence on downstream pathways critical for ipF initiation and disease progression.

surber lauded the work accomplished by intermune, which he said “pioneered the development of drugs for ipF,” and said he expects esbriet to be approved by the Fda in 2015, following an expected resubmission of the company’s new drug application in the third quarter. (see BioWorld Today, Feb. 26, 2014.)

But he’s confident about the prospects for Gp-101.

“You have to put a very large dose into the gut to be absorbed into the blood, where it circulates and, hopefully, a small amount is delivered to the lungs,” surber explained. “With an aerosol, you can deliver very small doses directly to the lung and get superior drug levels with very little spillover into the rest of the body, so the safety profile should be clean.”

surber spent the better part of a year experimenting with different formulations to develop just the right properties for Gp-101. The company’s university collaborator helped to advance Gp-101 through various milestones by demonstrating the ability to deliver the drug to the lung, validating its pharmacokinetic profile and providing early evidence of efficacy.

Genoa is keeping an eye on esbriet’s second try with the Fda,


which could factor into the small biotech’s strategy for an investigational new drug (iNd) application filing for Gp-101.

“if esbriet is approved, we’ll file under the 505(b)(2) pathway,” surber told BioWorld Today. “in europe, where the drug is approved, we’ll follow the hybrid pathway.”

phase i studies likely will be conducted in australia, enabling the company to include early clinical data in a pre-iNd meeting with the Fda, leading to “a much more fruitful discussion with the agency,” surber said. he expects a global phase ii program, with staged filings in the U.s., europe and other countries.

Genoa completed a $1.2 million seed financing in 2012, primarily through friends and family. as the company looks to move Gp-101 into the clinic in 2015, surber is meeting with venture funds about backing a $10 million series a that

would close sometime this summer and carry the company for 18 to 20 months, funding the phase i and remaining pre-iNd activities. on a parallel track, the company is holding discussions with potential partners.

“We’ll see which strategy wins the day,” surber said. “The most important thing to me, personally, is to get the drug into patients’ hands. if the quickest way to do that is to work with venture capital, then that’s the preferred path. if it’s better to go through a partnership – whether with an option structure or by licensing ex-U.s. rights – then that’s the path we’ll take. Both strategies are underlined by our need to satisfy the needs of our current investors, so there’s a balance. But, certainly, there’s a large push to make sure we follow the most expedient pathway.” //



gLionoVA getS $6M in SerieS A for new ApproAch in cAncerBy Cormac Sheridan, Staff Writer

dUBliN – Glionova aB, a swedish start-up exploiting a novel mechanism of action in cancer, raised sek42 million (Us$5.7 million) in a series a round to take forward its lead drug, GlN-1001, which is in development for glioblastoma.

healthcap and Novo seeds a/s co-led the investment round, which may be extended to bring in two other investors in the coming weeks. “We are actively building a syndicate that can not only bring this into the clinic – we have that now – but maybe to carry the company through phase ii,” acting Ceo eugen steiner, who is also a partner in healthcap, told BioWorld Today.

The company’s scientific founders, patrick enfors and lars hammarstrom, both of the karolinksa institute in stockholm, led a team that identified GlN-1001 through a phenotypic screening program aimed at detecting small molecules with selective toxicity for glioblastoma calls. The molecule activates a hitherto unrecognized process in cancer cells – the company’s founders call it “catastrophic vacuolization” – which results in cell death, by a mechanism that is independent of apoptosis.

a paper that appeared in the april 10, 2014, issue of Cell, titled “vulnerability of Glioblastoma Cells to Catastrophic vacuolization and death induced by a small molecule,” describes their research findings. Following ex vivo exposure to vacquinol-1, GlN-1001’s predecessor compound, glioblastoma cells exhibited membrane ruffling, cell rounding, massive accumulation of cytoplasmic vacuoles through macropinocytosis (internalization of extracellular fluid), aTp depletion and eventually cytoplasmic membrane rupture. The effect was specific to glioblastoma cells – several other types of cancer cell, as well as fibroblasts, neurons, mouse embryonic stem cells and mouse astrocytes were all unaffected.

vacquinol-1 also prolonged survival in animal models. Two of eight mice exposed to a glioblastoma tumor cell line that received the drug died during the 80-day experiment, whereas median survival for the control group was 31.5 days.

“There are huge amounts of data behind this. They’ve been working on this for six years,” steiner said. The company plans to move the program into the clinic by late 2015 or early 2016. it is also exploring additional indications that may be

appropriate. “There are some other cancers that have similar pathways,” steiner said. The company’s scientific founders have yet to identify the precise molecular target(s) of GlN-1001, but the mitogen-activated protein, or map, kinase mkk4 is required for its activation of the macropinocytosis process. That is likely to be a downstream element of the signaling pathway, steiner said. subsequent work has focused on finding the upstream switches.

Glioblastoma remains a cancer with high unmet need. Three-year survival is just 3 percent to 5 percent. “people have been working for two decades, and no progress has been made since temozolomide,” he said.

originally developed by schering plough (now part of merck & Co. inc., of Whitehouse station, N.J.), that drug works as an alkylating agent, but resistance is common.

a big part of the problem is the genetic complexity of glioblastoma.

it can often involve both loss-of-function and gain-of-function mutations in different pathways. “looking for single targets is not going to be a successful approach,” steiner said. phenotypic screening offered an alternative way of identifying a new biological aspect of the glioblastoma cells, which may not be directly involved in the biology of the cancer, but which may nevertheless be essential to its survival.

several other firms are targeting glioblastoma in different ways. one, vBl Therapeutics ltd., of Tel aviv, israel, unveiled plans in November 2014 to move its anti-angiogenic gene therapy treatment vB-111 into a phase iii trial in the first half of 2015, based on promising survival data from an ongoing phase ii trial. vB-111 comprises a nonreplicating adenovirus vector carrying a pro-apoptotic transgene encoding Fas and TNF receptor 1. expression of the transgene is under the control of a proprietary, modified murine pre-proendothelin promoter, ppe-1-3x, which is selectively active in the endothelial cells of newly formed blood vessels. patients with recurrent glioblastoma, who had previously received vBl-111, were randomized to receive either a second course of vBl-111 plus avastin (bevacizumab, roche aG) or avastin alone.

Those who received the combination (n = 23) had a median overall survival of 504 days vs. 235 days for those on avastin only (n = 23).

https://cortellis.thomsonreuterslifesciences.com/ngg/qsearch/Glionova%0D


other companies involved in glioblastoma include Celldex Therapeutics inc., which is developing a therapeutic vaccine that targets endothelial growth factor receptor viii (eGFrviii); Northwest Biotherapeutics inc., which is developing a

dendritic cell-based vaccine; and dnatrix inc., which is testing an oncolytic virus. (see BioWorld Insight, oct. 28, 2014.) //



iMeVAx getS $10M in SerieS A for H. PylORi VAccineBy Cormac Sheridan, Staff Writer

imevax Gmbh, a newly formed spinout from the Technical University of munich (Technische Universität münchen; TUm), raised €7.5 million (Us$9.6 million) in a series a round to fund clinical trials of a vaccine against Helicobacter pylori.

The munich-based company builds on the work of scientific founder and chief scientific officer markus Gerhard, who identified an H. pylori virulence factor, gamma glutamyl transpeptidase (hGGT), which enables the pathogen to evade the host immune system by inhibiting T-cell proliferation.

its vaccine, imx-101, comprises two recombinant antigens, inactivated hGGT and an outer membrane protein from the same bacterial species, which contains T-cell epitopes. These are combined with a mucosal adjuvant, based on an inactive subunit of the Cholera toxin, which elicits a B- and T-cell response, and which is linked with a targeting peptide from Staphylococcus aureus.

The serum concentration of the human form of the hGGT is a marker of liver dysfunction and alcohol consumption, but the H. pylori version show little homology to it, which minimizes concerns about cross reactivity.

a vaccine-based approach to targeting hGGT is not the only potential route to controlling H. pylori without resorting to antibiotics, although it is the most advanced. The company is carrying out preliminary work on a monoclonal antibody. “i’m not sure if a monoclonal would be sufficient to do the job,” Gerhard told BioWorld Today. it also has investigated small molecule inhibitors of hGGT. it discarded one promising molecule, however, because of likely toxicity issues in humans, even though it was effective in mice.

“That still seems an interesting approach,” he said.

its vaccine should be ready for clinical trials by late next year or early 2016. it plans to conduct a phase ia study in healthy volunteers, after which it will test the vaccine in infected but asymptomatic individuals. The latter study was included at the behest of the German regulator, the paul ehrlich institute, given the uncertainties arising from the host-pathogen interactions that accompany H. pylori infection. “You could argue that people are primed already to the vaccine because of the existing infection,” Gerhard said. Then again, because of its ability to induce tolerance, immune responses to a vaccine

could also be suppressed.

“Nobody knows which direction it’s going to go,” he said.

about 50 percent of the world’s population is infected with H. pylori.

The majority are asymptomatic, but in a minority infection can lead to peptic ulcers, gastritis and gastric cancer. Current therapy is based on triple regimen, comprising two antibiotics and a proton pump inhibitor, but resistance is rising, raising fears that this approach will lose its utility in future.

several previous vaccine development programs have failed to demonstrate either efficacy or tolerability in humans. These included an inactivated whole-cell vaccine and vaccines based on recombinant urease, which the bacterium uses to neutralize stomach acid. as of now, nothing is in the clinic.

epivax inc., of providence, r.i., is developing a peptide-based vaccine with the help of National institutes of health funding, although this effort is still preclinical. “The approach is interesting but has certain limitations, as all peptide approaches have,” Gerhard said, referring to the major histocompatibility complex (mhC) restriction that accompanies peptide antigens.

“all the other approaches are relying on a single antigen or a combination of antigens that are highly variable,” Gerhard said. For example, Novartis aG, of Basel, switzerland, conducted trials of a vaccine based on two other H. pylori virulence factors, vacuolating cytotoxin a (vaca) and cytotoxin-associated gene a (caga) protein.

although imevax is a newly formed entity, imx-101 has been in the works for the last seven years, with the help of translational research funding from Germany’s Go-Bio program. “We had substantial support – €4 million – which means you can do things you normally can’t do in academia,” Gerhard said. its investors are getting a lot of leverage for their cash, as the company is also getting a further €5.9 million in non-dilutive from the same source – this was contingent on matching the cash with venture capital investment.

Wellington partners led the round, with equal participation from Biomedpartners, emBl ventures and santo venture Capital, which is affiliated with the strüngmann family. //



iMMunoVAccine reportS SucceSS protecting AniMALS froM eBoLABy Michael Fitzhugh, Staff Writer

shares of immunovaccine inc. (Tsx:v:imv) gained 14.4 percent aug. 25, 2014, to close at C$1.11 (Us$1.01), after the halifax, Nova scotia-based company reported that monkeys dosed with an ebola vaccine employing its depovax formulation technology survived exposure to a lethal dose of the virus in a challenge study performed by the National institute of allergy and infectious diseases (Niaid).

Four cynomolgus macaques received two doses of the depovax-formulated vaccine, once at the study’s start and again on day 56. at day 70, researchers gave all six monkeys in the study a lethal dose of the wild type Zaire strain of the ebola virus. seven days later, the two control animals were dead. The vaccinated monkeys, however, survived with no disease symptoms more than two weeks following exposure.

impressed by the results of the company’s ongoing anthrax vaccine program, the Niaid approached the firm about four months ago, asking if it would like to incorporate depovax into some of the vaccines it was already testing, immunovaccine Ceo marc mansour told BioWorld Today.

The results won’t change the company’s focus on developing cancer and infectious disease vaccines already in its pipeline, said mansour, but they have sparked preliminary talks with potential partners who could incorporate depovax into existing ebola programs. (see BioWorld’s special report: The push to Contain the ebola virus.)

Niaid will next move the depovax-formulated vaccine into wider testing with bigger animal groups, testing different timing and other factors. ”What that means for us is that with these data we can now talk to various organizations about whether there’s a development program we can get involved in for an ebola vaccine,” mansour said.

CaNCer, Too

While the ebola trials have piqued investor interest, immunovaccine has been working on infectious disease vaccines for years. The company’s depovax-formulated respiratory syncytial virus is already slated for a phase i study, expected to begin this year, while it continues to pursue its collaboration with the Nih to develop and test a rapid response anthrax vaccine.

more advanced, however, are immunovaccine’s depovax-formulated cancer vaccines, dpx-0907 and the survivin-targeted dpx-survivac, which is expected to enter a phase i/ii study in glioblastoma and a phase ii study in ovarian cancer later this year.

The ovarian cancer trial will enroll 250 patients and will be sponsored and conducted by Canada’s NCiC Clinical Trials Group, while the ovarian cancer study is sponsored by the University of rome. Furthermore, the company is looking at running additional smaller phase ii trials to investigate the clinical activity of dpx-survivac in ovarian cancer and lymphoma.

The company has also drawn attention from the dana-Farber Cancer institute, which recently selected depovax as the underlying enhancement technology for a new hpv-related cervical and head and neck cancer vaccine. The vaccine will be the focus of a clinical study, expected to start in 2015, that will be funded by a grant from stand Up To Cancer and the Farrah Fawcett Foundation.

hUNGrY seals

immunovaccine got its start at halifax’s dalhousie University, thanks to cod-hungry seals. looking for an alternative to clubbing the animals in order to control their numbers, the Canadian government gave the dalhousie team $5 million to develop a more humane method of population control. While contraceptive vaccines already existed, getting seals to revisit researchers for an annual booster shot was out of the question. “There’s only one time a year that you can get close to a seal,” mansour said, “when it’s breeding on sable island, a sand strip 200 kilometers off shore.”

To solve the problem, researchers came up with a highly adjuvanted vaccine technology. researchers returned the following year to check in on the animals that had returned for another breeding season. Not one of the vaccinated seals was pregnant or had pups. Ten years later, there were still no babies, all from the single vaccination. “it was a very dramatic result,” mansour said.

as an adjuvanting platform, depovax provides controlled and prolonged exposure of antigens and adjuvant to the immune system, by encapsulating both antigens and adjuvant in a liposome shell. The vaccine is then stored in a dry format.

http://www.bioworld.com/latest_news/Ebola

http://www.bioworld.com/latest_news/Ebola


When it’s time for administration, the vaccine is suspended in oil and injected, creating a “depot” to which antigen-presenting cells are attracted.

The cells pick up the vaccine, process and display the antigens through the mhC pathway. killer T cells recognize the antigens, are activated and multiply, going on to search out tumor cells that display the antigens, then dispersing cytotoxic molecules that disrupt cell membranes or kill the cancer cell by signaling apoptosis.

seeiNG GreaTer poTeNTial

since then, the company has changed and grown, delivering positive results from a phase i/ib study of its lead cancer vaccine candidate at the american society of Clinical oncology in 2013 and showing early evidence of clinical activity in ovarian cancer patients.

immunovaccine’s original business model focused on out-licensing: finding companies with vaccines that need improvement and out-licensing its technology to do that. But “immunocontraception is very difficult commercially,” mansour said. so, in 2004, the company started a collaboration with Csl ltd., which later became pfizer inc.’s animal health, then Zoetis inc. Csl was interested in single-dose veterinary vaccines to address the compliance problems in the industry. “ours was one of the few single-dose vaccine technologies they believed in,” mansour said.

in 2008, with studies proving the technology a success, pfizer exclusively in-licensed the platform for cattle applications, a deal that brought immunovaccine $1.8 million plus the promise of future milestone payments and royalties.

While that helped finance the company to a degree, the company was was realizing that it really wanted to focus on the human health care market, not the veterinary market.

The challenge its executives faced was that although the technology looked great in animal studies, to move it into human application, the company needed to work out the manufacturing. so, starting in 2005, it began developing a manufacturing process that’s implementable in a Gmp environment, that’s fully scalable and can demonstrate the commercial potential.

“it might work great, but if you can’t manufacture and produce it for human use, what’s the point?” at the same time the company was investing in process development, it started changing its business model from a pure out-licensing model to a combination model, still out-licensing but also developing its own products.

The company liked the idea of cancer vaccines but wasn’t sure the technology would be good for that application. around 2006 or 2007, the firm tested it in animal models and saw “some pretty dramatic results compared to what was out there and being published,” mansour said. “That’s when we realized we had something that had a shot at enabling cancer vaccines.”

it was then immunovaccine began seeking targets, antigens and even other companies that it could bring in-house. By 2008, it had found a set of cancer antigens that fit the criteria: seven antigens discovered by doylestown, pa.-based immunotope inc., which was discovering cancer antigens using the same technology as Germany’s immatics Biotechnologies Gmbh (a company that recently signed a deal with roche aG for its discovery platform). Based on the confidence in the discovery and validation process behind those antigens, immunovaccine exclusively in-licensed them. (see BioWorld Today, Nov. 14, 2013.)

immunovaccine quickly put the antigens in depovax to create its first cancer vaccine, dpx-0907. in about a year the company conducted a phase i in about 23 prostate cancer patients. While the firm were running the trial, execs started to connect with merck kGaa, which had a cancer vaccines focus on the target survivin. merck was losing interest in the program, which was making an unimpressive showing in a phase i, mansour said. “They had good antigens, but they weren’t formulated the right way. They didn’t have an adjuvanted delivery platform for it.”

immunovaccine ended up in-licensing the antigens on an exclusive worldwide basis to create its second vaccine, dpx-survivac. it quickly took the program into a phase i trial focused on ovarian cancer. “That’s when our thinking around immune therapies began to evolve and mature,” mansour said.

Now the company is focused not just on having the right targets and adjuvanting them properly, but also “really thinking about the therapeutic area we’re going into and how a cancer vaccine fits.”

ThroUGh The raNks

since its founding in 2002, when a three-person team spun the company out from halifax’s dalhousie University, immunovaccine has grown to a team of 20 employees today. When mansour talks about it, he speaks easily, fueled by an intimate knowledge of the company’s ascent since he first joined as a staff scientist more than 12 years ago. since then, he’s served as the company’s chief operating officer, chief scientific officer. Finally in June 2014, he took the next logical step to become Ceo. //



noVArtiS, AtLAS fund criSpr-cAS9 Venture inteLLiA in $15M SerieS ABy Michael Fitzhugh, Staff Writer

intellia Therapeutics inc., a new company formed to develop Crispr-Cas9 therapeutics for gene editing and repair, closed a $15 million series a round led by atlas venture and Novartis institutes for Biomedical research.

Built with genome engineering expertise from Berkeley, Calif.-based Caribou Biosciences inc., intellia joins a growing cast of companies leveraging the young technology, including Basel, switzerland-based Crispr Therapeutics aG and Cambridge, mass.-based editas medicine inc. (see BioWorld Today, april 25, 2014.)

The Cambridge, mass.-based company will initially focus on ex vivo applications, removing cells collected from blood or bone marrow, modifying them to correct disease-causing genes, and putting them back in play for therapeutic benefit. later, it plans to turn its attention to in vivo applications in ophthalmic, central nervous system, muscle, liver and anti-infective areas.

intellia’s Ceo and founder, Nessan Bermingham, told BioWorld Today that the company will seek to differentiate itself from others in the nascent space first by leveraging the basic research capabilities of partner – and now equity investor – Caribou to further devolop the Crispr-Cas9 technology. in addition, it has developed teams to focus separately on building up its capabilities in the basic science of Crispr-Cas9, delivery and specific therapeutic applications.

Though it got a running start before promoting its launch and series a in November 2014, the company is starting out with an all-star management line-up, including atlas venture partner Bermingham, who founded ascelegen Therapeutics inc. and Tal medical inc. during a break from atlas; and industry veterans such as the former Novartis institutes for Biomedical research executive director serving as chief technology officer and former abbot laboratories head of pharma r&d John leonard serving as chief medical officer.

“From the minute of the company’s inception, we have the full spectrum of capability and thinking as we start to move the company toward the clinic and think about all the key challenges that we’re likely to face,” said Bermingham.

a TeChNoloGY For repair

Crispr/Cas, named as one of the top 10 breakthroughs of

2013 by Science, has been heralded as a genome-editing system that is simpler than zinc finger technology. it harnesses the body’s natural dNa repair machinery to enable the repair, knockout or replacement of specific genes in the human genome, an approach that informed its naming, Bermingham said. (see BioWorld Today, dec. 20, 2013.)

intellia is derived from the Greek word “entelia,” a situation of absolute excellence, without any faults. “We’re going at the source of disease itself, seeking to repair the genome to its natural state, to a place where it doesn’t have any faults driving toward a disease phenotype.”

The Crispr-Cas9 approach leverages an ability developed by bacteria to fight off viruses that bind to them. over time, bacteria developed what are essentially very targeted scissors that can effectively cut nucleic acids, preventing the virus from replicating while leaving the bacteria prepared to target the same virus should it come in contact with it in the future. (see BioWorld Today, sept. 25, 2014.)

since 2012, when scientists began to more fully grasp the mechanism’s workings and how to co-opt it for therapeutic use, interest in its application has only grown.

For intellia, the exploration dates back about two years, when Bermingham and others at atlas began looking at a variety of technologies, seeking out those that could serve as foundational platforms for establishing a company. The Crispr-Cas9 technology stood out, he said.

The attraction of establishing a company with Caribou, founded out of the lab of Crispr research pioneer Jennifer doudna and led by Crispr expert rachel haurwitz, quickly became clear, he said. With a sub-$1 million seed investment, atlas began to explore early opportunities around licensing, recruit consultants and explore ip, all to incubate the opportunity to a point where it was ready to attract a strong management team.

doudna, a co-founder of editas and former member of its scientific advisory board, recently won the Breakthrough prizes in life sciences together with emmanuelle Charpentier, an advisor to the company.

The initial explorations led to talks with Caribou and Novartis and the decisions by both to back intellia.

Before it moves to the clinic, intellia will have to work through


at least one big challenge on the regulatory side: Crispr-Cas9 is a new therapeutic modality, so it will need to talk with regulators to understand the data package that they’ll require to support an investigational new drug application filing. That said, it certainly wouldn’t be the first gene-editing technology to move into the clinic. Both zinc finger and gene therapy

technologies have gone before it.

The company is gearing up to have 25 to 30 employees by the end of 2015. it just moved into a 15,000 square foot facility in Cambridge and is actively recruiting, Bermingham said. //



StArt-up keSioS LAuncheS with $9.2M, pLAn to tArget nf-κB pAthwAy in cAncerBy Nuala Moran, Staff Writer

loNdoN – seventeen years of research into the intricacies of the transcription factor NF-κB (nuclear factor kappa-light-chain enhancer of activated B-cells) has culminated in the formation of kesios ltd., which has £5.75 million (Us$9.2 million) initial funding to deliver human data validating a highly specific cancer target on the NF-κB pathway.

it has been known since the 1990s that NF-κB inactivates programmed cell death mechanisms in cancer cells. But the wider roles NF-κB plays in healthy cells in immune and stress response systems meant attempts to inhibit it caused serious side effects.

Guido Franzoso, of the department of medicine at imperial College london, the scientist behind kesios, has invested many years in the search for target genes downstream in the NF-κB pathway that are responsible for its role in preventing apoptosis in cancer cells.

others have since joined the search and adopted the same approach to hunting for specific targets on other disease pathways. “When we started to look for downstream genes, we were the only ones talking about it,” Franzoso said. “The principle may seem obvious now, and it may look trivial, but it isn’t,” he told BioWorld Today.

“The beauty of the pathway is that it mediates [dNa transcription] using different genes, depending on the function. You need to understand it in depth,” Franzoso said.

Using cells from patients with multiple myeloma, Franzoso and his colleagues identified a protein complex, Gadd45β/mkk7, that plays a critical role in blocking apoptosis. They screened more than 20,000 compounds to find one that disrupted the complex, with further optimization producing the lead product, dTp3.

Franzoso said the peptide is highly selective in its effect. “in preclinical testing in mice, rats and dogs, it is as good as it comes. We have not found any serious toxicity, despite exposure to efficacious doses,” he said.

kesios has been awarded a £3.9 million Uk government grant, which will enable it to take dTp3 into a clinical trial in multiple myeloma in 2015.

separately, the technology transfer arm of imperial College, imperial innovations plc, has invested £1.8 million to seed the commercial foundations of kesios. That has enabled the company to bring in seasoned biotech executive alain maiore, founding partner of the €140 million (Us$177 million) kurma Biofund, as Ceo.

in addition to delivering clinical data in multiple myeloma, Franzoso now wants to assess in which other cancer indications dTp3 is relevant, and also see if it could be applied to treating inflammatory diseases.

The details were published on oct. 13, 2014, in Cancer Cell in a paper, titled “Cancer-selective targeting of the NF-κB survival pathway with Gadd45β/mkk7 inhibitors.” The paper describes the interaction between the NF-κB-regulated anti-apoptotic factor, Gadd45β, and the JNk kinase, mkk7, in preventing programmed cell death in multiple myeloma.

The data show that dTp3, a d-tripeptide, disrupts the Gadd45β/mkk7complex, killing multiple myeloma cells without affecting normal cells. kesios said dTp3 has similar anticancer potency to the clinical standard, velcade (bortezomib, millennium: The Takeda oncology Co.), but shows a more than 100-fold higher cancer-cell specificity in vitro.

Franzoso said, “This is highly conceptual – it represents a new way to target a pathway which pharma has been trying to address for some time. The fact that NF-κB is needed by cancerous and by normal cells means that as of today, no inhibitors are on the market.”

kesios also has a companion diagnostics program in which it aims to select biomarkers to indicate likely responders to dTp3 and for assessing its pharmacological effect. in addition, the company intends to develop an oral formulation of the compound.

While the formation of kesios is in some senses the culmination of a long effort, it also opens a new chapter of research. “You can plan and think about it as much as you want. But i couldn’t foresee getting to this point 15 years ago,” Franzoso said. “i hope in the future the research will make an important impact on health.” //



kindex Brewing diABeteS drug with hopS-deriVed huMuLone; $5M SerieS ABy Randy Osborne, Staff Writer

it’s only $5 million in series a funding, but enough to move start-up kindex pharmaceuticals inc. into a phase ii trial with lead compound kdT 501, a hops-derived candidate for type 2 diabetes that regulates the cross-talk between macrophages and adipocytes to influence the complex of proteins that regulate inflammation, also known as the inflammasome.

among the investors in seattle-based kindex is the venture capital firm polaris partners, and at the helm of the company is Jeffrey Bland. some may recognize the Ceo’s name from metagenics inc., of aliso viejo, Calif., where he was president and chief scientific officer. That firm specializes in medical foods. Bland also founded the not-for-profit personalized lifestyle medicine institute and healthcomm international inc., of Gig harbor, Wash. metagenics and healthcomm merged in 2000.

kindex’s work focuses on humulone, an alpha acid in hops. Brewers of beer have long known about alpha acids, which lend bitterness to beer and which make up a group that also includes cohumulone, regarded as particularly harsh, as well as the less-studied adhumulone. Cohumulone also gets credit for providing the foamy head on beer, by way of cross-linked proteins. But the star of the group – and the focus of research at kindex – is humulone, said by brewers to provide the pleasant bite to beers such as india pale ale. The name for the chemical comes from the plant species of hops from which oils are extracted, Humulus lupulus (a member of the family Cannabinaceae, which also contains another news-making medicine: cannabis).

research on humulone has been published in the likes of PLoS One, in which scientists detailed work showing that kdT 501 normalized glucose metabolism and body weight in rodent

models of diabetes, and Angewandte Chemie International Edition, where a team at the University of Washington in seattle got a kindex-funded better look at humulone side chains by deploying x-ray crystallography. The crystallography work was important because it discovered that the structure of the humulone molecule – how its five carbon atoms are placed – has a bearing on whether it will show efficacy against disease. kdT 501 apparently influences how cells differentiate in brown fat, and kindex is exploring the idea that its approach may not only improve glucose homeostasis, but also modify total cholesterol and triglycerides and – “beer gut” to the contrary – reduce weight gain.

The compound is still preclinical as an anti-inflammatory agent. Behind kdT 501 are kdT 600 and others, still at the discovery and candidate selection stage.

humulone research is not new. a study in 2012 at sapporo medical University in sapporo, Japan, cited promise with the chemical against respiratory syncytial virus. some investigators have examined the possibility that it could protect against osteoporosis, too.

kindex plans to push its work farther. among the scientific advisors for the company is paul schimmel, co-founder or co-founding director of biotech firms such as alkermes inc., alnylam pharmaceuticals inc., sirtris pharmaceuticals inc., Cubist pharmaceuticals inc., momenta pharmaceuticals inc. and repligen Corp.

With the series a, kindex pharmaceuticals was formed by the reorganization of kindex Therapeutics llC, the company said. //



Beyond chiLd’S pLAy: LegocheM’S pLAtforM to expedite drug diScoVeryBy Marie Powers, Staff Writer

legochem Biosciences inc. (lCB) boasts an intuitive name, hearkening to the use of lego-like scaffolds to enable the discovery of drug candidates. But the platform is more than a toy for scientists. The daejeon, korea-based biopharma, which completed its initial public offering (ipo) in 2013 on the korean exchange’s kosdaQ, has advanced a pipeline of six drug candidates across multiple indications since the company’s formation in 2006 and now has multiple partnered candidates in human proof-of-concept studies.

The company’s legochemistry, or fragment-based drug discovery platform, starts with a variety of “building blocks” developed by lCB to construct antibody-drug conjugates (adCs) and protein-drug conjugates (pdCs) that are assembled using the company’s linker technology, explained James Jungkue lee, lCB’s business development advisor. To date, lCB has developed more than 20 of the lego block-like scaffolds, which are used to discover drug candidates faster and more efficiently.

lCB then applies a so-called “gate decision system” – an internal guideline for examining each step of drug candidate discovery and development – to determine whether to add a product from its legochemistry platform to its compound libraries. The process shortens hit-to-candidate timetables, offering industry partners a potential time and cost advantage.

The company’s second chemistry platform technology, Conjuall, provides another elegant differentiator. in contrast to conventional adC technology, which is designed for antibodies, Conjuall enables lCB to conjugate an assortment of payloads to all types of proteins, no matter what their size or configuration, lee said. The resulting compounds provide better tissue penetration and easier manufacturing while yielding improved potency and longer half-lives than comparator molecules, lee explained.

“our conjugation chemistry is very site-specific, very homogeneous, very potent and very clean,” lee told BioWorld Today.

The company’s adCs and pdCs are constructed using a simple chemistry process that results in well-defined CmC parameters. The conjugates are assembled in a process that essentially replicates lego construction, using a protein to serve as the

targeting module, a peptide to serve as a functioning module and a cleavable or noncleavable linker module.

lCB demonstrated the advantages of its technology by comparing in vivo findings from lCB14, an adC the company is developing in multiple oncology indications, with adC technology developed by Waltham, mass.-based immunogen inc., whose platform has been used with the blockbuster antibody herceptin (trastuzumab, roche aG). preclinical studies in mouse and rat plasma showed that less than 1 percent of conjugated payloads were released within seven days from adCs using lCB’s Triazole linker. in contrast, studies in mouse plasma showed that 70 percent of conjugated payloads were released within two hours from adCs using the val-Cit-paBC linker developed by seattle Genetics. lee suggested more stable linker technology could be the key differentiator in building a herceptin adC that offers improved plasma stability, translating to drugs with better efficacy and safety.

“after examining our data, we are now considering building a herceptin adC,” he said.

‘We WaNT To pUsh oUr CompoUNds To phase i or ii’ aloNe

lCB’s management team honed its expertise largely at giant lG life sciences, one of korea’s leading pharmaceutical firms. prior to founding lCB, Ceo Yong Zu kim served for two decades as director of lG’s New drug research Center, where he was instrumental in the discovery of the oral quinolone Factive (gemifloxacin), which was the first Fda-approved drug that originated in korea. lG originally licensed the drug to smith-klinebeecham plc, now part of Glaxosmithkline plc, of london, which failed to gain approval and returned the drug to the korean company. lG then licensed the drug to privately held Genesoft pharmaceuticals inc., of south san Francisco, which moved Factive to approval in 2003 in mild to moderate community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. (see BioWorld Today, april 21, 2003.)

While at lG, kim also was involved in joint research, co-development and out-licensing deals with global pharmas. he formed lCB with a number of lG colleagues, including Tae kyo park, who serves as chief technology officer, and sung ho Woo, vice president and director of biology.


some of the lessons learned at lG were applied at lCB.

“With small molecules, we want to push our compounds to phase i or ii by ourselves, but we don’t rule out earlier collaborations,” lee said. in biologics, however, the company seeks quicker deals, typically for rights outside korea.

lCB’s lead asset, lCB02-0133, is an oral factor xa antagonist partnered with korea’s Green Cross Corp. to prevent and treat thrombosis. in 2013, Green Cross completed a randomized, double-blind, placebo-controlled, single-ascending-dose phase i study in the U.s. that enrolled approximately 48 healthy subjects. The drug was well tolerated and was detected in blood plasma proportionally across a dose range of 2.5 mg to 80 mg per patient, according to Cortellis Clinical Trials intelligence (CTi). The drug also showed a clean safety profile.

in preclinical studies, the compound’s efficacy was equivalent to that of low molecular weight heparin, with a lower frequency of bleeding than approved products eliquis (apixaban, Bristol-myers squibb Co./pfizer inc.) and xarelto (rivaroxaban, Johnson & Johnson). lCB02-0133 is preparing to move into phase ii trials this year, lee said.

lCB also has lCB01-0371, an oral oxazolidinone targeting antibiotic-resistant bacterial infections, such as methicillin-resistant Staphylococcus aureus. partnered with korea’s dream pharma for the korean market, the drug completed a randomized, double-blind, placebo-controlled, single-dose phase i study in 70 healthy volunteers and has advanced into a multiple dose-escalation study, according to Cortellis CTi. lCB01-0371 demonstrated noninferiority or superiority to linezolid and improved safety – especially with respect to myelosuppression – in preclinical studies. The compound offers the advantages of twice-daily oral dosing and intravenous/oral switchability, according to lCB, which expects to advance it into additional human studies this year.

The company has a second antibacterial, lCB10-0200, targeting multidrug-resistant pathogens, including enterobacters, Pseudomonas aeruginosa and Acinecobacter baumannii. The compound formerly was partnered with

london-based astrazeneca plc, which returned the asset as part of an internal re-prioritization, so lCB is investing its own resources to advance it to the investigational new drug application stage.

in addition, lCB has three oncology assets. paris-based sanofi sa has an option deal on lCB17, a novel small molecule for the undisclosed oncology target selected by the pharma, lee said. sanofi is funding research until candidate selection. if the option is exercised, which could occur next year, the pharma will finance the drug’s additional development, with lCB entitled to pre-structured up-front and milestone payments as well as royalties.

lCB14 is an adC partnered with Green Cross in multiple oncology projects, while lCB19, a pdC with an alternative scaffold developed using Conjuall, is in preclinical proof-of-concept studies. The company files global patents on its technology and drug candidates, lee said.

in addition to its biopharma partnerships, lCB has inked joint research projects with academic institutions in the U.s., korea and europe.

prior to its ipo, lCB completed multiple financing rounds, beginning with an initial raise of 4.5 billion won (Us$4.4 million) in 2007 from korean venture capitalists. The company also has a number of research grants from the korean government, and its pharma collaborations generate cash, giving the company an operating runway of more than three years, lee said.

With a market cap of approximately $150 million and 50 employees, lCB envisions itself one day becoming a world-class drug development company. after spending its formative years building its pipeline, the company now is focused on sustaining growth by discovering a handful of drug candidates, out-licensing multiple assets and conducting at least one clinical trial each year. and it all started with chemistry modeled after interlocking plastic toys. //

– BioWorld Today, sept. 2, 2014


LongeVity’S hyBridtideS not juSt ‘Me-too’ peptideSBy Marie Powers, Staff Writer

Based on its name, longevity Biotech inc. might be mistaken for a company seeking a prescription for aging. in a way, that’s true, admitted scott shandler, president and Ceo, since the company is building a platform designed to help patients to live longer and healthier lives. But the name also is a bit of a double entendre, alluding to the company’s technical ability to improve the half-life of molecules of interest.

Just 3 years old, longevity is a newco in the strict sense of the word, but its technology evolved over more than two decades in the laboratory of samuel Gellman, professor of chemistry at the University of Wisconsin-madison and a company co-founder. much of Gellman’s work focuses on foldamers, or “peptidomimetics,” which are unnatural oligomers that adopt protein-like conformations.

in 2007, one of Gellman’s 200-odd peer-reviewed papers became the basis for the company’s formation. in the work, published in Chembiochem, Gellman explained how to bring natural and non-natural amino acids together in a certain way to preserve or even enhance function for a unique class of peptides, which longevity calls hybridtides, while dramatically improving – by “orders of magnitude,” shandler said – their structure and metabolic stability.

The company isn’t alone in that approach. shandler cited the discovery platform at peptidream inc., of Tokyo, as one example among companies developing competing mechanisms to stabilize peptides.

The distinction between longevity’s hybridtides and the peptide platforms of other companies is that “we stabilize our compounds from the inside out,” shandler explained. “That concept is a major advance in the field. although a number of companies are competing with us across different technology approaches, we’re the only company in this arena focused on stabilizing the interior of the molecule.”

The hybridtide scaffold enables philadelphia-based longevity to assemble compounds that “rebalance” the body’s natural circuits, according to shandler. The company is targeting cell surface receptors that already are validated as key disease pathways, with candidates in lead optimization across metabolic, cardiovascular, oncology and antiviral programs.

The hybridtide molecules are capable of modulating a variety

of pathways, shandler pointed out, with the potential to achieve specific therapeutic outcomes using G protein-coupled receptors (GpCrs), which remain complex and challenging despite several decades of pharmaceutical interest. From a commercial perspective, the company is seeking to offer improved mechanisms together with improved stability with the goal of enhancing clinical outcomes.

“We’re not another ‘me-too’ or another slightly improved widget,” shandler told BioWorld Today. “We are not limited by secondary structure, intracellular or extracellular programming. We’re focused on what we think are the lower-hanging fruit – looking at GpCrs primarily – but the technology so far has proven robust across a variety of different target classes.”

‘have oUr Cake aNd eaT iT, Too’

longevity holds licenses on three patent families from the University of Wisconsin and has filed additional intellectual property (ip) developed internally. although the company’s pipeline is still in the preclinical stage, the ability of its technology to lower digestive resistance and improve molecular half-life has turned heads among potential partners, and shandler had a full dance card in January 2014 when the company presented data in san Francisco at Biotech showcase 2014, held in conjunction with the J.p. morgan healthcare Conference.

“as a platform company, we have internal assets that are under development, and we’ve chosen those rather carefully,” shandler said. “one of the goals of Biotech showcase was to extend the platform technology to potential partners, worldwide.” longevity’s ip offers collaborators the potential to improve the structural and metabolic stability of drug candidates “across any number of different programs, preclinical or otherwise,” he said, leading to an improved commercial profile.

The platform appeals to some potential partners more than a single molecule, he acknowledged, adding, “We’re in discussions with a number of large pharmas about applying the hybridtide scaffold to their internal programs.”

in particular, preliminary data suggest the technology’s metabolic stability, demonstrated “many times over across programs,” is beginning to lead to oral delivery. “That is


obviously an attractive profile enhancement for any peptide program,” shandler pointed out.

observing that “everything in biotech or pharma gets partnered at some point,” shandler said the company also hopes to attract suitors for its internal assets after the programs demonstrate preclinical proof of concept (poC). longevity’s metabolic program, already in preclinical studies, garnered strong interest at Biotech showcase.

“The mechanisms are exciting, and the compounds are unique,” he said. “on the asset side, the ability for us to get to an appropriately de-risked poC is the ultimate goal from a partnering perspective.”

shandler declined to cite the amount of money raised by longevity or the runway provided by those funds but said a

mixture of “grants, angels and funds” is propelling several programs toward the clinic. Thus, the company will be compelled in the near future to seek additional capital, either through a deal or a financing.

“Those two competing efforts are running right now, and i’m not sure which option we’ll have the luxury of entertaining,” he said.

With fewer than 10 full-time equivalent employees and a stable of academic and clinical collaborators, shandler doesn’t expect longevity to become “the next pfizer or merck” anytime soon. “But i don’t expect us to become a shell company, either,” he quickly added. “Given our technology, i think there’s an opportunity for us to have our cake and eat it, too.” //



Lti tApS LySoSoMAL expertS, ModeL for pArkinSon’S workBy Jennifer Boggs, Managing Editor

if you’ve discovered a new therapeutic approach for rare and neurodegenerative diseases stemming from lysosomal biology and need help starting a company, you go to the experts.

That’s what lysosomal Therapeutics inc. (lTi) founder dimitri krainc did. krainc was at massachusetts General hospital (mGh) when he published work in a 2011 issue of Cell identifying the mechanism of a previously reported link between rare lysosomal storage disorder Gaucher disease and the more common parkinson’s disease. so he approached biotech heavyweight henri Termeer, who for more than 25 years helmed Genzyme Corp., the company that launched Cerezyme (imiglucerase) in 1994 as the first commercial enzyme replacement therapy (erT) for type 1 Gaucher disease.

Gaucher is caused by a defect in the GBa1 gene, which directs production of glucocerebrosidase, an enzyme that breaks down lipids. Without that enzyme, those lipids – glucocerebrosides – accumulate in the cells of organs, causing increasing damage to those organs. The disease affects an estimated 10,000 people worldwide, and erTs like Cerezyme have been generally successful in treating people with type 1 disease.

But the advent of erTs, which allow patients to live longer, has highlighted the increased risk of those patients in developing parkinson’s disease. in fact, Gaucher patients are at a 20-fold higher risk of being diagnosed with the neurodegenerative disorder compared to the overall population, explained lTi Ceo kees Been.

krainc’s work at mGh discovered why that is. he found that mutations in glucocerebrosidase (GCase), the same enzyme implicated in Gaucher disease, are also the biggest genetic risk factors for parkinson’s. patients who have mutations in one copy of the GBa1 gene also had high levels of glucocerebroside and those elevated lipid levels bumped up levels of synuclein, which forms the toxic neuronal deposits characteristic of parkinson’s.

and as the synuclein levels rose, GCase levels decreased, again increasing lipid levels and maintaining a vicious cycle. krainc discovered, however, that boosting GCase activity could reduce the synuclein levels.

“it’s a different approach” from the traditional erTs, Been said. “This is a small molecule that goes into the brain” to enhance GCase activity.

The idea was compelling enough to attract Termeer, who has continued serving on several boards, including the board at mGh, since Cambridge, mass-based Genzyme was acquired by sanofi in early 2011. Toward the end of that year, he helped krainc found lTi, even bringing along two other former Genzyme execs, Bob Carpenter and peter Wirth, Been said.

The founders secured the intellectual property and licensed rights to the small-molecule GCase activator from the National institutes of health before naming Been as Ceo in 2013. among Been’s first tasks was raising money, and lTi closed a $4.8 million seed round this week led by atlas venture, with participation from hatteras venture partners, lilly ventures, sanofi-Genzyme Bioventures, roche venture Fund, partners innovation Fund and angel investors including orion equity partners llC. That initial funding is expected to get the lead program from hit to lead status, and Been estimated that lTi is about three years from the clinic.

lYsosomal disorders as ‘model sYsTem’

once in the clinic, the company should be able to prove its approach fairly quickly. in fact, beyond the science itself, what “really attracted a lot of interest is the opportunity . . . to get into the clinic and establish early proof of concept,” Been told BioWorld Today.

lTi plans to move cautiously, however, mindful of the host of biopharma failures when it comes to translating approaches for tough neurodegenerative diseases into clinical success stories. in alzheimer’s disease, for instance, “we’ve seen how difficult it is to find anything close to being predictive.”

so lTi’s plan is to test its lead small molecule in Gaucher patients first. “We’ll edge our way into the clinic,” Been said, adding that lysosomal storage disorders will serve as the firm’s “model system.”

plus, there’s still a need in Gaucher, Been pointed out. erTs are limited to the type 1 subset of the disorder, but types 2 and 3 are neuronopathic, meaning patients in those subsets need treatments that can cross the blood-brain barrier. erTs can’t, but lTi’s small-molecule program is designed to do just that.

once the company has established proof of concept in Gaucher patients, it will then look to test the approach in parkinson’s patients who have GBa1 mutations. But Been said boosting GCase levels should be effective in all parkinson’s patients,


whether they have the GBa mutations or not. he explained that recent studies have shown that patients with idiopathic parkinson’s – i.e. those with two functioning genes – still have compromised levels of GCase.

in that regard, “we don’t care about cause and effect,” he added. “We know that somehow activating the enzyme lowers the risk of parkinson’s.”

The Cambridge, mass.-based company’s initial program builds on discoveries that link Gaucher with parkinson’s disease, but its approach could extend to other lysosomal enzyme deficiencies and neurodegenerative disorders. specific programs haven’t been disclosed, “but we clearly

intend to expand,” Been said.

research also continues at Northwestern University, where krainc now serves as Ward professor and chairman of the department of neurology, working with Joseph mazzulli, assistant professor of neurology.

Joining Been on the company’s board are new members Bruce Booth, of atlas partners; Clay Thorp, of hatteras; steve hall, of lilly ventures; Bernard davitian, of sanofi-Genzyme Bioventures; and Carole Nuechterlein, of roche venture Fund. atlas’ Nessan Bermingham and partners innovation Fund’s reza halse were appointed as board observers. //



LuMoS Seeking to Light the wAy with drug for uLtrA-rAre ctdBy Marie Powers, Staff Writer

The ultra-rare disease creatine transporter deficiency (CTd) wreaks havoc on its patient population of young boys. The x-linked autism spectrum disorder prevents the transport of creatine – a nitrogenous organic acid that serves as fuel for the body’s cells – into the brain, causing patients to suffer seizures, speech delay, behavioral abnormalities and severe cognitive impairment.

after keeping its in-licensed technology under wraps for several years, lumos pharma inc. is seeking to “turn the light on” for these patients with a compound that corrects the inborn error of metabolism, caused by a defect in the creatine transporter slC6a8 gene, by providing a mechanism to deliver creatine into the brain.

lumos – named for the wand-lighting charm in the blockbuster Harry Potter books – was founded by serial entrepreneur rick hawkins, who began his career at Johnson & Johnson (J&J), where he was part of the team that developed pimozide to treat Tourette’s syndrome. The process served as a lesson of a different sort for hawkins when it became a test case leading to the passage of the orphan drug act of 1983.

“This early experience sensitized me to the orphan space potential,” he told BioWorld Today.

after a decade, hawkins left J&J and founded the contract research organization pharmaco dynamics research inc. When that company was sold in 1991 to applied Bioscience international inc., he formed innovations in drug development, or id2, a pharmaceutical and biotechnology research management firm. in turn, that role led to the creation of a limited partnership that morphed into privately held sensus drug development Corp., of austin, Texas, which hawkins co-founded and chaired. sensus developed the growth hormone antagonist somavert (pegvisomant) to treat acromegaly. somavert subsequently was approved in the U.s., europe and Japan, and sensus was acquired by pharmacia & Upjohn, now part of New York-based pfizer inc. (see BioWorld Today, march 8, 1993, and march 8, 2001.)

hawkins, who is a director of sciclone pharmaceuticals inc. and Cytori Therapeutics inc., was pursuing other biotech opportunities when a friend pointed him toward a drug

that had been “sitting on a shelf” for some 15 years at a big pharma, which hawkins declined to name. researchers at the University of Cincinnati had conducted promising early studies of the compound in CTd, showing in knockout mice that the drug crossed the blood-brain barrier, was phosphorylated and dephosphorylated by both mitochondrial and cytosolic creatine kinases and substantially improved cognitive function in spatial learning, memory and object recognition tests. impressed with the data, hawkins executed a two-way license, acquiring all rights to the drug, dubbed lUm-001, and forming austin, Texas-based lumos.

a small molecule with orphan drug designation from the Fda, lUm-001 is being repurposed in CTd after failing to show efficacy in a solid tumor indication. The compound was previously studied in 50 patients under an investigational new drug (iNd) application, using an intravenous formulation. lumos filed new use patents in early 2012 and is advancing the compound as an oral medication.

in 2011, the company was selected for a drug development collaboration with scientists at the National institutes of health’s (Nih) Therapeutics for rare and Neglected diseases program – a partnership hawkins credited with dramatically advancing lUm-001.

“Their work over the last two and a half years was instrumental in getting us here and putting us in a position to attract a top tier of venture firms,” he said.

in February 2014, lumos raised $14 million in a series a financing to support preclinical and clinical development of lUm-001. The round was co-led by sante ventures and New enterprise associates. in addition to the Nih partnership, the company is preparing to consummate several nondilutive grants in europe.

over the next 12 months, lumos plans to complete toxicology studies, file a new iNd application and begin phase i studies in healthy volunteers, following quickly with a CTd patient cohort. depending on early findings, the company could seek Fda breakthrough therapy designation for lUm-001.

“it’s a small molecule, so we’re not encumbered with the problems of making a large protein,” hawkins said, noting the company can produce sufficient batches of the drug quickly enough for toxicology and early human studies. lUm-


001 previously demonstrated a strong safety profile, and the company plans to incorporate much of the existing safety data into its filings in CTd.

in the meantime, the Nih plans to conduct a comprehensive natural history study to characterize CTd further and to establish a patient registry that could aid in identifying and recruiting patients, who traditionally were under- or misdiagnosed, according to hawkins.

“We’re very excited about this compound,” he said, observing that CTd is the largest autism spectrum disorder after Fragile x syndrome. “What we provide with lUm-001 is a very flat form of creatine that not only gets across the blood-brain barrier without the need for a transporter but also gets into the

neurons and gets phosphorylated just like creatine.”

The compound could have more applications, and lumos is in the process of filing additional patents covering other indications in the orphan space.

For now, CTd is the singular focus of the company, which has two employees and plans to add several more over the coming weeks. long term, lumos “will remain opportunistic,” hawkins said. “if it makes sense to partner, that’s the direction we’ll go. otherwise, if we continue to get the positive results we’ve seen so far, i don’t think it will be difficult for us to go back to the capital markets and raise additional money to do a larger phase iii program.” //



18-Month-oLd MABSpAce AiMS to fASt trAck foBS in chinA for cAncer, ckdBy Shannon Ellis, Staff Writer

shaNGhai – For xueming Qian, Ceo and founder of mabspace Co. ltd., an antibody discovery engine based in suzhou, the writing was on the wall. While pharma was de-emphasizing early stage research and putting it into the hands of biotechs in the U.s., the economy in China had hit an inflection point, the momentum was building. China was the place to be.

Qian admits his timing might be considered a bit late to the party. he came here four years ago, lagging behind the earlier wave of returnees. and that was only after a year of coaxing, before he was able to leave his post at amgen inc., in Thousand oaks, Calif., where he was working on its second fully human antibody, to come work for biotech start-up shenogen pharma Group in Beijing. (see BioWorld Today, may 8, 2014.)

after 20 years in the U.s., where he spent several years during his post doc working on molecular genetics, before moving on to inflammation and immunology and then metabolic disorders, Qian found he was “kind of detached” from the country where he was born. his time at shenogen gave him the chance “to get to know China, establish the right network and think about the best business model.

“i spent almost three years at shenogen, they are doing very innovative things. most of the senior team is returnees; there is a common language, values and culture. i really enjoyed that time – i enjoyed it because i could also truly make a contribution.”

it is that sense of making a difference that drives Qian, who admits he could have started up his antibody discovery company anywhere, but ultimately decided to do it China. “The main reason i came back is you need to be in the battlefield,” he said. “You need to be in the center of the activity to make an impact on the place where you want to contribute to the change.”

FasT FolloW-oN aNTiBodies

mabspace was founded in suzhou 18 months ago, to discover and develop fast follow-on antibody therapeutics for cancer and first-in-class antibodies for chronic kidney disease, two areas of high unmet need in China.

Using a proprietary, immune tolerance breaking technology that enables antibody generation against conserved epitopes in protein antigens using hybridoma, the company has

its own pipeline, as well as works with local and global pharmaceuticals.

The resulting antibodies generated with this technology have diverse epitope coverage, and are cross-reactive with rodent antigen. according to Qian, the company’s competitive advantage rests on antibodies that can deliver shorter development times and better patent protection, the key to fast follow-on therapeutic development. That is because the technology enables the isolation of the best therapeutic and diagnostic antibodies with pharmacology and toxicology evaluation in rodents that is well suited to ip protection.

“China has a lot of people doing process development, they are very good,” said Qian. “There is a lot of money invested in building facilities to make proteins for antibodies, but there are not many people with sophisticated skills to develop or discover novel antibodies. That is the niche we are targeting, the upstream part of the value chain. We discover ip protected antibodies with differentiated targets then partner them with other parties or develop ourselves for select products.”

iN The pipeliNe

The company is working on several programs, three of which have been announced publicly. msB-001 is a vGeFr2 best-in-class antibody that targets the microenvironment for the treatment of gastric cancer. msB-002 is a follow-on anti-pdl-1 immunotherapy antibody designed to treat lung cancer and other tumor types with high mutation rate and thus immunogenicity. For both of them, the company is looking to co-develop for the China market and partner ex-China rights.

For mBs-003, a first-in-class antibody for tissue fibrosis related to chronic kidney disease, the company is working with an american-based pharma for ex-China rights, with global ip already filed.

in November 2013, mabspace signed a supply and licensing agreement with Cro shangpharma Corp. it has projects with both local and major international pharmas on therapeutic antibody development or surrogate antibody generation.

The deal tied mabspace exclusively to shangpharma. The company said that mabspace’s antibody discovery technology would help it “to achieve higher growth and attract more collaboration partners in the biologics space.”


FirsT There’s sUrvival

While Qian’s long-term goal is to advance innovative antibody-based therapeutics to provide effective medicine for Chinese patients, like many companies a year after formation, the first order of business is survival.

seed funding came from angel investors in the single-digit millions. With the funding, the company has been able to set up an 18-person team and establish a fully integrated facility for antibody discovery, and a spF grade animal facility. The first and only such facility in the suzhou Biobay industrial park, where they are located just minutes from other leaders in the field, such as China’s innovent or Cold harbor springs Chinese laboratory. he said from the outset the focus has been on quality and

providing a global standard for their partners. “We want to be on the same standard.”

The next step will be to establish a reliable revenue generating business. Qian is looking to do at least one to two deals a year for important targets, either partnering with global pharma on first-in-class drugs or by out-licensing and collaboration.

“While we are talking with vCs about funding to expedite product development,” said Qian, “we have established mechanisms to survive, and continue to contribute to innovation, to be a part of this exciting antibody development in China, whether or not we obtain vC support.” //



uk’S MAgnuS LAuncheS with $25M round, ‘reAL underStAnding of diSeASe’By Nuala Moran, Staff Writer

loNdoN – one of the academic lynchpins of Uk biotech, John martin, has attracted £15.5 million (Us$24.9 million) in private equity for magnus life sciences ltd., a start-up shaped to overcome his frustrations at current shortcomings and gaps in the process of translating research from lab to bedside.

at the heart of the model is that as a University College london (UCl) spinout, magnus is based not in an incubator on the academic fringe, but embedded in the university’s Faculty of medical sciences.

second, magnus is not one company, but five, each with its own product and founding scientist, who is a shareholder in the business and acts as the research/clinical lead.

although independent, the magnus family of companies will share resources in a central core, including project management, business development and commercialization, and structure-based drug design.

The five companies cover indications ranging from diabetes and melanoma to fetal growth restriction, reperfusion injury and cardiovascular disease. The unifying factor is martin’s own academic specialty as chair of cardiovascular medicine at UCl and adjunct professor at Yale University, with all the products centered on an understanding of blood flow.

“The company is built on a scientific platform, not a technology platform,” said david Campbell, Ceo. “What we’ve got is biology; we have real understanding of disease,” he told BioWorld Today. That is the key ingredient that many pharmaceutical companies lack, Campbell added.

The whole adds up to a unique model for european biotech, Campbell claims, with commercial development juxtaposed with university innovation. “The money will be spent at the coalface, by innovative scientists, but with a support network, access to the National health service, and also commercialization strength and vigor,” he said.

in addition to the £15.5 million of seed funding from an unnamed private equity group, two of the magnus programs

have grant funding of €11.5 million (Us$14.5 million) from the european Union’s Framework 7 r&d program.

some of magnus’ intellectual property, for example, relating to the use of gene therapy to increase production of vascular endothelial growth factor to promote extra blood flow to the placenta, as a treatment for fetal growth restriction, arises from martin’s previous company, ark Therapeutics plc. other ip comes from outside UCl.

martin, who will act as chief scientific officer of magnus, has long argued that the system for transforming academic science into new drugs has become dysfunctional, and that a new relationship is needed between universities, the pharmaceutical industry and the National health service. his vision is that patented inventions from universities are advanced to phase i trials in their associated university hospitals, increasing the value and the quality of programs before they are sold to pharma for further development.

putting projects through the early stages of commercialization in the context of a university gives a greater chance of success than feeding them into the bottom end of pharma’s pipeline or into a biotech spin-off, because of the close involvement of the discovery scientists and clinicians.

embedding magnus within UCl “combines the creativity of the university, the research potential of the Nhs and novel funding, in a powerful mix,” martin said.

all five magnus programs are currently preclinical. Campbell said each will be advanced into phase i within the scope of the initial funding, with two programs going into the clinic in 2015, one in 2016 and two in 2017. “We’ve spent a lot of time building the budget to make sure we are well funded,” Campbell said.

Beyond phase i, the magnus companies may continue to work on programs individually, or may look for partners, with Campbell saying he is now beginning to discuss the programs with possible collaborators. “We’ve got big connectivity, but we can also go back to the [founding] investor.” //



Mount tAM Biotech to expLore Buck inStitute coMpound in SLe By Marie Powers, Staff Writer

Nearly two years after the Buck institute for research on aging partnered with British firm Biotica Technology ltd. to explore diseases of aging through the creation of delos pharmaceuticals inc., a similar deal is afoot in the area of autoimmune disorders. This time, start-up mount Tam Biotechnologies, established by U.s. equity holdings, inked an exclusive global licensing and collaboration agreement with Buck to explore the mTor inhibitor, Tam-01, in systemic lupus erythematosus (sle). The deals, like the partners, have a shared history.

Buck’s primary area of research is “geroscience,” or the study of the connection between normal aging and chronic disease. The institute’s researchers work collaboratively to discover causes and potential treatments across a range of indications, including alzheimer’s and parkinson’s diseases, cancer, cardiovascular disease, osteoporosis, autoimmune diseases, macular degeneration, diabetes and stroke.

delos was launched in 2012 to focus on common pathways that are affected in aging and aging-related diseases. one of the company’s first targets was mammalian target of rapamycin, better known as mTor, which is among the signaling molecules that appear to play a role in diseases of aging. (see BioWorld Today, Nov. 6, 2012.)

delos licensed its rapamycin analogues from Biotica after they were discovered at the University of Cambridge, Uk, and the technology was expanded by Biotica to enable the production of novel, target-specific polyketides. Chemically, rapamycin is a polyketide – a class of compounds that includes statins and approved drugs in many other indications – but polyketides have been difficult to optimize. Biotica’s expertise in polyketide drugs enabled delos to advance compounds that are highly specific for pathways believed responsible for disease progression.

although the technologies at delos and mount Tam are complementary, “delos is focused on a different aspect of mTor,” explained stelios Tzannis, entrepreneur in residence at Buck and co-founder and Ceo of both companies. in contrast, the properties of Tam-01 and related compounds “are focused exclusively on the treatment of lupus and autoimmune disease.”

The assets at mount Tam – named for the iconic peak, mount Tamalpais, that is the highest point in Buck’s home base of marin County, Calif. – also are more advanced than those at delos, which specializes in early stage exploration and discovery.

“Wearing my other hat at Buck, we decided early on that we wanted to pursue the autoimmune assets in a different way that would enable them to move forward in development in an expeditious manner,” Tzannis said.

lead compound Tam-01 is positioned to start investigational new drug (iNd)-enabling studies in sle after completing discovery, optimization and pre-development activities, including preliminary scale-up. The family of autoimmune assets, which involve a particular undisclosed chemotype, are supported by an intellectual property portfolio consisting of more than 45 worldwide issued patents and applications, including composition of matter, manufacturing and therapeutic area applications, Tzannis said.

delos retains the rights to the remaining chemotypes from the technology originally licensed from Biotica, he added.

proCess avoids ‘GeTTiNG iNTo loNG r&d CYCles’

rapamycin has been around for decades, though it’s used mainly to prevent transplant rejection as the drug rapamune (sirolimus, pfizer inc.). its use in chronic illness has been limited mainly by a poor side effect profile, including glucose intolerance, insulin resistance, anemia and lipid dysregulation, Tzannis explained.

he described Tam-01 as a “balanced” mTor inhibitor specifically designed for lupus that maintains the efficacy of rapamycin, as demonstrated in multiple preclinical sle models, while reducing or eliminating its side effects. That balanced profile represents a huge differentiator from other rapamycin compounds, he said.

“This is a unique asset,” Tzannis told BioWorld Today. “We are very confident that it’s going to work in the clinic, in terms of efficacy. That’s one reason why it took us a little bit longer, at Buck, to try to find the right people to push this forward.”

Chester aldridge, a marin County native who serves as chairman and Ceo of U.s. equity holdings and chairman of


mount Tam Biotech, had followed the research at Buck for some years. as he watched the assets acquired from Biotica advance in the lab, he was impressed by the science underlying Tam-01 and the related compounds.

“i’m more interested in something i can take commercial rather than getting into long r&d cycles,” aldridge told BioWorld Today, voicing optimism about the progress of the science and its nearness to human trials.

mount Tam is raising a series a, with a goal of securing $6 million, which will allow the company to complete the iNd for Tam-01 in 18 months or less and begin a phase i study in humans, according to Tzannis. during that time, U.s. equity holdings will provide assistance with operational issues while Tzannis and the company’s leadership team focus on moving the pipeline forward.

With just three employees – all of them part-time – mount

Tam operates virtually from Buck, where it enjoys extensive access to labs, researchers and equipment. The company also is outsourcing certain work to contract research and manufacturing organizations. once the series a closes, Tzannis plans to fill several key roles in clinical management and regulatory affairs.

With rights to its compounds across the spectrum of autoimmune disorders, including a number of orphan indications, mount Tam could grow into a standalone biotech or go the partnering route. For now, the company is simply putting one foot in front of the other, like the hikers on its famous namesake.

“We are open to a number of possibilities,” Tzannis said, “but our key concern right now is moving these compounds as aggressively as possible into the clinical stage of development.” //



nightStArx gene therApy MAy heLp reStore ViSion to choroidereMiA pAtientSBy Nuala Moran, Staff Writer

loNdoN – Nightstarx ltd. has been launched with £12 million (Us$19.8 million) funding to commercialize a gene therapy that has been demonstrated to partly restore vision in patients losing their eyesight as a result of the x-linked inherited disorder, choroideremia.

The money, from the Wellcome Trust’s syncona llp venture fund and imperial innovations plc, will be used to set up manufacturing, a regulatory route and finance a clinical trial of the product, which uses an adeno-associated virus (aav) vector to deliver a correct version of the choroideremia gene to retinal cells.

a report in January 2014 in The Lancet revealed that the first six patients to be treated showed an improvement in their vision at six months post-treatment. Two of the six were able to read more lines on an eye chart and one saw stars in the night sky for the first time in years.

“The name of the company comes from the restoration of night vision described by some of the patients,” said melanie lee, newly appointed Ceo. “The study is showing good effects and there’s nothing like clinical efficacy to get you excited,” she told BioWorld Today.

Choroideremia is caused by mutations to a gene which encodes rab-escort protein 1 (rep1). The disorder affects approximately 1 in 50,000 people.

The first symptom is usually an impairment of night vision, which often occurs in early childhood. That is followed by progressive narrowing of the field of vision, as well as a decrease in the ability to see details, culminating in blindness, most commonly in late adulthood. Currently, there is no effective treatment.

The vector used in the gene therapy, aav.rep1, was developed by researchers at oxford University led by robert maclaren. The data in the Lancet paper relate to the first cohort in a 12-patient trial that is being funded by the research charity the Wellcome Trust and the Uk department of health.

Two of the six patients in the first arm of the study spoke at a press conference held in london when the Lancet paper was published, describing improvements they experienced since having one eye treated.

maclaren currently is halfway through treating the six patients in the second, higher dose arm of the trial. To date there have been no safety concerns.

“one of the patients was operated on two years ago. i heard him say he still feels there is an [ongoing] improvement,” lee said. “We now want to build on what robert maclaren has achieved.”

patients with choroideremia are affected for their entire lives, but with different manifestations at different ages. lee said Nightstarx will now engage with regulators to try and agree to a clinical endpoint and on which stage of disease progression a trial should focus.

“We want to have a discussion with the regulators to see if patients can be selected for a quick-to-market study,” lee noted.

This is likely to involve treating more severely affected patients, who have lost visual acuity.

“The data already show this treatment restores visual acuity, and that’s a clear clinical endpoint,” lee noted.

once the treatment has been shown to be effective in later stages of choroideremia it could be used to treat younger people who carry the defective gene but still have good vision, preventing loss of sight.

“The investigators believe there is the potential it is a once-in-a-lifetime treatment that will stop degeneration and prevent loss of retinal cells,” lee said.

While the initial focus will be on translating maclaren’s success in correcting the gene defect in choroideremia, Nightstarx also will work on other retinal dystrophies.

“We want to really make a go of delivering an approved product for choroideremia, but with backers like syncona, there is an opportunity to build a broader ophthalmic company,” lee said.

The biology of the eye is relatively poorly understood. however, an emerging body of basic science and medical science, coupled with advances in tools such as those for imaging the eye, is opening up new therapeutic avenues.

“The eye is a discrete organ, and is easy to reach, and this provides new opportunities for treatment,” lee said.


a possible limitation in using gene therapy to treat other, more common, eye disorders, for example, macular degeneration or diabetic retinopathy, is that the size of the gene or genes that must be delivered may well be beyond the carrying capacity of an aav vector.

“Choroideremia is a single gene defect; other eyes diseases are not. Using aav.rep-1 to treat choroideremia is so simple we think it could be the answer. For complex diseases it may make more sense to have another approach,” lee added. //



noVAn SeekS to unLeASh power of nitric oxide in ‘tunABLe’ drugSBy Marie Powers, Staff Writer

For nearly two decades, scientists have appreciated the healing power of nitric oxide (No), a free radical that garnered researchers at three U.s. institutions the 1998 Nobel prize in physiology or medicine for their discoveries involving No as a signaling molecule in the cardiovascular system. despite its promise, No’s potential has been limited by the fact that the substance is gaseous and highly reactive, confounding the ability of drug developers to store and deliver it safely in the right amount, to the right location and at the right time.

Novan Therapeutics inc. believes it has created the magic bullet to overcome those problems. The company’s core technologies solve delivery issues by storing the gaseous species as an engineered molecule that allows for the timed release of No in short- or long-term applications. By storing nitric oxide as part of an engineered molecule, the technology can be controlled to “tune” the level of No storage, the rate of No release and the molecule size to target No delivery. The result is a stabilized form of No that can be used as a drug across a variety of indications, beginning with topical use in acne vulgaris, atopic dermatitis and common warts.

Novan was initially formed to pursue a device application, but in 2010 the company turned its attention to drug development, using core technology licensed from the University of North Carolina at Chapel hill, according to Nathan stasko, co-founder and president of the durham, N.C.-based firm. The company subsequently in-licensed additional complementary technology, amassing an intellectual property portfolio that comprises more than 70 patents and applications.

The key to the company’s technology is its ability to tailor the formulation of No to each particular application. Novan can engineer the release profile of No-releasing macromolecules to provide a rapid burst, a sustained release and anything in between, creating No therapeutics with a release half-life ranging from seconds to days.

“our macromolecular delivery mechanism is the differentiator,” stasko told BioWorld Today.

‘We doN’T plaN To Be a oNe-hiT WoNder’

Novan is focusing first on dermatology applications because a large body of evidence has demonstrated No’s role in tamping down inflammation and killing even the most virulent, drug-

resistant pathogens.

“Nitric oxide is part of the body’s natural immune response,” stasko said. “We’re taking a cue from the body.”

in 2013, Novan reported findings from a phase i trial in 30 volunteers showing that lead candidate sB204 reduced skin colonization by Propionibacterium acnes. The results suggested the candidate was effective against acne, particularly in combination with previous findings related to sebum production, with several subjects experiencing greater than 90 percent reduction of P. acnes. The study also showed a statistically significant difference (p < 0.05) between the active arm and vehicle after just two weeks.

Novan followed that study with a 12-week, multicenter, double-blind, randomized, vehicle-controlled, parallel-group, dose-ranging phase ii trial evaluating the safety, tolerability and efficacy of sB204 gel in approximately 150 subjects with acne vulgaris. Novan plans to disclose the findings in march 2014 at the annual meeting of the american academy of dermatology in denver but, suffice to say, the company is excited about the data.

acne is an indication begging for new molecular entities, stasko maintained. most products on the market today are generics, reformulations or drug combinations.

“most dermatologists will tell you that they’re starving for new mechanisms of action,” he said. “The really big unmet need in acne is the ability to reduce sebum, and we believe our drug has shown the ability to do that.”

stasko also is confident that clinical validation from the acne program will translate to other therapeutic areas, with wound care – infection, chronic wounds and burns – next on the agenda.

“our goal as a company is to generate a pipeline of drugs based on nitric oxide,” he said. “We don’t plan to be a one-hit wonder.”

acne, alone, is a potential $3 billion market in the U.s., according to stasko. From a product development standpoint, the aesthetics space also is hot, giving the company the potential to generate sustainable revenue to expand its development programs.

With that in mind, Novan had something of a coming-out party in January 2014, when stasko was a presenter at the


inaugural dermatology summit in san Francisco, held in conjunction with the 32nd annual J.p. morgan healthcare Conference. The summit attracted keynoters from industry powerhouses such as Galderma sa, merz pharma Gmbh & Co. kgaa, Glaxosmithkline plc unit stiefel laboratories inc., kythera Biopharmaceuticals inc. and allergan inc., as well as top academic researchers and investment firms.

“it was an exciting time for us, because we had just come off the phase ii trial in acne, and this was Novan’s first step toward becoming a player in the derma industry,” stasko said.

his goal in san Francisco was “to meet with enough parties on both sides of the house” to explore the company’s options in partnering as well as outside financing.

To date, Novan has raised $20 million in private funding from high net worth individuals and captured more than $15 million in grant monies from a variety of federal agencies, including the National institutes of health, National science Foundation,

department of defense and Biomedical advanced research and development authority.

The company now is talking with private equity firms, investment banks and venture funds and beginning to explore strategic collaborations with potential partners. stasko’s goal over the next 12 to 18 months is to complete at least three proof-of-concept studies in dermatology applications, which are “within striking distance,” he said. The company also is receptive to collaboration in larger indications, such as oncology or cardiovascular disease, that would require much larger trials.

“The breadth of nitric oxide is so large that we’re not going to be able to develop it alone,” stasko acknowledged. “To access all of the potential applications for all the patients who could benefit is going to require collaborations of one form or another.” //



StArt-up ocugen eyeS new opthALMoLogy opportunitieSBy Michael Fitzhugh, Staff Writer

entrepreneur shankar musunuri’s newest venture, ocugen inc., is jumping into the race to develop a treatment for the rare disease retinitis pigmentosa (rp) and another therapy for wet age-related macular degeneration (amd), with two preclinical biologics exclusively licensed from the University of Colorado.

musunuri, co-founder and former Ceo of Nuron Biotech inc., is now president and Ceo of iogenetics inc. he co-founded aurora, Colo.-based ocugen in late 2013. as chairman of the fledgling company, he’s putting development of oCU100, the company’s lead candidate, into motion and recruiting an executive team to lead the work. meanwhile, with Fda orphan status for the drug already in hand, musunuri told BioWorld Today that oCU100 could enter phase i testing for rp in late 2015, assuming the company can secure financing.

if successful, oCU100 could provide the first approved drug for some of the 100,000 people in the U.s. with the rare inherited eye disease. people with rp experience a gradual decline in their vision as the photoreceptor cells in the retina die. most people with the condition are legally blind by age 40. While medical need in the area is high, so is development interest, with 33 active phase i, ii and iii trials, according to Cortellis Clinical Trials intelligence.

ocugen’s other co-founder and board member, Uday kompella, invented both drugs. a former classmate of musunuri’s, the CU professor took the academic path, focusing on drug delivery and opthalmology, while musunuri honed his business chops at pfizer inc. and Wyeth. The two kept in touch and, when kompella reached out to share his inventions with musunuri, they decided to found ocugen to develop the drugs.

after what musunuri said was an easy and efficient negotiation with CU, in march 2014 ocugen finished licensing assets for the recombinant lens epithelium-derived growth factor 1-326,

now called oCU100, and an anti-angiogenic tumstatin fusion protein, now oCU200.

a variety of mutations, including p23h mutation in rhodopsin, an important protein in the retina, have been linked to the development of rp, kompella said. “p23h rhodopsin is known to form large clusters or aggregates within retinal cells, leading to cellular stress and ultimately cell death,” he said. oCU100 can “rescue” retinal cells from protein aggregation and the stresses that aggregation poses.

Though musunuri declined to say how much ocugen would need to advance the drug, sucampo pharmaceuticals inc. in 2013 secured up to $22 million, which it said would cover the majority of development costs for its unrelated rp drug. That phase iii program, testing the already-approved eye drug unoprostone rescula (isopropyl) for the new indication, is expected to yield top-line results in early 2015.

ocugen’s second candidate, oCU200, has shown early promise in treating wet amd, a disease that leads to blindness for the majority of the nearly 600,000 cases diagnosed globally each year.

musunuri provided some of the seed funding for ocugen himself, he said. as he begins the journey to finance the company further, he’ll likely be helped by growing investor interest in advanced opthalmology therapies. optogenetics is taking off as researchers and investors take a closer look at techniques to deliver genes or chemicals to activate neurons in response to light. Genable Technologies ltd., for instance, recently tapped philadelphia-based spark Therapeutics llC to provide manufacturing services and clinical development assistance on its preclinical lead program, GT038 for rhodopsin-linked autosomal dominant rp. (see BioWorld Today, sept. 30, 2013, and march 26, 2014.) //

– BioWorld Today, June 6, 2014


finAncingS, LicenSing, purchASe round two for forMer phArMASSet execS with hBV StArt-up oncore

By Marie Powers, Staff Writer

after operating off the grid for nearly two years, oncore Biopharma inc. has unveiled three recent deals to mark its presence in the hepatitis B virus (hBv) space in a big way.

The most recent, with the ink still wet on the page, was an all-cash acquisition of privately held enantigen Therapeutics inc., giving oncore control of enantigen’s two discovery programs in hBv. one of those targets the inhibition of surface-antigen (s-antigen) secretion while the other targets capsid assembly inhibition.

The companies were neighbors at the pennsylvania Biotechnology Center in doylestown, also the home of the hepatitis B Foundation and the Foundation’s research center, the Baruch s. Blumberg institute, where oncore originally struck deals for its internal assets. oncore had “eyes on” enantigen almost from the time of its own launch, according to patrick higgins, oncore’s Ceo. That move came within a year after oncore’s founders orchestrated the $11 billion buyout of their previous company, pharmasset inc., by Gilead sciences inc. (see BioWorld Today, Nov. 22, 2011.)

days before that deal, pharmasset had launched pivotal phase iii studies of its all-oral, interferon-free hepatitis C virus (hCv) nucleotide analogue, then known as psi-7977. Following the acquisition, the compound became Gs-7977, then sofosbuvir, before it was approved in 2013 as the blockbuster sovaldi. (see BioWorld Today, Nov. 2, 2011, and dec. 10, 2013.)

higgins, who was pharmasset’s executive vice president of sales and marketing at the time of the Gilead acquisition, took some time to investigate “the state of the science” in hBv, both in academia and biotech, before gathering an all-pharmasset leadership team at oncore. The other co-founders are michael sofia, chief scientific officer and r&d head, who was head of chemistry and an inventor of sovaldi; mike mcelhaugh, chief operating officer, who was director of business development and market analytics at pharmasset; and Bryce roberts, chief legal officer, who was vice president and senior counsel at pharmasset – duties he also assumed, for a time, at Gilead.

oncore’s platform technology focuses on inhibiting the formation, controlling transcription and destabilizing hBv covalently closed circular dNa (cccdNa), thought by some to represent the best opportunity to cure chronic hBv-infected

patients, according to higgins. oncore’s strategy is to target cccdNa with the goal of achieving a “functional cure” by combining agents against cccdNa with other direct-acting antiviral mechanisms and strategies to boost the patient’s immune response.

enantigen’s approach targets hBv s-antigen (hBsag), a key viral protein involved in controlling the host immune response. hBsag exists in large quantities not only as a constituent of hBv virions but also in hBv subviral particles, which significantly outnumber infectious virions circulating in the body. hBsag has been shown to inhibit the innate immune response through effects on T-cell and dendritic cell function, so the inhibition of hBsag production or secretion could reduce the impact of the viral infection on the host’s immune function.

“our goal is to bring multiple technology assets into the program that actually will hit various targets on the viral cycle,” higgins explained. “The additional target that enantigen provides is the s-antigen inhibition.”

The enantigen buy also gives oncore a second capsid assembly inhibitor program – another lynchpin in its multipronged hBv drug development effort. oncore’s internal cccdNa program targets the eradication of viral genomic material characteristic of hBv, according to sofia. Covalently closed circular dNa transcription produces hBv pregenomic rNa, or pgrNa, which is bound covalently to the hBv viral polymerase. The entire complex must be encapsidated by a sphere of viral capsid proteins to continue the viral lifecycle. By inhibiting pgrNa encapsidation, oncore hopes to halt that progression and prevent viral replication.

“We realized early on in our strategic planning that hepatitis B – like other viruses, such as hiv and hCv – requires a combination therapy approach, using drugs with different mechanisms of action,” sofia explained. “We set out very early to understand what mechanisms were being studied and focus on trying to acquire assets across a wide variety of therapeutic areas in the field. We’re trying to cover our bases, as best as possible, with assets that target key steps in the virus replication cycle as well as the immune modulatory strategy.”

members of enantigen’s team, headed by michael xu, president and chief operating officer, are expected to join oncore to help accelerate the development of its hBv pipeline.


xu and sofia, both chemists, had known each other for some time before the deal.

‘a Broader Base oF The viral TarGeT ThaN aNYBodY else’

oncore started september 2014 by closing a series r, or roll-up, financing, using the same strategy pursued during an early round at pharmasset. higgins declined to name the single investor or disclose the amount but said the funding allowed the company to consolidate a number of drug candidates into a single hBv platform company. “We’re experts at this,” he told BioWorld Today.

a few days later, the company inked an exclusive global license with Neurovive pharmaceutical aB, of lund, sweden, encompassing a series of second-generation cyclophilin inhibitors to treat hBv. The potential $150 million deal included an undisclosed up-front payment, development and sales milestones, and royalties on product sales.

The deal with Neurovive, which specializes in mitochondrial drugs, gave oncore access to cyclophilin inhibitors known as sangamides, based on Neurovive’s polyketide chemistry platform. data presented in april 2014 at the international liver Congress suggested that Neurovive’s lead cyclophilin compound, Nvp108, appeared to inhibit hBv by two mechanisms in vitro, directly inhibiting several stages of viral replication in liver cells and indirectly strengthening the host immune response via interferon regulatory factors, or irFs, including inhibition of an interaction between cyclophilin a and irF9, a key component of the Jak/stat pathway. data also suggested that the risk of developing resistance to Nvp018, a significant issue in hepatitis treatment, was low. preclinical studies on Nvp018 are nearly complete, and oncore expects to move the compound into human trials next year, according to higgins.

oncore – the name alludes to the “encore” effort by the “core” team at pharmasset – isn’t seeking a head-on confrontation with erstwhile suitor Gilead. But even though the company isn’t pursuing hCv, where Gilead has planted a very big global stake, the quest for an hBv cure likely will land oncore

right back where it started. Gilead is advancing tenofovir alafenamide (nucleotide reverse transcriptase inhibitor), or TaF, as well as Gs-4774 (tarmogen T-cell immunity stimulator) and Gs-9620 (Tlr-7 agonist) in chronic hBv.

TaF also is part of the company’s once-daily single tablet regimen of elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/TaF 10 mg in hiv. in late November 2014, Gilead reported data from two phase iii trials (studies 104 and 111) showing the TaF regimen met the primary endpoints in treating hiv-1 infection in treatment-naïve adults, demonstrating noninferiority to stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) with more favorable renal and bone safety. Based on the findings and data from ongoing phase iii studies of the combo drug, Gilead said it will submit regulatory applications for the regimen in the U.s. and european Union in 2014.

as a single agent, TaF is in phase iii development in hBv, with Gilead’s other candidates in phase ii. That puts Gilead’s hBv development timetable far ahead of oncore’s.

Based on the speed in which oncore was assembled and other moving parts were locked into place – not to mention the team’s experience in the hepatitis space – higgins is unconcerned. Though the enantigen buy is probably not the last strategic move by oncore, it puts the company in a position to cover “a broader base of the viral target than anybody else that’s out there,” he maintained.

oncore’s team already is looking to replicate its success at pharmasset through aggressive internal development and global licensing deals that allow it to pursue related indications, such as liver fibrosis and hepatocellular carcinoma. higgins expects little trouble attracting attention from the investment community along the way, hinting that a run at the public markets might not be far away.

“There are investors who were with us at pharmasset, and most of those investors have a mandate to be in the public market,” he said. “i think we’ll have to consider that down the road.” //



oSteoqc MineS cAnAdiAn tALent to BuiLd new Bone diSeASe VentureBy Michael Fitzhugh, Staff Writer

osteoqc inc., a new montreal-based company that will develop therapies for the treatment of bone-related diseases, is leveraging a portfolio of candidates for promoting bone growth developed by overland park, kan.-based osteogenex inc. to build a new venture.

in November 2014, the start-up was founded and closed a seed financing round led by lumira Capital investment management’s merck lumira Biosciences Fund and said it would leverage montreal’s wealth of medicinal chemistry talent to accelerate its work.

“montreal is a big hub for pharmaceutical r&d,” debra ellies, who founded osteogenex in 2006 and remains that company’s Ceo and president, told BioWorld Today. ellies will lead osteoqc as well, serving as its president.

“over the years, there’s been a lot of site closures, big campuses that have closed down. For example, merck had a huge campus on the West island,” said ellies. “after their merger with schering, they pretty much wound down the site. so you have all these talented r&d people in montreal that are starting little companies everywhere. They have extreme talent and a lot of know-how in terms of taking a pharmaceutical through to the market.”

osteoqc could pursue any number of areas in bone disease, ellies said, including osteoporosis, bone fractures, dental applications, joint reconstruction and osteopetrosis. But first, it will be carrying ahead work on sclerostin-targeted small molecules.

sclerostin is an osteocyte-expressed negative regulator of bone formation.

meanwhile, osteogenex will move into other nonbone-related markets where ellies said the company sees applicability for a pathway it has researched that triggers osteoblasts to differentiate into bone or fat cells, a pathway she said could be leveraged in the treatment of cancer and obesity.

she’s said she’s excited about the relationship with lumira because it will bring additional expertise, a broadened network and resources that will streamline and accelerate

osteoqc’s development.

Furthermore, working in montreal gives ellies a chance to return to the city where she grew up. her journey had taken her to london, where she gained her phd, studying how neural crest cells migrate from the brain into the jaw to pattern the face and teeth and later, to kansas City, mo.’s stowers institute for medical research in 2000, where she was part of a team investigating a protein that turned out to be a master regulator of bone density, before deciding to form osteogenex.

“a couple of years ago, all that was really understood in the scientific arena was bone loss,” said ellies. That led to the development of a number of therapies, such as prolia (denosumab, amgen inc.) and Fosamax (alendronate sodium, merck & Co. inc.), that focus on bone loss. But while those therapies can help prevent patients’ bones from getting worse, they don’t help them get any better either, she said.

improving bone density has generally required light exercise or therapy with Forteo (teriparatide, eli lilly and Co.). Forteo works well for building bone, but ellies said its potential side effects, including bone cancer, and the need for patients to inject themselves daily have given some doctors and patients pause. patient compliance with the regimen is often poor.

“so, obviously, there’s a need in the market for something much better,” ellies said. That’s what made the discovery of sclerostin exciting. lilly, amgen and Novartis aG all have antibodies against sclerostin, but as large molecules, they’re all injectibles. developing a pill to build bone could prove a potent advantage. (see BioWorld Today, sept. 17, 2014.)

daniel hetu, a managing director at lumira Capital, the sole investor in osteoqc’s seed round, told BioWorld Today that his firm had been following osteogenex for at least two years and was eager to establish a collaboration with ellies.

“as the company progressed, we thought that it would be a good time to invest to accelerate the work that they’re doing,” hetu said. “There are a number of therapeutic modalities or drugs that target resorption, working on the osteoclasts. But very little targets osteoblasts, or bone-building.” //



$4.1M froM incuBAtor, StAte

SerieS A round SetS otoLogic heAring-LoSS piLL on pAthwAy to cLinic

By Randy Osborne, Staff Writer

otologic pharmaceutics inc.’s $4.1 million in series a funding will help the oklahoma City-based firm start a phase i trial this year with NhpN-1010, an oral combo therapy designed to reverse noise-induced hearing loss.

“The military is interested because Nihl is their number-one expense for disability,” said Clayton duncan, chairman and Ceo of the aptly named oklahoma City-based biotech accelerator accele Biopharma inc., the investing arm of which put the new money into 2009-founded otologic. also contributing was the oklahoma life science Fund contributed.

about $1.5 billion per year is spent by the armed forces on Nihl, duncan said. “You’ve got aircraft carriers with noise, and artillery, and you just can’t block it all out,” he said, noting that, if the compound works, it could also find use in traumatic hearing loss due to heavy machinery noise in construction and manufacturing – an orphan indication.

“The initial insult, the initial blast or high-frequency noise, causes damage, and it’s temporary at first,” duncan said. “With [NhpN-1010], it seems the ear can repair itself, and the damaged nerve cells can recover. if they don’t, then you end up with a hearing aid.”

NhpN-1010 is a combination of known therapies hpN-07 (2,4-disulfonyl α-phenyl tertiary butyl nitrone) and N-acetylcysteine (NaC). The latter is approved for intravenous use in liver toxicity (such as can be caused by acetaminophen).

“it’s been tested a lot in a lot of situations,” duncan said, including a 300-patient hearing loss trial conducted by the military with firing-range patients. “There were some interesting trends, and we got close,” he said. “if they were right-handed shooters, it made a difference in the right ear vs. left ear.”

hpN-07, the second ingredient of NhpN-1010, is “a very potent antioxidant, and it has some other mechanisms,” duncan said. london-based astrazeneca plc tested the compound in stroke, missing the endpoint in phase iii trials. “it’s been in about 3,000 patients and looks pretty safe,” he said.

The next indication in which NhpN-1010 will be tried is hearing loss caused by toxicity, a much larger patient population. This year, the firm will start investigational new drug application-enabling studies to support experiments with the drug in

preventing or reversing acute cisplatin-induced hearing loss. Cisplatin causes significant hearing loss in more than 75 percent of the nearly 700,000 patients treated each year.

“We’re exploring preclinical models at this point,” duncan told BioWorld Today. “From what i know of the mechanisms, it should work.”

otologic and its collaborators, the hough ear institute and the oklahoma medical research Foundation, also plan to test NhpN-1010 in tinnitus, vestibular injury and traumatic brain injury-associated hearing disorders.

duncan rattled off the firms doing research in otologic’s area. auris medical aG, of Basel, switzerland, has a phase ii-stage compound for hearing loss that involves an injection through the tympanic membrane. auris caused players in the space to sit up straight in 2013 with a series C round of $51 million to boost its N-methyl-d-aspartate receptor antagonist in tinnitus, along with the peptide-based blocker of c-Jun N-terminal kinase signaling for hearing loss. (see BioWorld Today, april 17, 2013.)

san diego-based otonomy inc. is pursuing, at the preclinical level, a method of similarly directed drug delivery of dexamethasone. sound pharmaceuticals inc., of seattle, has ebeslen (also known as spi-1005), a glutathione mimic and antioxidant, at the phase ii stage for Nihl due to long-term exposure to noise, such as ipods and inserted ear buds. otonomy also scored a hefty series C in 2013, gaining $45.9 million in a round led by orbimed advisors llC. (see BioWorld Today, sept. 5, 2013.)

in 2014, indianapolis-based eli lilly and Co. entered the hearing loss arena by investing in a series a round for audion Therapeutics Bv, of amsterdam, and providing a series of compounds, including its γ-secretase inhibitors, to test their potential in hair cell regeneration. (see BioWorld Today, Feb. 11, 2014.)

also conducting research that is related but not directly competitive to otologic are london-based autifony Therapeutics ltd., which is focused on age-related hearing loss, exploiting potassium channels to improve cognitive ability to understand signals from the ear, and Genvec inc., of Gaithersburg, md., which is trying rNai therapies to restore hearing loss.


in connection with otologic’s series a, duncan has been appointed as the company’s Ceo, replacing david karlman in this position. other members of the team include richard Gammans, also of accele Biopharma and recently appointed to the newly created positions of otologic’s chief operating officer

and head of research and development; otologic’s co-founder and chief medical officer, richard kopke; co-founder and chief science officer robert Floyd; and kelle Jones, vice president of finance. //



Like A cAnoe, protein cAn ‘portAge’ cArgo AcroSS ceLLSBy Marie Powers, Staff Writer

portage, with its meaning of carrying cargo between two bodies of water, seems an intuitive name for a Canadian biotech. Certainly, the significance was meaningful to Toronto-based portage Biotech inc. (pBi), which is applying transporter technology to create cell permeable peptide fusion proteins in a variety of potential indications.

pBi was formed in 2012 by Greg Bailey, chairman, who is a managing partner at palantir Group inc.; declan doogan, Ceo, a biopharma veteran of pfizer inc., prometheus laboratories inc. and amarin Corp.; and Jim mellon, director, chairman of port erin Biopharma investments and co-author of the 2012 book Cracking the Code, which examined developments in the biotech industry.

in June 2013, the company conducted a reverse merger with publicly traded Bontan Corp. inc., moved its legal domicile from Canada to the British virgin islands and gained a listing on the Canadian National stock exchange (CNsx:pBT.U) and $3 million in cash, to which pBi added $500,000. as the parent company, pBi is focused on in-licensing technologies and negotiating with potential partners. a series of subsidiaries will conduct drug discovery and development on in-licensed assets.

portage pharmaceuticals ltd. (ppl) is the first of those subsidiaries. ppl is conducting early stage translational research using antennapedia protein (aNTp) transduction technology exclusively licensed in all indications except oncology from Trojantec ltd., of Nicosia, Cyprus, and london. The aNTp platform features a transport mechanism that enables the delivery of a therapy into the cell and/or subcellular compartments, including the nucleus, and across the blood-brain barrier.

The organizational structure was established because managing an early stage asset requires a different skill set from that of a compound that has demonstrated proof of concept and is ready for pivotal trials, doogan said. Thus, ppl has its own leadership team, which includes Ceo Bruce littman, a former pfizer r&d executive and faculty member at virginia Commonwealth University’s medical College of virginia, and chief scientific officer, Frank marcoux, also a former pfizer executive and academic researcher.

The antennapedia protein is used in the embryology of fruit

flies, enabling the “transport” of various types of information between cells during development so that each appendage forms in the proper place, Bailey explained. The protein’s unique attribute is its ability to carry large payloads without disrupting the cell membrane.

The company licensed the full protein from Trojantec with the idea that it could likewise transport active cargoes into a cell without disrupting the cell membrane, in a process Bailey likened to a ghost moving through walls. The company is conducting preclinical studies in chronic obstructive pulmonary disease, inflammatory eye diseases and inflammatory skin diseases and is examining opportunities in congenital blindness, polycystic kidney disease and huntington’s disease. The technology also offers the potential for multiple delivery mechanisms, including topical applications and nasal sprays.

The company isn’t limiting its approach to applications that use familiar pathways. “additionally, we’re intrigued by drugs that have failed because they don’t get to the right place or they give up before they get to the right place,” Bailey told BioWorld Today. “We think the technology will be interesting to pharma partners that have an exciting drug” but are stymied in the delivery process.

moreover, each new aNTp payload creates additional intellectual property (ip), enhancing the value of the platform, according to doogan.

“We see the potential for rolling out a new fusion protein or a new transporter payload entity and creating new ip and value down the line,” he said. “We could do this for ourselves or with another company where we’re working to solve a bioavailability problem.”

For now, ppl is conducting “the most careful experiments to create robust proof of principle, which will then give us the confidence to invest further in certain payloads” to move the company toward human trials, doogan told BioWorld Today. Though he declined to project a timetable for the clinic, doogan said the company expects to conduct key experiments in the first quarter of 2014 that, if successful, will move the technology toward an investigational new drug application filing as well as co-development talks with pharmas and big biotechs.

in early 2014, pBi expects to add a second subsidiary housing an asset that’s farther along the development pipeline, Bailey


said. pBi’s operational structure will allow that unit to hire a separate, appropriately experienced management team.

“This is a de-risking strategy, as well,” doogan said, “so we’re not solely dependent on one experiment. We see this as multiple, intelligent shots on goal, but we’re not going to spread ourselves so thin that we fail to achieve the appropriate goal for the milestones.”

For now, pBi itself operates virtually, with Chief Financial officer kam shah as the only full-time employee, and doogan

and a network of external experts flexing their schedules to meet the company’s workload. Though pBi is not a conventional venture capital-backed biotech, the company has sufficient financial runway “to prove the viability” of the aNTp transduction technology platform and to bring in a second product, Bailey added.

“With the money we have, we can hit inflection points that will trigger further financings within a year,” he said. //



proteLicA Steering itS own pAth to deVeLop next-gen protein drugSBy Marie Powers, Staff Writer

Whether to imitate the tortoise or the hare is a constant challenge in drug development. a go-slow approach enables more methodical evaluation of technology, targets and potential applications, with the prospect that precious funds might not be wasted going down a blind alley. speeding to market is more likely to result in first-mover advantage and the opportunity to expand a drug into additional indications before competitors come a-calling.

serial entrepreneur roberto Crea considered both options with protelica inc., and not for the first time.

Crea was a member of Genentech inc.’s founding scientific team and served as the first director of the company’s nucleic acid department, where he helped to develop the lead drugs in Genentech’s pipeline. in 1982, Crea left to launch his first start-up, Creative Biomolecules inc., which joined with ontogeny inc. and reprogenesis inc. in 2000 to form the public company Curis inc. (see BioWorld Today, Feb. 16, 2000.)

Crea then formed Creagen inc., acquired in 1994 by Neurex inc. Four years later, Neurex was picked up by elan Corp. in a $741 million stock swap weeks after reporting positive phase iii findings for its lead compound, the pain drug prialt (ziconotide). (see BioWorld Today, July 19, 1994, april 1, 1998, and april 30, 1998.)

he went on to form three more companies, including Bioren inc., which specialized in technology to engineer monoclonal antibodies (mabs). in 2005, Bioren was acquired by pfizer inc. for an undisclosed amount.

But pfizer didn’t pick up all rights to the company’s technology, so “i found myself with some money to invest and some technology,” Crea told BioWorld Today. armed with development momentum and technology validation from the pfizer deal, in 2006 Crea set off on his newest venture. This time, he took a slower trajectory that would enable him to control the direction of the company and the potential applications.

over the ensuing years, hayward, Calif.-based protelica amassed a sizable protein engineering and optimization platform to discover and develop next-generation protein drugs, hormones, enzymes and antibody mimics. The company uses a patented, site-directed mutagenesis technology that can be applied to

almost any protein of interest, enabling the development of high affinity binding proteins in a matter of weeks.

The technology can be used to develop diagnostic kits, probes for imaging and flow cytometry, immuno peT, protein microarrays, affinity chromatography, clean tech and more. But the long-term proposition is drug development. Based on a patented fibronectin scaffold, protelica identified a handful of potential candidates – all of them still in the discovery phase but many already well characterized.

at its core, protelica is seeking to discover desirable mutant proteins. its protein mutagenesis platform encompasses three technologies: look Through mutagenesis, or lTm, Walk Through mutagenesis, or WTm, and Combinatorial Beneficial mutagenesis, or CBm. lTm and WTm are used to generate chemistry-based libraries with sufficient diversity for initial hits but a manageable size for screening. CBm is used to create rationally designed, combinatorial libraries around the initial hits.

protelica focused its early efforts on developing its platform and library of antibody mimics to discover protein antagonists, based on the use of a human protein scaffold known as the 14th fibronectin type-iii repeat of human fibronectin, or 14Fn3, a fibronectin protein that is prevalent throughout the human body. in its pronectin technology platform, the company amassed a library of more than 25 billion fibronectin biomolecular sequences that can be screened against therapeutic and clinical diagnostic targets of interest.

“We wanted to establish a solid position in the industry as a very innovative company with a couple of technology platforms that can lead to breakthrough products,” said Crea, protelica’s president, Ceo and chairman.

in fact, the company was founded as protelix inc. – a name that referred to the combined power of protein-based molecules and the dNa double helix – before changing to protelica to avoid confusion with a neighboring biotech whose name differed by a single letter.

‘No raTes or roYalTies . . . [For] NeW TeChNoloGY’

protelica now is moving to develop fibronectin-based therapeutics to replace first-generation mabs. like antibodies,


fibronectin resides outside cells, where it is exposed to and tolerated by the human immune system, Crea explained. Fibronectin binds to other proteins using protein structures called “loop domains.” The 14Fn3 scaffold consists of the natural amino acid sequence of one of the Fn3 repeats of human fibronectin and three targeting loops. protelica’s dNa mutagenesis technology modifies those loops to make analogues, which then bind to a therapeutic target of interest.

“protelica spent some time to build the technology,” he explained. “We matured the pronectin platform and looked at the opportunities for us and for corporate partners.”

in a nutshell, protelica’s story “all starts with the technology,” added mike honeysett, the company’s chief business officer. The company’s diverse platform enabled it to tap the protein conjugate and enzyme optimization markets to develop probes for imaging and clinical diagnostics. revenues from those activities, in turn, help protelica to advance its therapeutic pipeline.

The company’s library of antibody mimics is a key to that work.

“The real difference with our library is the way we’ve designed it to mimic nature,” honeysett explained. “other mutagenesis technologies typically generate libraries that have a lot of meaningless mutations that don’t create much value. if you look at our molecule, just mutating the loop structures you can get as many as 4.8 quintillion possible combinations, which we’ve been able to reduce to a natural library of around 25 billion molecules.”

The company holds three U.s. patents, with 18 related claims, just on the library, he added.

protelica has grown organically, largely self-financed by Crea with grant funding from the National science Foundation, and

now has 12 employees. But, as honeysett observed, “there are no rates or royalties when you develop new technology.”

The next step is to attract corporate partners for preclinical or phase i studies in the company’s lead therapeutic programs. They include veGFr-2 antagonists for cancer and wet age-related macular degeneration, axl tyrosine kinase inhibitors in cancer, cell receptors for cancer and stem cell biology using the WNT/frizzled pathway and TNF-alpha antagonists.

“all four have tremendous biophysical properties,” honeysett said. “But we need to fund the early tox work and pharmacokinetic studies.” For that, “we’re absolutely seeking partners,” he added, suggesting the company will need $1 million to $2 million per molecule to complete preclinical work.

as part of its calculated approach, protelica will continue to eschew venture funding, at least for now. maintaining control enables the company to steer the technology in a direction “where there’s the highest potential to succeed,” Crea said. at the same time, he acknowledged that collaborations could allow the company to de-risk its therapeutic pipeline, adding, “We think there’s a lot of low-hanging fruit for protelica to explore.”

The company has seen interest “from the usual subjects,” honeysett said, with three proof-of-concept studies under way plus a seven-figure bioagricultural deal for enzyme optimization. With potential exit strategies in mind, the company also expanded its board and strengthened its corporate governance. With revenue now flowing, “we can carry some projects forward quickly and efficiently without diluting the company,” he pointed out. “Collectively, as a company, we’re doing whatever we can to build value around the technology.” //



roMAncing A rAre diSeASe deAL pASSion for Science iS pAying off in protheLiA pArtnerShip

By Marie Powers, Staff Writer

Talk about a great act one. after six years quietly developing laminin-111, a protein replacement therapy for ultra-rare merosin-deficient congenital muscular dystrophy (mdC1a), privately held prothelia inc. snagged leading rare disease firm alexion pharmaceuticals inc. as its first strategic partner earlier this month in a three-way deal with the University of Nevada, reno, where the technology was developed. and alexion isn’t just pacing in the wings. The biotech inked a sponsored agreement to accelerate research on laminin-111 that includes a binding deal for the exclusive option to acquire milford, mass.-based prothelia and license laminin-111 upon the attainment of undisclosed r&d milestones.

Brad hodges, prothelia’s chief scientific officer, founded the company in 2007 after starting his career as a scientist at Genzyme Corp., where he was immersed in protein, gene therapy and small-molecule treatments for a variety of orphan diseases, including pompe, Fabry, Gaucher, Batten, Niemann-pick, duchenne muscular dystrophy (md) and hemophilia.

hodges’ greatest expertise was in md – an indication he had studied since the early ’90s, when he was pursuing his phd. attending an md patient conference in 2006 reignited his passion for the space.

“meeting these parents, who just learned maybe weeks before that their child has muscular dystrophy, was very compelling,” he told BioWorld Today.

hodges decided to form his own company. he left Genzyme, cashed in not only his but also his wife’s 401(k) accounts and began reviewing manuscripts about md, seeking the best candidate to serve as the star asset for a start-up.

That’s when hodges discovered a body of work developed by dean Burkin, a former colleague at the University of illinois who had moved to the University of Nevada school of medicine as assistant professor of pharmacology and director of the Nevada Transgenic Center. hodges was exploring the potential therapeutic value of laminin-111 in md.

laminins are a group of high molecular weight glycoproteins that help with the formation of the basal lamina, or basement membrane – a type of extracellular matrix. mdC1a is caused by a genetic deficiency of the laminin-211 protein, which provides structural integrity to muscles. patients with mdC1a

present with respiratory insufficiency, poor muscle tone, muscle atrophy, delayed or absent motor milestones, feeding difficulties, scoliosis and joint contractures. The condition currently has no approved therapies.

laminin-111 is a form of laminin found in embryonic skeletal muscle that was shown in early animal studies to substitute for the loss of laminin-211. hodges envisioned the technology as a single drug that could be targeted to multiple disorders, treating a variety of patients, regardless of their gene mutation.

“i knew a lot about laminin, and to me, this was an extremely innovative way to treat muscular dystrophy,” hodges recalled. “muscular dystrophy is basically a disease where muscle cells stop sticking to each other. if you can find a drug that can restore the stickiness, or reform this glue between muscle fibers, you can have a way to treat many forms of muscular dystrophy.”

‘GeT YoUr haNds oN The riGhT drUG’

he jumped on the technology, inking an exclusive license with the University of Nevada, reno, in 2008. in addition to his own money, hodges then secured four small Business innovation research grants from the National institutes of health, totaling nearly $1 million. prothelia also received more than $250,000 in funding from a combination of advocacy groups, including Cure Cmd, struggle against muscular dystrophy, parent project muscular dystrophy and hope for Gus.

prothelia demonstrated that laminin-111, delivered systemically in mdC1a and duchenne md mouse models, showed good efficacy with no toxicity and protected muscle from exercise-induced damage. laminin-111 also was stable and scalable in the manufacturing process.

in 2009, Burkin – who serves as one of prothelia’s scientific and medical advisors – introduced hodges to rich Cloud, who had co-founded and was chairman of the nonprofit Cure Cmd, which is seeking to advance therapies for congenital md. With a background in executive management and a keen personal interest in the md space – his oldest daughter has mdC1a – Cloud “seized the opportunity” to join prothelia as Ceo.

The company kept its head to the plow, leveraging researchers in Burkin’s lab, at other universities and at prothelia’s lab in massachusetts to advance the science behind laminin-111.

The goal was to propel the drug’s development to a point


where a large pharmaceutical company would have interest “and the economics might make sense,” Cloud said.

in the meantime, the company had almost free reign in the mdC1a space. according to Thomson reuters Cortellis Clinical Trials intelligence, only santhera pharmaceutical holdings aG’s omigapil, in-licensed from Novartis aG, is a potential competitor in the rare form of md, but the drug has not progressed beyond a phase i study.

in 2011, prothelia received orphan drug designation for its compound from the Fda, both in mdC1a and duchene md. Cloud then began to accelerate business development efforts, recognizing that taking laminin-111 to clinical trials would require more than a handful of grants. during the process, the company was introduced to alexion, where romance blossomed.

“They loved the idea, and we loved alexion,” hodges said. “They were forward-thinking and had an innovative approach to rare diseases. We could not be happier with

the deal that transpired.”

prothelia officials were coy about specifics of that deal, citing a strict confidentiality agreement and noting that it’s still “early days” in the collaboration, in which alexion will perform certain r&d studies with the potential to expand its own product portfolio. however, the prothelia team is confident that “alexion is the right partner, given their commitment to patients with ultra-rare diseases like mdC1a,” Cloud said.

For prothelia, like alexion, the process literally began with one scientist with a vision of helping desperately ill children.

“in the end, it all boils down to science,” hodges said. “There are a lot of great discoveries at universities, just sitting around. They’re waiting for a scientist who’s willing to risk a lot to carry something truly innovative forward. The process may take longer than you expect and a little more money than you expect, but if you get your hands on the right drug and develop a company around it, you can fulfill your dream.” //



rAni Set to StArt triALS of inSuLin- deLiVering cApSuLe next yeArBy Catherine Makino, Staff Writer

TokYo – rani Therapeutics llC is working on a delivery system for insulin that could provide relief for millions of people who must undergo regular painful injections to deal with conditions such as diabetes, rheumatoid arthritis, osteoporosis and multiple sclerosis.

rani’s chairman and Ceo, mir imran, spent years trying to find a way to administer injectable drugs orally. he found inspiration in the unlikeliest of places: a glass of alka-seltzer.

The challenge is that the digestive juices in the stomach destroy the proteins that make up large molecules such as insulin, rendering them ineffective before they enter the bloodstream. so rani created a capsule coated with an ingestible polymer, using carbon dioxide to expand the capsule and then using tiny hollow sugar needles to push the medication into the wall of the intestine, where it can then naturally enter the bloodstream.

“after i got the initial concept of injecting drugs in the intestinal wall, it took nearly three years to perfect the capsule technology,” imran said. “We had to overcome many challenges in material science and the manufacturing process development.”

imran is an entrepreneur and innovator who has founded more than 20 life sciences companies and is the founder of the silicon valley search lab and business incubator incube labs llC, of san Jose, Calif. he owns more than 300 patents and helped develop the first implantable cardioverter defibrillator to correct irregular heartbeats. Google is an investor in incube.

preclinical results in animals have shown that the capsule is effective to deliver drugs based on proteins, antibodies and even insoluble small molecules. Clinical trials on people have not started yet.

“in all the preclinical testing that has been done with the capsule with various molecules such as insulin, humira, etc., we have not seen any adverse effects caused by the delivery platform,” imran said.

humira (adalimumab) is an anti-TNF antibody drug marketed by abbvie inc.

rani plans to start human trials in 2015 and to have the delivery mechanism available in about three years, but that

timing is dependent on rani’s drug and pharma partners.

“our capsule has bioavailability that is close to 90-plus percent, which is as high as a drug’s absorption when administered using a syringe,” a rani spokesperson said.

imran claimed “the new capsule also has the potential to transform the entire biotech industry, especially the insulin market.”

“The impact on type 1 diabetic patients could be very significant,” he said. “Type 1 diabetics are totally reliant on insulin because their pancreas has stopped working. Currently, the market for basal insulin is over $10 billion annually. rani Basal insulin could take a big portion of this market and expand it quite significantly.”

The three biggest markets for insulin are currently the U.s., europe and Japan. Nearly 3 million people in the U.s. have type 1 diabetes, and there are nearly 1 million sufferers in Japan.

rani aims to form partnerships with pharma companies in asia, North america and europe as it searches for the massive financing needed to manufacture the millions of capsules imran anticipates will be needed. With that as a goal, the U.s.-based medtech entrepreneur visited Japan in July 2014. one top multinational pharmaceutical company has signed a confidential agreement with rani, he said.

“We are now seeing simultaneous development in these three regions, because of the opportunity cost of a delay in any of the regions,” said reed maurer, a Japanese pharma industry watcher and president of international alliances ltd.

“Those with the disease learn early on to cultivate a healthy distrust for announcements of ‘cures’ or ‘breakthroughs,’” said harry mahaffrey, a diabetic activist and graduate student at purdue University who was diagnosed with diabetes at age 12. “a cure for diabetes has been ‘five years away’ since i was diagnosed.”

rani’s capsule delivery system is not a cure but a management system that can have a direct impact on patients’ lives because constant self-injections have consequences like bruising, hardening of the fat at frequently used injection sites and even infections.

“as a diabetic, i have faith in the biotech industry,” mahaffrey


said. “after all, they’ve kept me going this far. ”

Biotech and medtech companies are working on a number of alternatives to injections. on June 27, 2014, the Fda approved inhaled insulin product afrezza developed by mannkind Corp. to improve glycemic control in adults with type 1 and type 2 diabetes. afrezza is not a substitute for long-acting insulin and needs to be used in combination in patients with type 1 diabetes. (see BioWorld Today, June 30, 2014.)

There are still some unknown factors regarding possible adverse effects of afrezza, which should not be used by patients with asthma and chronic obstructive pulmonary disease; nor is it recommended for the treatment of diabetic keloacidosis or in patients who have chronic lung diseases. The Fda has required

four postmarketing studies for afrezza.

developing a marketable oral delivery system would be a game-changer, which has led to a number of attempts over the years to perfect such a method that can compete with injectable delivery in terms of bioavailability. and rani is not alone.

empisphere Technologies inc., a small New York pharmaceutical firm, also is developing a pill coated with a special molecule that allows the insulin to penetrate the wall of the intestine and enter the bloodstream. emisphere has partnered with Novo Nordisk a/s to develop and commercialize the oral delivery of Novo’s insulin compounds, and the project is in the preclinical stage. //



‘cure, not cAre’ iS the MAntrA for jApAn’S regiMMuneBy Marie Powers, Staff Writer

since launching in Tokyo in 2006, followed by the establishment of a U.s. subsidiary a year later, regimmune Corp. has endured both financial and natural disasters: the meltdown of the global capital markets and the Tōhoku earthquake and tsunami.

Bent but not broken, the company survived and in February 2014 raised a $9.2 million series d after moving its lead compound, rGi-2001 (Tolerovax), into a phase ii trial in graft-vs.-host disease (Gvhd) associated with hematopoietic stem cell transplantation (hsCT).

regimmune’s revax technology re-educates the immune system by inducing immune regulatory cells. in contrast to immunosuppressants that broadly down-regulate the immune system, revax suppresses the immune system target while maintaining normal immune reaction. in addition to advancing revax as a treatment, with Gvhd as the lead indication, the company is exploring the vaccine’s use as a prophylactic, without the need for adjuvants.

regimmune had no trouble attracting top Japanese venture funds to its seed round, which closed in 2006 at more than $1.6 million, with investment primarily from NiF smBC ventures, Nikko antfactory and Japan asia investment Co. (JaiC). a year later, after establishing its U.s. office in mountain view, Calif., the company pulled in a $4.2 million series a, adding JaFCo Co. ltd., orix Capital Corp., Yasuda enterprise development Co. ltd., New Business investment Co. ltd., mitsubishi UFJ Capital Co. ltd. and Fund Creation Co. ltd.

in addition to establishing development operations in California, proceeds helped to advance the preclinical development of rGi-2001 – a liposomal formulation of Cd1d ligand alpha-GalCer that induces regulatory T cells – and rGi-1001, a recombinant cedar antigen designed to treat cedar allergy. rGi-2001 was exclusively licensed from kirin pharma Co. ltd., which had conducted studies of the compound, then known as krN7000, in cancer, hepatitis B and hepatitis C. rGi-1001 – initially expected to become regimmune’s lead therapy – was being advanced in a collaboration with the Japanese public research institute rikeN, which provided the company with exclusive license to certain rikeN patents.

regimmune continued to attract funding, including an $8

million series B in 2008 that added Csk venture Capital Co. ltd., Gh holdings k.k., resona Capital Co. ltd., aC ventures Co. ltd. and Friendly partners Co. ltd., and more than $12 million in grant funding from the Japanese ministry of economy, Trade and industry, the Japan science and Technology agency and the country’s National institute of Biomedical innovation.

Then the lean years started, with turmoil in the financial markets slowing the company’s ability to fortify its coffers. Though regimmune had ramped up its U.s. development operation, employing approximately 20 people, the company eventually was forced to cut that number in half. Then the tsunami hit Japan’s east coast. Though regimmune’s Japanese operation, based in Tokyo, was spared, the immensity of the loss of life and physical destruction brought the Japanese economy to a standstill while recovery efforts were under way.

“every two years we had a problem, but somehow we survived,” recalled haru morita, regimmune’s president and Ceo.

in a way, the delay was fortuitous for regimmune. as preclinical and early clinical studies progressed, the company realized rGi-2001 was a bigger opportunity, clinically and financially, than the cedar allergy treatment. although allergy to cedar pollen is an enormous problem in Japan, affecting one-fourth of the Japanese population – including morita – it wasn’t the ideal lead indication “because allergy is not usually a life-threatening disease,” he pointed out.

‘We Feel We’re iN a verY Good posiTioN’

The company explored a variety of indications before settling on Gvhd, the serious and often life-threatening complication that results from rejection of donor hsCT, where revax technology is preferentially suppressed only against the target – a first in the industry, as far as regimmune is aware. Thus, patients are able to continue life-sustaining treatment without succumbing to the ravages of Gvhd.

“most people are not dying from rejection but from relapse and infection,” morita told BioWorld Today. “it’s really problematic.”

instead of providing temporary care for the disease, “basically, we provide a cure,” he added. “That’s the benefit of our technology.”

By late 2011, regimmune was back on track and ready to


begin a phase i/ii study of rGi-2001 in Gvhd. That study was initiated in January 2012, enrolling approximately 50 bone marrow or peripheral blood stem cell transplant leukemia patients following chemotherapy, at six U.s. centers. simultaneously, the company closed the first tranche of a $5 million series C financing, led by daiwa enterprise Co. ltd. and JaiC and adding two new investors.

in February 2014, regimmune reported that the dose-escalation phase of the study showed a clean safety profile and supported initiation of phase ii, which began enrolling immediately. The expansion phase is evaluating the pharmacologic effects of either a maximum tolerated dose, maximum feasible dose or optimal pharmacologically active dose of rGi-2001 in patients undergoing allogeneic hsCT. The company expects to have top-line data mid-year.

in the meantime, regimmune is negotiating with several pharma companies on a collaboration and licensing agreement that could take the therapy through a phase iii program and into registration.

regimmune also plans to investigate rGi-2001 in autoimmune disorders, according to morita.

plus, the company has inked partnerships with undisclosed pharmas for rGi-3100, another formulation of alpha-GalCer

designed as a potential treatment for type i diabetes, and rGi-5000, an enzyme replacement therapy with applications in hemophilia and lysosomal disease. The collaborations are structured with a variety of terms, some with rights for Japan and others with global options, according to morita.

Next up on the financial front is an initial public offering in Japan that morita expects to close later in 2014.

“The Japanese market is very generous at this point,” he said, noting that some Japanese firms have gone public in 2014 with market caps of several hundred million dollars and up. “Compared to companies that have gone public in this market, we feel we’re in a very good position,” morita added.

With a diverse group of investors, regimmune has an inside track in accessing capital, which remains problematic for Japanese biotechs, and has embraced the more collaborative business model that is more common in the U.s. and europe than in asia.

“There is much opportunity in Japan,” morita said, “but there is not great access for companies outside Japan into that untapped market. We are in a great position to have that access.” //



repLiceL MArcheS AheAd with ceLL therApy triALSBy Michael Fitzhugh, Staff Writer

replicel life sciences inc. is ramping up its pipeline of autologous cell therapies with intentions to file within the next several weeks its plans to initiate early stage trials of its therapies for chronic achilles tendinosis and aging and sun-damaged skin ahead of pre-trial meetings with shiseido Co. ltd., the world’s fourth largest cosmetics company and its partner on a developing hair regeneration therapy.

The vancouver, British Columbia company, built by leveraging cell replication technologies originally pioneered by Trichoscience innovations inc., expects by the end of 2014 to begin the phase i/ii trial of rCT-01, the experimental achilles tendinosis therapy, and a phase i trial of rCs-01, an experimental fibroblast therapy to treat aged and damaged skin by providing Uv-naïve collagen-producing cells directly to the affected area.

The company’s approach turns on addressing functional cellular deficits for therapeutic effect and taking an approach with a relatively low regulatory burden globally due to its process for isolating target cells from hair follicles vs. the more highly regulated use of adult or embryonic stem cells. Using a small biopsy from the back of a patient’s scalp, it isolates desired cells from 20 to 25 hair follicles, grows them, and mixes them with a carrier for later injection using the company’s proprietary injection device.

With initial positive data from a small phase i study that appeared to validate its approach in chronic achilles tendinosis already in hand, replicel’s phase i/ii trial will put fibroblast cells from hair follicles’ nonbulbar dermal sheaths to work to break the cycle of incomplete healing caused by a deficit of the cells. By injecting the type i collagen-producing fibroblasts directly into the site of injury, it expects to promote organized tissue formation that’s lacking in injured patients. The trial will test the approach in 28 patients, treating 21 individuals while providing a placebo to seven. Though its primary endpoint is safety, Ceo david hall told BioWorld Today the company will be closely watching the trial’s secondary endpoint, efficacy at 26 weeks, a point at which investigators will be measuring function, pain, tendon appearance, biomechanics, blood flow, activity scale and quality of life.

in a separate phase i trial, replicel will recruit 28 healthy subjects to test the safety of its NBds-derived fibroblast therapy rCs-01. since aging fibroblasts in the skin produce

less collagen over time, causing skin to loose its elasticity and structure, replicel contended that the injection of collagen-rich fibroblasts can effectively “reverse” skin damage. To get a read on that goal, secondary endpoints in the study will include measures of gene expression of skin aging markers and an assessment of molecular markers associated with skin aging.

in the wings, the first of three planned phase ii trials of the company’s autologous cell therapy treatment for pattern baldness, rCh-01, awaits. replicel inked a collaboration and technology transfer agreement for the autologous cell therapy with shiseido first announced in July 2013. replicel granted shiseido an exclusive license to rCh-01 in Japan, China, south korea, Taiwan and aseaN countries in exchange for ¥400 million (Us$3.8 million) up front, potential sales milestones of up to ¥3 billion, plus royalties. shiseido has already invested in the trial, building a cell-processing facility it opened in may 2014 just to support the trial.

replicel estimated more than $3 billion is spent on hair loss treatments globally each year, most with thin results. While surgical transplants of hair follicles into balding areas is the current “gold standard” treatment, hall said, the procedure is highly dependent on a surgeon’s skill and multiple procedures are often required to achieve the desired result and patients are limited by the number of hairs that can be redistributed.

replicel extracts dermal sheath cup cells from patients’ hair follicles, replicates them in culture, and then reintroduces them back into balding areas on a patient’s scalp. it expects the implanted cells will rejuvenate damaged quiescent hair follicles leading to the growth of new healthy hair fibers. a phase i study confirmed the therapy’s safety and provided an early proof of response, with patients showing hair growth at treatment sites. But since the primary objective of the study was to establish long-term safety, replicel will be following patients treated with the cell therapy for five years.

The company plans to enroll about 160 men with mild to moderate androgenetic alopecia in the phase ii trial. after injections of rCh-01 are performed using rCi-01, the company’s dermal injector device, subjects will return to the clinic for assessment of total, terminal and vellus hair density and cumulative hair thickness, as well as safety. The primary endpoint of efficacy will be measured a year after the final injection by assessing total density, hair thickness, cumulative


hair and treatment response rate.

meanwhile, replicel is looking for other potential asian market partnerships and pushing ahead with a prototype of the second generation of its proprietary cell injection device for skin and scalp, a device it expects to license for the dermal filler market.

replicel shares (Tsxv:rp.v) closed at C48 cents each sept. 8, 2014. at June 30, 2014, the company had cash and equivalents of about C$4.3 million. it expects readouts on the tendinosis and skin aging trials in 2015. //



reVirAL’S SerieS A proVideS runwAy to MoVe rSV cAndidAte into the cLinicBy Nuala Moran, Staff Writer

loNdoN – Uk start-up company reviral ltd. has attracted one of the global stars of nucleoside chemistry and antiviral drugs to its board, as it prepares the ground for a series a later in 2014 to raise £4 million to £5 million (Us$6.8 million to Us$8.5 million).

That would provide funding to take the lead program, an orally available inhibitor of respiratory syncytial virus (rsv), into phase i.

Now the company has the validation of signing up raymond schinazi, the scientific brains behind antivirals, including the hepatitis C drug sovaldi (sofosbuvir, Gilead sciences inc.), as a nonexecutive director to point to in its fundraising efforts.

“We showed him the technology and he thought it would be good to be involved,” khatereh ahmadi, Ceo and founder of reviral, told BioWorld Today.

reviral is revisiting ground staked out by its founders when they were running another antiviral specialist, arrow Therapeutics ltd., a company acquired by astrazeneca plc for $150 million in February 2007. arrow’s lead program at the time of the acquisition also was a treatment for rsv.

“reviral was founded by the ex-arrow Therapeutics drug discovery team,” ahmadi said. “There’s no underlying platform technology, but they have a huge amount of experience in small-molecule antivirals; they know the patent spaces and their knowledge of the field includes understanding of the shortcomings of other compounds.”

The medicinal chemistry expertise informed the design of a new class of compounds for which patents were filed in 2011. on the back of that, reviral won a Wellcome Trust seeding drug discovery initiative grant in 2012 to develop its lead rsv fusion inhibitor to completion of investigational new drug filing.

“We didn’t start operations until august 2013, but we have got very promising leads with good, drug-like characteristics. We will do candidate selection later this year, when we will also look for further funding,” ahmadi said. “The lack of treatment options for rsv and limited competition offers a significant market for therapies like ours.”

schinazi, a professor of pediatrics and director of the laboratory

of Biochemical pharmacology at emory University, will add significant heft to reviral, having founded several biotech companies, including pharmasset inc., where he oversaw development of sovaldi. pharmasset was acquired by Gilead in 2012 for $11.4 billion.

having looked at the chemistry of reviral’s compounds, schinazi said they “have the potential to revitalize and transform” the rsv market. he should know. in total his work has resulted in 12 Fda new drug applications, and according to his biography more than 94 percent of hiv-infected individuals in the U.s. on combination therapy take at least one drug invented by schinazi.

rsv is a significant respiratory pathogen causing 64 million infections and 160,000 deaths annually. There are no effective treatments and reviral execs say a safe, convenient oral antiviral or a vaccine would rapidly gain market share. its small-molecule drug would be suitable for immunocompromised patients, including infants.

schinazi may be a star name, but the founders of reviral are no slouches. The company is chaired by ken powell, the founder and Ceo of arrow Therapeutics, who steered it through to its sale to astrazeneca.

The scientific founder is stuart Cockerill, a named inventor of the tyrosine kinase targeted cancer drug Tykerb (lapatinib, Glaxosmithkline plc), who previously was research director of arrow Therapeutics, a post he held until 2010.

The rsv product arrow was developing was out-licensed to Novartis aG in July 2005 for $10 million up front, with $217 million to come in milestones. ahmadi said there have been no recent mentions or updates on the compound from Novartis. “it’s not got a long patent life, so i doubt it will be commercialized,” she said.

in terms of the commercialization strategy for reviral’s lead program rv521, ahmadi said the aim will be to provide proof of concept in humans in a challenge study and look for a partner at that point.

The company also has an rsv replication program at an earlier stage and plans to extend its reach into other viral infections. //



rigontec getS $12M for rnA-BASed iMMunotherApieSBy Cormac Sheridan, Staff Writer

dUBliN – rigontec Gmbh, a spinout from the University of Bonn in Germany, took in €9.45 million (Us$12 million) in a first closing of a series a round to take forward an rNa-based approach to immunotherapy, based on activating retinoic acid inducible protein i (riG-i), a pathogen-associated molecular pattern that recognizes certain forms of viral rNa.

The company’s platform is based on the work of scientific founders Gunther hartmann and veit hornung, of the University of Bonn, who identified a viral rNa species, 5’ triphosphate rNa (3prNa), as the ligand for riG-i several years ago. activation of riG-i triggers an antiviral response, characterized by the generation of type i interferons and strong activation of natural killer cells. “The big advantage of rigontec, in my opinion, is it’s something completely new,” interim Ceo annegret de Baey-diepolder told BioWorld Today. “We’re not the 10th oncolytic virus company.”

hartmann’s and hornung’s paper on the work appeared in the Nov. 10, 2006, issue of Science, under the title “5’-Triphosphate rNa is the ligand for riG-i.” it was published simultaneously with a paper from Caetano reis e sousa, of Cancer research Uk in london, and co-workers, although the company had filed patents on its work in advance. “We have covered everything in four patent families,” de Baey-diepolder said. “We have freedom to operate here.”

seattle-based kineta inc., disclosed a riG-i-targeting program for treating viral disease several years ago, for which it raised Nih funding, although de Baey-diepolder said she was unaware of any progress since then. rigontec aims to file for an investigational new drug application on its lead program, imol100, before the end of 2016 and to complete a phase i trial during the second half of 2017.

imol100 is a short, synthetic double-stranded rNa ligand of riG-i, which carries a triphosphate group on its sense strand. “it’s not nucleotide sequence-specific,” de Baey-diepolder said. it has, however, undergone lead optimization in order to maximize stability and potency.

it has exhibited activity in a range of rodent cancer models, including comparative studies involving dNa molecules with CpG motifs, which also trigger immune activation via Toll-like

receptor 9 (Tlr-9).

“We could see we were much more potent,” she said. “in many animals, the tumor completely disappeared.”

The effect was permanent, moreover. reintroduction of cancer cells did not result in new tumor growth, indicating that the activation effect led to the induction of immunological memory.

Behind imol100, the company is working on several programs that combine gene silencing with riG-i activation, although those programs remain at an early stage of development. The firm has yet to pick its lead cancer indication. it also plans to develop antiviral therapeutics, based on the same platform.

The round was co-led by Boehringer ingelheim venture Fund and Wellington partners, with participation also from NrW Bank and high-Tech Gründerfonds. The company aims to take the round to €12 million in total, de Baey-diepolder said.

The deal is one of the few bright spots on the horizon for early stage German biotech. The investment is the fifth that the Boehringer ingelheim venture Fund has completed this year but its first with a German firm – its other recent transactions involved companies in denmark, the U.s., switzerland and israel. Wellington partners has led a €2.7 million series a round in Neuway pharma Gmbh, a spinout from life science inkubator Gmbh in Bonn, which is focusing on orphan central nervous system indications, and it also participated in a €9 million series B round at Cologne-based proteomics analysis firm ayoxxa Biosystems Gmbh.

“The climate is very difficult. There are only a few fresh funds to finance start-ups,” de Baey-diepolder said. Family offices have been the sector’s mainstay in recent years. despite the improving funding climate in europe, only more mature German companies are, in the main, raising finance at present. and several are looking outside their home markets in order to do so. halle-based probiodrug aG, which is seeking up to €32.2 million, will price an initial public offering (ipo) in amsterdam in the coming weeks. heidelberg-based cancer immunotherapy firm affimed Therapeutics recently raised $56 million in an ipo on Nasdaq.

“i’m not sure if Frankfurt will ever open again,” de Baey-diepolder said. //



finding itS ‘niche’: StArt-up SchoLAr rock tArgeting growth fActorS By Jennifer Boggs, Managing Editor

scholar rock inc. Ceo Nagesh mahanthappa’s previous biopharma experiences include stints at rNai powerhouse alnylam pharmaceuticals inc. and privately held avila Therapeutics inc., which was snapped up by Celgene Corp. in a potential $935 million deal in 2012, and he is the first to admit that “those are high standards.”

so when it came time to look for his next opportunity, he said the focus was on revolutionary new scientific ideas that offered development paths “within a meaningful time frame.”

he found that opportunity through polaris partners general partner amir Nashat, who introduced mahanthappa to Timothy springer, latham family professor at harvard medical school and professor of medicine at Boston Children’s hospital.

springer, who mahanthappa described as a “luminary” in immunology and structural biology, “had the idea of braiding together two independent strands in a novel way,” he explained. one strand comprised the advent of monoclonal antibody development – the ability to target specific antigens, for example – and the other built on advances in molecular structure and architecture. The end result is an approach for selectively targeting growth factors.

long recognized as disease targets, thanks to their broad roles in regulating cell growth and differentiation, growth factors have proved difficult to attack therapeutically, largely because of their broad activity and ubiquity within the body. Going after a growth factor carries a risk of causing unwanted side effects.

The trick, then, was to figure out how to target growth factors in a way that produced specific therapeutic effects at the sites of disease. springer and fellow researcher leonard Zon discovered a way to modulate what they came to call “niche activators” of growth factors that are found in the microenvironment of specific cell and tissue types.

initial focus, mahanthappa said, has been on the TGF superfamily, a family of growth factors implicated in a wide variety of disease. still, “there has not been huge progress in about 20 years in modulating their activity therapeutically.”

in the case of TGF-beta 1, research has found that part of the trouble is that the “vast majority” of TGF-beta 1 is actually dormant. That explains why the traditional drug approach hasn’t worked.

“Targeting the active form of the molecule and inhibiting it in a traditional way had not borne a lot of fruit,” he said, largely because it’s hitting only the mature growth factor “and by then it’s too late to do much good.” researchers, instead, had to figure out how to modulate the dormant version of TGF-beta 1. Niche modulators and niche activators offer “a whole new way to tap into [a scientific discovery] that has not yet yielded robust results,” he added.

in fact, the attraction of scholar rock is that it’s working in a “validated area – TGF-beta 1 – with a validated modality – antibodies” but with an approach that would lend itself to multiple programs and indications, mahanthappa said. “it wouldn’t be a one-off. it would be a bona fide biotechnology platform.”

seed funding was contributed in late 2012 by springer and polaris. That was when mahanthappa came on board and the company began official operations in early 2013.

despite its early stage, the potential of modulating TGF-beta 1 also was appealing enough for scholar rock to land its first big pharma collaborator early this year. The Cambridge, mass.-based firm inked a research deal with Johnson & Johnson affiliate Janssen Biotech inc. to discover and develop therapeutics designed to regulate the immune system by targeting TGF-beta 1 for applications in both immune disorders and cancer.

modulating TGF-beta 1 in the immune system via niche activators plays on the role of regulatory T cells. in the case of autoimmune disease, the companies would look at developing antibodies capable of selectively activating TGF-beta 1, resulting in the promotion of regulatory T cells; in the case of cancer, the goal would be to inhibit Treg production to amplify the immune system against disease.

scholar rock hasn’t disclosed the terms of the collaboration, but Janssen is providing research support and has pledged option payments, preclinical, clinical and regulatory milestone payments, plus royalties and commercial milestones on any approved products, in exchange for a worldwide option to license, develop and sell therapeutics resulting from the alliance.

Janssen is “essentially fully funding” the work, mahanthappa said. “We had discussions with other [potential] partners,” he


told BioWorld Today, “but Janssen came forward with a concept of how to work together that was compelling.”

The young biopharma also is moving forward on its own, with plans over the next year to get some of the important discovery pieces in place, including making recombinant versions of identified proteins, developing antibodies against those proteins, as well as assays. it also will build up capacity and shift its antibody discovery work, currently being done by a contractor, in-house.

scholar rock, whose name comes from the ancient Chinese concept of collecting rocks with unusual patterns for philosophical contemplation – the patterns also indicate a similarity to the 3-d structure of proteins – hasn’t committed itself to any particular programs this early in the game.

“as a small company, one can get diffuse very quickly,” mahanthappa noted, though he said the firm is tending toward diseases related to fibrosis and musculoskeletal disorders. The goal is to reach the clinic sometime in 2016.

That means adding to the team. scholar rock boasts 10 full-time employees and a handful of consultants. “We’ll probably grow that number this year on the order of another 50 percent or so,” depending on development plans.

it also means fundraising, and, on that front, the company is keeping its options open, mahanthappa said.

“as is true with all biotechs, we’ll raise additional funds through various means.” //



ScioderM SeekS fASt trAck with BreAkthrough drug for rAre Skin diSorderBy Jennifer Boggs, Managing Editor

“The worst disease you’ve never heard of.” That’s how patient advocacy and nonprofit group debra (dystrophic epidermolysis Bullosa research association of america) refer to epidermolysis bullosa (eB), a rare genetic disorder characterized by fragile skin that it often leaves its sufferers with chronic open wounds and blisters.

Currently, there are no approved therapies for eB. patients – typically children, since the disorder is diagnosed in infancy – face continual wound cleaning and bandaging, with families spending upward of $10,000 or more on bandages per month. in addition to pain and itching, the wounds also leave these children – called “butterfly children” due to the fragility of their skin – susceptible to infection, thus raising their risk for developing antibiotic resistance.

“There’s nothing out there for them,” said robert ryan, president and Ceo of scioderm inc., a 2012 start-up looking to change that, possibly as early as next year if data from the ongoing phase iib drug testing topical candidate sd-101 prove compelling.

ryan and scioderm’s chief operating officer, robert Coull, acquired the asset from another firm, which had demonstrated a wound healing effect at a lower concentration of the active ingredient before the topical cream product’s advancement was stalled by lack of funding. a subsequent open-label study in children with one of three subtypes of eB – simplex, recessive dystrophic or junctional – demonstrated complete closure of 88 percent of target chronic lesions within one month, plus a 57 percent reduction in body surface area coverage of lesions and erosions after three months of daily treatment.

Those data won sd-101, the Fda’s coveted breakthrough therapy designation, which allows for a possibly expedited development and review process for drugs designed to treat serious or life-threatening conditions. and scioderm is hoping that data from the ongoing phase iib study will convince the Fda to great accelerated approval.

The company recently enrolled 48 patients and anticipates data by late summer, ryan said. The three-month study, which will be followed by an active rollover period, is designed to measure complete wound closure at the primary endpoint, “the gold standard at the Fda,” he added.

additional endpoints include improvement in the body surface area. and sd-101 could have benefits beyond wound healing, most notably in reducing itching, a complication of eB that can be the most difficult for the youngest patients.

“We saw signals in earlier testing, so we’ll be looking for that [in the phase iib study], too,” ryan said.

assuming data are positive, scioderm will approach the Fda about the possibility of approval and, if the agency agrees, sd-101 could be on the market in the second quarter of 2015.

accelerated approval is no guarantee, ryan said, “but we have a lot of optimism. The agency is clearly engaged with us on this product. [The Fda] knows about this disorder, knows that there really isn’t anything out there and that this is also a very painful disease.” sd-101 also has been granted orphan status. eB affects roughly one of every 20,000 live births. and rare diseases, particularly those affecting pediatric patients, gained additional measures under 2012’s Food and drug administration safety and innovation act. “so we’ve got avenues that weren’t there before,” ryan noted.

if data from the phase iib are allowed to serve as the basis for a regulatory filing at the end of this year, scioderm should be able to get through registration on its first venture funding round, a $16 million series a financing raised in 2012 from lead investor morgenthaler ventures and participating investor Technology partners.

prior to that round, scioderm had been self-financed.

regardless of the Fda’s decision on accelerated approval, the company is moving ahead with plans for a phase iii study for european approval. That trial, which will include sites predominately in europe, though a few might be added in the U.s., is expected to launch at the end of this year and to have a similar design to the phase iib.

“We do believe the endpoints and the duration likely will be the same,” ryan told BioWorld Today.

durham, N.C.-based scioderm operates with six full-time employees, including a recently hired chief scientific officer along with four to five “almost full-time” consultants, and has come a long way on just a modest amount of venture financing.

moving forward, the company is pursuing a “parallel-track strategy at the moment,” Coo Coull explained. one of those


tracks is to possibly go public via an initial public offering, though the “market has been pretty fragile in the last few weeks,” to raise money necessary for scioderm to bring the product to market on its own, at least in the U.s., where physicians treating eB patients could be reached with only a small sales force.

at the same time, the company also will look at potential corporate partners.

it’s already working closely with patients. ryan serves on the

board at debra, and “we participate as much as we can at events,” Coull said.

sd-101 might also have use in other skin disorders, though pursuit of additional indications will be farther down the road. as will the possibility of in-licensing additional orphan candidates, Coull said. The focus now for scioderm is “100 percent on eB.” //



SerenuS BiotherApeuticS LookS to tAp AfricA’S underdeVeLoped MArketBy Michael Fitzhugh, Staff Writer

sub-saharan africa’s economic takeoff has carried a growing number of the region’s 1.1 billion people ahead on a wave of innovation, bringing new advances in mobile commerce, bioagriculture and green energy. innovative drugs from the West, however, have arrived much more slowly.

When new drugs do become available, they’re usually generics, delivering yesterday’s therapies to the masses at affordable prices. While the model functions, it’s far from ideal and it’s falling far short of meeting the needs of africa’s growing middle class, according to global drug development expert menghis Bairu. That’s why Bairu, an african-born veteran of Genentech inc. and elan Corp. plc, is launching serenus Biotherapeutics inc., a new company dedicated to in-licensing, registering and commercializing therapies approved in the U.s., europe and Japan to address unmet medical needs in sub-saharan africa.

“Why should sub-saharan african patients wait for drugs to go off patent and become available in generic formulations?” asked Bairu, during a recent conversation with BioWorld Today. “When i started talking with colleagues based here and in africa who have been in the biotech industry for years with successful track records behind them, the more we dug, the more we found missed opportunities.”

The new san Francisco-based company, led by Bairu as Ceo and chairman, is assembling teams in Johannesburg, the west african nation of Ghana and east africa as it pulls together several near-term in-licensing deals. With initial backing by angel investors, the company will look to land a first venture round within 12 months, Bairu said.

and with Bairu’s credentials, chances are good he’ll find the funding. in addition to his six-year career at elan, where he concurrently served as executive vice president, chief medical officer and head of global development, he spent nearly six years in managed care, medical and commercial roles at Genentech. since 2008, he has served on the board of oneworld health, a U.s. nonprofit pharma company, funded mostly by the Bill and melinda Gates Foundation, that’s working to develop and provide affordable pharmaceuticals to needed patients in developing countries.

“at Genentech, we use to focus on the three p’s,” Bairu said, naming “patients, partnership – you can’t do it all, you have to

partner – and possibility. You have to dream, but you also have to focus and execute.”

africa’s health care system is in a period of widespread, if halting, transformation, driven by economic growth, growing political stability and strengthening state institutions. still, said Bairu, “getting into a fragmented health care or regulatory system without having talents on the ground is a big challenge to implement.” in an effort to live up to the latin roots of its name, serenus hopes to orchestrate, plan and coordinate a clear path for its partners’ registration activities in africa, where new drugs are desperately needed to address a fast-changing health landscape.

rapid urbanization is fueling an increase in the incidence of chronic disease in sub-saharan africa, with rising incidences of cardiovascular disease, cancer, diabetes and hypertension. obesity and its attendant problems are on the rise, too, with a recent study in The Lancet estimating that in south africa as many as 70 percent of women and 40 percent of men are overweight or obese. as the region’s population more than doubles between now and 2050, african cities will absorb as much as 85 percent of the growth, suggested the african development Bank Group, likely making the problem worse.

With the continent’s annual pharmaceutical spend expected to reach $30 billion by 2016, according to ims health, it’s little wonder global drugmakers have taken notice. paris-based sanofi sa has led the pack, with 2013 sales exceeding €1 billion (Us$1.4 billion) in 2013.

in march 2014, Glaxosmithkline plc announced a series of new strategic investments in sub-saharan africa designed to help stimulate more research into chronic diseases, increase capacity by localizing medicines supply and strengthen health care infrastructure.

But even as Gsk, abbott, pfizer inc. and other global pharma players build their positions in africa, they are grappling with the sobering challenges of other high-profile emerging markets such as China and russia, a focus that may leave often-complicated africa’s opportunities underattended at exactly the time they need to be most engaged. (see BioWorld Today, Jan. 31, 2013.)

impatient for new therapies, the region’s top market, south africa, in January 2014 accelerated plans to allow generic drugmakers such as aspen pharmacare holdings ltd.


and adcock ingram holdings ltd. to make cheaper copies of patented medicines while simultaneously cutting off evergreening of existing patents.

even with that threat, south africa at least ranks 41st in the World Bank’s most recent 189-country ease of doing Business index, suggesting that companies may be able to negotiate the market without too much trouble. Negotiating successes in the

next largest markets, Nigeria and kenya, ranked 147 and 129, respectively, may take more work. as Bairu and his team start serenus, they’re looking to smooth that experience, creating what he suggests could be a win-win, allowing patients to get access to the drugs they need while helping companies expand their reach. //



Acute, chronic pAin therApy in ‘Site’ for jAnSSen LABS SpinoutBy Marie Powers, Staff Writer

siteone Therapeutics inc., incubated at Janssen labs – Johnson & Johnson’s external r&d hub – took a step toward independence by completing its initial equity financing. led by sears Capital management and Biobrit llC, with additional investors mission Bay Capital and Joe Zakrzewski – former amarin Corp. plc chairman and Ceo and a siteone board member – the $1.5 million round will enable san Francisco-based siteone to press forward on its oral Nav1.7 inhibitor program for pain and to plumb its platform for long-acting local analgesics, pain diagnostics and other pain-related technologies.

The effort will be abetted by a $1.4 million, two-year, phase ii small Business innovation research grant from the National institutes of health to support siteone’s program to develop selective, oral inhibitors of Nav1.7 to treat acute and chronic pain.

The biological underpinning for the company’s technology was discovered by co-founders Justin du Bois, associate professor of chemistry at stanford University and a siteone scientific advisory board member, and John mulcahy, who was a post-doc in du Bois’ lab and serves as the company’s vice president of research. The two were studying the activity of naturally occurring small-molecule marine guanidinium toxins (GTx), which had “evolved over millions of years” to be highly potent and selective for binding to – but not within – the sodium channel (Nav) protein family, explained serial entrepreneur stan abel, siteone’s Ceo.

“The light bulbs began going off,” he added, as the industry recognized the value of the Nav1.7 sodium channel and its role in the generation and conduction of pain signals – particularly the loss-of-function mutation in Nav1.7 associated with complete analgesia, or congenital (channelopathy-associated) insensitivity to pain.

“The idea was that we could take these naturally occurring marine guanidinium toxins and apply our unique, proprietary medicinal chemistry capabilities to create highly selective sodium channel inhibitors for pain, and some other indications, as well,” abel told BioWorld Today.

du Bois and mulcahy founded siteone – named for the particular binding site for the company’s compounds on the

Nav1.7 sodium channel – in 2010 and began to assemble a small team. abel joined the company in February 2014, after leading a series of biotechs to increasingly lucrative m&as, including the $245 million buyout of peninsula pharmaceuticals inc. by ortho-mcNeil pharmaceuticals inc., the $480 million acquisition of Cerexa inc. by Forest laboratories inc. and the $620 million grab of Corthera inc. by Novartis aG. (see BioWorld Today, april 20, 2005, dec. 15, 2006, and dec. 24, 2009.)

in the interim, siteone’s team had made “tremendous progress” developing synthetic analogues that are selective and potent for Nav1.7. The team determined its needs for a small round to see it through the next nine to 12 months, and abel reached out personally to “folks i’ve known and worked with for many years.”

in addition to Zakrzewski, lowell sears of sears Capital joined siteone’s board, while dan Bradbury of Biobrit llC and doug Crawford of mission Bay Capital were named board observers.

‘We’d CerTaiNlY look aT a poTeNTial sTraTeGiC deal’

The company’s top priority now is to advance its as-yet-unnamed lead program, an oral Nav1.7 inhibitor that could replace, with improved safety and efficacy, the use of opioids and nonsteroidal anti-inflammatories to manage pain. abel declined to characterize the timetable for the Nav1.7 program, but company documents indicated the naturally occurring GTxs, when locally injected, demonstrated safety and initial efficacy in early stage trials enrolling more than 400 patients.

“We’re looking forward, in the very near future, to sharing our progress,” abel said.

siteone also plans to explore “pipeline expansion opportunities” derived from the platform technology, including an oral Nav1.7 inhibitor targeting itch, a long-acting analgesic and long-acting muscle relaxants and diagnostic imaging agents for pain and for cancer.

Certainly, Nav1.7 has piqued the industry’s interest, with nearly two dozen companies pursuing drugs that selectively target the sodium channel to treat pain, according to Cortellis Competitive intelligence. They include pharmas abbvie inc., astrazeneca plc, daewoong pharmaceutical Co. ltd., eli lilly and Co., merck & Co. inc., pfizer inc. and sumitomo


dainippon pharma Co. ltd., along with more than a dozen biotechs. like siteone, most programs are still in discovery, although small molecules from astrazeneca and pfizer targeting the sCN9a sodium channel and a small molecule from sumitomo targeting the sCN10a sodium channel have moved into phase i.

Convergence pharmaceuticals ltd., of london, is leading the pack with its small molecule CNv1014802, which originated in the labs of Glaxosmithkline plc and was licensed to the biotech, along with other ion channel modulators, when the company was formed in october 2010. earlier this year, Convergence reported positive data from a phase ii study in trigeminal neuralgia, and the company is planning another trial before year-end in erythermalgia, a peripheral pain disorder associated with a Nav1.7 mutation. Convergence also is laying the groundwork for a raise of £40 million to £50 million (Us$68 million to $84 million) to fund a phase iib/iii trial of CNv1014802. (see BioWorld Today, June 17, 2014.)

abel is undaunted by the crowd, noting that the number of non-opioid candidates in the development pipeline remains relatively small in the face of the unmet medical need.

“our unique approach is to start with naturally occurring

compounds and to create synthetic analogues that take advantage of our knowledge of the site and how the compounds bind to the site,” he said. “We feel that knowledge will yield significant advantages over other Nav inhibitors that have been taken into the clinic, in terms of potency, selectivity and solubility.”

With five – soon to be six – employees, siteone will remain housed for the time being at Janssen labs in the facility created by the collaboration between J&J innovation and the California institute for Quantitative Biosciences, or QB3. long term, the company could seek a partnering deal, build out its own team or look at a collaborative approach, according to abel, who has experience in each type of scenario.

in previous companies, “we always planned to build our own teams to advance our programs,” he said. “however, i think there will be a lot of strategic interest in siteone if we continue to make progress with our development programs. at the right point in time, we’d certainly look at a potential strategic deal, whether it’s a partnership or an acquisition. i guess that’s not too surprising, since the last three biotechs where i worked were all sold to big pharma.” //



More thAn So-So progreSS for Sotio in cAncer iMMunotherApyBy Marie Powers, Staff Writer

The small biotech sotio as, of prague, has shunned the limelight since its founding in 2010. instead of promoting its potential to treat various forms of cancer, the company is letting its technology do the talking.

sotio’s active cellular immunotherapy-multiple antigen presentation (aCi-map) platform is the basis for an oncology product pipeline that uses a patient’s activated dendritic cells to induce an immune response that targets particular cancer cells.

The technology, called dCvaC, offers the potential to enhance the overall therapeutic effects of standard-of-care treatments. early trials showed no serious adverse effects or reactions related to dCvaC, which does not appear to increase the toxicity of existing therapies.

in may 2014, the company enrolled the first patient in its global phase iii viaBle (active immunotherapy using dendritic cell-Based treatment for late stage prostate cancer) study of dCvaC/pCa, an aCi to treat prostate cancer. The randomized, double-blind, multicenter, parallel-group study is evaluating the efficacy and safety of dCvaC/pCa as adjunctive therapy to first-line standard-of-care chemotherapy in metastatic castration-resistant prostate cancer, compared to placebo with standard of care.

sotio, which has approximately 260 employees at facilities in the U.s., China and russia in addition to its headquarters in the Czech republic, expects to enroll approximately 1,170 patients in North america and europe in the trial. The primary endpoint is overall survival, with secondary endpoints of progression-free survival, duration to prostate specific antigen progression and duration to skeletal related events, according to Cortellis Clinical Trials intelligence (CTi).

The viaBle trial proceeded after the Fda reviewed sotio’s complete response to a July 2013 clinical hold of the study and allowed the company to proceed under its investigational new drug application.

Company spokesman richard kapsa did not comment about the reason for the clinical hold, explaining that company officials were unable to comment directly about sotio’s clinical development program due to strict oversight and the risk of penalties from Czech and european Union regulators.

Nevertheless, sotio presented positive phase i/ii findings for

the dCvaC/pCa therapy as well as the clinical rationale and methodology for phase ii studies of its dCvaC/ovCa program in ovarian cancer at the american society for Clinical oncology meeting in June 2014. The dCvaC/ovCa program, which has orphan drug designation from the Fda, is recruiting patients in the Czech republic, Germany and poland, according to Cortellis CTi.

sotio also is completing preclinical studies of dCvaC/luCa in lung cancer and plans to initiate phase i/ii trials.

‘We are NoT seekiNG parTNers’

sotio uses high hydrostatic pressure to kill tumor cells from cancer cell lines, which are used as the source of a broad range of tumor antigens, kapsa explained. The tumor cells, which undergo so-called “immunogenic cell death,” are incubated with dendritic cells cultivated from a patient’s blood monocytes. apoptotic tumor cells, engulfed by immature dendritic cells, are subsequently activated, and mature dendritic cells with the tumor antigens are reintroduced into the patient’s body through an immunotherapeutic vaccine, triggering a response from the patient’s immune system.

prostate cancer was selected as the initial indication for the company’s technology since it was the first explored by the company’s scientists and the most advanced program. if the phase iii succeeds, “we will submit our medicinal treatment for approval by the relevant regulatory authorities,” kapsa said.

immunotherapy as a standalone treatment offers the greatest chance to be effective in early stages of disease with low tumor burden, according to kapsa. The company is exploring potential synergies between traditional treatment modalities and its aCi-map platform mainly to attack advanced disease.

sotio also is examining whether its aCi strategy may offer a long-term boost to patient immune response by providing repeated administration of dCvaC for two- to six-week periods over the course of approximately one year.

The concept is supported by experimental evidence and clinical observations showing that long-term immune specific response can be maintained by the continuous boosting of a patient´s immune system with the manufactured dCvaC/pCa, kapsa said.

The treatment is administered subcutaneously on an outpatient basis, with a one-year supply of dCvaC manufactured from a


single leukapheresis procedure.

Backed by Czech investment group ppF Group, which took a majority stake in the company in 2012, sotio has the luxury of advancing its technology without constant fundraising. although the phase iii prostate study is expected to take four to five years to complete – precluding predictions of a timetable for regulatory filings – the company is not worried about its runway.

“We are not seeking partners,” kapsa told BioWorld Today. “We are fully funded by ppF.” The investment firm has shown an appetite to expand its biotech portfolio, especially in oncology, he said, citing ppF’s recent minority stake in French biotech oribase pharma, which also specializes in developing drugs to treat pancreatic cancer, liver cancer and other solid and liquid tumors. //



tip of the ‘Spero’: roche, StArt-up tArget new AntiMicroBiAL pAthwAy By Marie Powers, Staff Writer

Just a year out of the gate, atlas venture-backed spero Therapeutics llC snagged roche aG as a partner to develop anti-infectives for drug-resistant bacterial infections, targeting a pathway that involves both virulence and persistence of gram-negative bacteria such as Pseudomonas aeruginosa (P. aeruginosa). although financial terms were not disclosed, roche is providing r&d funding to Cambridge, mass.-based spero, with the option to acquire the lead program at the investigational new drug (iNd) application phase.

in conjunction with the collaboration, spero closed a $3 million series a, with investment from atlas, sr one – the corporate venture arm of Glaxosmithkline plc – and partners innovation Fund.

“The sum of the equity capital and roche’s contribution by virtue of the option is a reasonable war chest for us to push ahead for the next multiple quarters into 2015,” said ankit mahadevia, venture partner at atlas and spero’s acting president. as programs continue to grow, the company will seek to expand the syndicate in follow-on raises.

mahadevia founded the company in 2013, in collaboration with the partners fund and with seed funding from atlas.

“We conceived spero a couple of months before atlas started Fund ix,” which closed in may 2013 at $265 million, mahadevia explained. When atlas was examining potential investment opportunities, the infectious disease category quickly rose to the top. atlas had previous success with paris-based antibiotic developer Novexel sa, a 2004 spin-out from sanofi-aventis Group, which secured €90 million (Us$129 million) over two venture rounds along with a €75 million up-front payment in a licensing deal with New York-based Forest laboratories inc. for broad-spectrum beta lactamase inhibitor Nxl104. (see BioWorld Today, Jan. 23, 2008.)

in 2009, astrazeneca plc acquired Novexel for a potential $505 million, with Forest simultaneously acquiring broader rights to Nxl104 for $210 million. (see BioWorld Today, dec. 24, 2009.)

a physician by training, mahadevia also had a personal interest in infectious disease “because i’d seen first-hand the profound unmet need,” he told BioWorld Today.

But three other factors weighed more heavily in the decision.

in april 2013, the Centers for disease Control and prevention singled out antimicrobial resistance in general, and multidrug-resistant gram-negative pathogens in particular, as among “the most serious health threats” in the U.s. in an updated report on antibiotic-resistant bacteria, titled “antibiotic resistance Threats in the United states, 2013,” the agency conservatively estimated that more than 2 million people annually are sickened with such infections, causing at least 23,000 deaths a year. The report cited Clostridium difficile and carbapenem-resistant Enterobacteriaceae as among the nation’s “urgent” threats, followed by a dozen serious threats – multidrug-resistant P. aeruginosa among them – and several “concerning” threats.

The corollary to that warning was that “there just aren’t a lot of biotechs in the space,” mahadevia said, offering “quite an attractive opportunity” for a start-up.

Finally, adoption of the Generating antibiotic incentives Now, or GaiN, act eliminated the murkiness surrounding antibiotics development and provided a clear path to accelerated approval – plus market exclusivity – for such drugs under certain conditions. “my view is that the law will do for antibiotics what the orphan drug act did for rare diseases,” mahadevia observed. (see BioWorld Today, march 9, 2012.)

on top of those factors, payers were becoming more willing to reimburse higher-cost antibiotics as first-line therapy if the drugs were effective in reducing or eliminating patient stays in intensive care units to treat raging infections.

“We thought it was a great time to put together a small, highly skilled team to go off and look at the space,” mahadevia said.

‘CoNCepT has real TraCTioN iN The markeT’

spero – the latin root word for “hope” – brought together a five-person team with biology, chemistry, regulatory and operational experience. The group set out to “scour the landscape,” seeking to identify infectious disease programs with multiple shots on goal.

They struck gold just across the river in Boston, where laurence rahme, associate professor at harvard medical school and director of the molecular surgical laboratory at massachusetts General hospital, had spent 20 years exploring bacterial pathogenesis, including the regulatory systems that govern


virulence. she subsequently identified the P. aeruginosa quorum sensing transcription factor mvfr, which controls roughly one-fourth of the P. aeruginosa genome, according to mahadevia.

rahme, the company’s scientific founder, also had explored the development of drugs that block pathogenesis but not cell viability. essentially, her approach was designed to tamp down virulence, thus limiting the use of broad-spectrum antibiotics and potentially reducing the establishment of antibiotic resistance.

“When you inhibit this target, you’re not killing the bacterium like a lot of antibiotics do today but shutting them off,” mahadevia explained. The result, he said, is that the bacteria in a patient’s infection cause less damage, enabling the individual’s immune system – in combination with traditional antibiotics – to fight the assault more successfully.

Uniquely, inhibiting the target also prevents the bacteria from retreating into a quiescent state until drugs are discontinued, then re-emerge in even greater virulence.

“if you have a one-two punch of turning down the virulence of these bugs when they’re infecting and then not allowing them to play possum so you can clear them, you could have a very profound effect,” mahadevia said.

preclinical studies suggested the approach was promising, both on its own and in combination with approved antibiotics, in treating acute bacterial infections and preventing chronic persistence of pathogens in infection sites.

“We set out to prove that this concept has real traction in the market, and we got that [proof] very early,” mahadevia said.

The novelty of the lead program attracted a number of potential partners. spero selected roche for its growing appetite in antibacterials and its complementary capabilities. The Basel, switzerland-based pharma signaled its recommitment to infectious disease in a big way in November 2013 by in-licensing polyphor ltd.’s P. aeruginosa candidate, pol7080, in a deal valued at ChF465 million (Us$510.6 million). (see BioWorld Today, Nov. 5, 2013.)

in the event roche moves on spero’s as-yet unnamed lead program, the companies agreed to undisclosed up-front and milestone payments. Filing of an iNd likely will require several additional years of work, according to mahadevia.

Nearly four dozen trials are under way exploring the use of agents to treat P. aeruginosa, according to Thomson reuters Cortellis Clinical Trials intelligence. The candidates, mainly inhibitors, target mechanisms such as bacterial dNa gyrase and topoisomerase iv, 30s ribosomal protein and beta lactamase. in addition to allschwil, switzerland-based polyphor, other biotechs in the space include companies such as Cubist pharmaceuticals inc., Nektar Therapeutics inc., kalobios pharmaceuticals inc., ampliphi Biosciences Corp. and aridis pharmaceuticals inc.

however, more than three-quarters of the P. aeruginosa candidates now in the clinic are seeking to treat infections in patients with cystic fibrosis. spero is aiming for a much broader audience, since the opportunistic P. aeruginosa and other gram-negative bugs can attack even the hardiest of victims. one of the most recent, mahadevia observed, is olympic gold medalist ian Thorpe, who is hospitalized in sydney, after contracting two undisclosed infections that resemble methicillin-resistant Staphylococcus aureus following recent shoulder surgery.

No matter what the resolution of its lead candidate, spero has additional programs in discovery that address other infectious conditions.

“With or without roche, we’re pretty keen to keep pushing this forward,” mahadevia said, with long-term business strategy decisions dependent on the opportunities that arise.

“The company’s trajectory has been extremely rapid,” he added. “Based on our commitment to drive some of these programs forward in-house, we have a very good dialogue with other partners in the industry, and we’ll continue to see if it makes sense to work with them.” //



SynAffix cLoSeS SerieS A round for Adc pLAtforMBy Cormac Sheridan, Staff Writer

synaffix Bv closed a series a round to take forward its antibody-drug conjugation (adC) technology, which offers a fresh take on the problem of adC heterogeneity.

The company, based in oss, the Netherlands, has not disclosed the scale of the funding round. “it’s not a double-digit figure. let’s say it’s a sizable investment,” Ceo peter van de sande told BioWorld Today.

synaffix’s investors include ms ventures, the corporate venture arm of merck serono, which is part of merck kGaa, of darmstadt, Germany, and Zurich, switzerland-based aravis sa. The latter is already an investor in another contender in this space, la Jolla, Calif.-based ambrx inc. “so they know this field fairly well,” van de sande said.

The synaffix approach is based on combining glycan engineering with copper-free click chemistry to yield highly homogeneous antibodies tagged at two specific sites with an azide-containing sugar that can be readily conjugated to a toxic payload of choice, via a proprietary strained cyclooctyne species (bicyclo[6.1.0]nonyne, or BCN). The resulting adCs have a drug-to-antibody ratio (dar) of 2.

With first-generation adCs, the toxic payload is conjugated nonspecifically at cysteine or lysine residues on the antibody. That lack of specificity makes drug optimization difficult, as the conjugation process generates a population of molecules that have different dars, different drug placement sites – or no attached drug at all.

antibodies carrying too many toxins tend to be unstable, resulting in a leakage of toxins into the bloodstream, while those carrying none compete for binding sites with those that are properly loaded. establishing reliable pharmacokinetic, safety and efficacy profiles is therefore difficult.

ambrx and others, including seattle-based allozyne inc. and south san Francisco-based sutro Biopharma inc., have worked around the dar problem by incorporating non-natural amino acids into the base antibody molecule, in order to create a site-specific conjugation process. “You have to re-engineer the antibody, which is very labor intensive and complex and results in low yields of protein,” van de sande said.

others have built in recognition sequences that also allow

for site-specific conjugation. redwood Bioscience inc., of emeryville, Calif., has created an “aldehyde tagging” technology, for example, which involves the insertion of an amino acid sequence into the target antibody, which is recognized by an endogenous enzyme, formylglycine-generating enzyme (FGe). That selectively catalyzes the formation of an aldehyde-bearing amino acid, formylglycine, which acts as a chemical handle for a subsequent reaction with aldehyde-specific drug linkers. several others are engaged in cysteine engineering. “all these approaches require extensive mutagenesis,” van de sande explained.

synaffix also engages in protein engineering but at the level of the antibody’s glycan residues rather than its amino acid residues. “it is antibody engineering, but it is post-recombinant,” he said. it subjects an antibody of interest to an enzymatic glycan remodeling step, which alters the glycan profile of the protein to yield two azide-containing sugars at specific sites. “our product is more homogeneous than the starting material – the antibody itself,” van de sande said.

The company, whose scientific founders include chief scientific officer Floris van delft and chief technology officer sander van Berkel, is keeping details of its glycan remodeling step under wraps for now.

The attached azide-containing sugars undergo a copper-free “click reaction” with the BCN species, which is not damaging to the antibody. “it’s a kind of molecular fatal attraction,” van de sande said. “There are only a limited number of copper-free click probes that react with an azide, which are also stable and meet all the requirements to be used in bioconjugation,” he added. (Click chemistry is a general approach to organic synthesis first described by Barry sharpless, of the scripps research institute, and colleagues in 2001; many of the reactions involving azide species employ a copper catalyst.)

in a xenograft animal model, an adC developed with the synaffix technology cleared tumors without any recurrence for the 60-day duration of the experiment, whereas recurrence occurred 20 days after dosing with an analogue of trastuzumab emtansine (T-dm1), the her2-directed adC approved for breast cancer, which is marketed by Basel, switzerland-based roche aG.


Because of the efficiency and specificity of its process, synaffix adCs, said van de sande, deliver superior efficacy while only employing about half the amount of toxin used with conventional adCs.

synaffix’s business model is based on out-licensing its conjugation technology. it has no plans to develop an internal

drug pipeline for now, although it aims to seek participation in partner programs based on its technology. it already has several research collaborations with big pharma firms. it aims to move at least one of those toward an investigational new drug application filing in the near future. //



A-t, g-c . . . And More? Synthorx LAunched on new dnA BASe pAir tech By Michael Fitzhugh, Staff Writer

synthorx inc., a new synthetic biology company backed by avalon and Correlation ventures, is leveraging exclusive rights to a technology for creating synthetic dNa base pairs to improve the discovery and development of new medicines, diagnostics and vaccines.

The technology, developed at the scripps research institute, enables for the first time the in vivo incorporation and replication of a synthetic dNa base pair. The feat allows scientists to move beyond ubiquitous but limiting combinations of the dNa bases, a, T, G and C, and on to the creation of novel proteins, rNa and dNa, said the company.

Floyd romesberg, synthorx’s co-founder and an associate professor at scripps, has been creating and optimizing synthetic dNa bases in his lab for 14 years. Now, using some of those synthetic nucleotides, the san diego-based start-up plans to develop antibiotics and vaccines, both on its own and with partners. drugmakers already have expressed significant interest in the platform and at least two are likely to close deals with the new company in 2014, synthorx president and Ceo Court Turner told BioWorld Today.

The technology, documented in the may 7, 2014, edition of Nature, could “open up a new vista in which human engineering can leap chasms previously unfathomable to evolution,” wrote ross Thyer and Jared ellefson, colleagues at the Center for systems and synthetic Biology at the University of Texas at austin, in a letter accompanying the article.

in addition to medical applications, the unnatural nucleotides that romesberg and his team generated also could be applied to making shrinking microprocessors, batteries, and even producing improved anticounterfeiting technology, said Turner, who is also a partner at avalon. “We’ll be looking to partner

with companies within those spaces immediately,” he said.

synthorx is romesberg’s and Turner’s second start-up, following la Jolla, Calif.-based rqx pharmaceuticals inc., an antibiotics-focused company that is also jointly funded by avalon and Correlation. in February 2013, rqx landed a deal worth as much as $111 million with roche aG unit Genentech inc. for the discovery and development of new compounds for an undisclosed target. (see BioWorld Today, Feb. 12, 2013.)

like rqx, synthorx will pursue gram-negative bacterias, such as the difficult-to-treat pseudomonas and acinetobacter, which are common in hospitals.

Turner and romesberg incorporated the company in February 2014. “From a timing side, most pharmaceutical companies are continuing to look for new ways to externalize research and new ways to access innovation,” Turner said, referencing avalon’s ambitious deal to start 10 new early stage life sciences companies with Glaxosmithkline plc. (see BioWorld Today, april 24, 2013.)

Though synthorx is not part of that project, the idea to provide pharmaceutical companies access to early stage innovation is the same, he said.

Neither avalon nor Correlation is disclosing their initial investments in synthorx. But Turner said that even without additional funding from partnerships, the company has at least three years of runway to develop its own pipeline. synthorx also has significant opportunities to land grant funding to pursue material sciences and anticounterfeiting applications, he said.

The company has just two employees beyond Turner, having hired denis malyshev and kirandeep dhami from romesberg’s lab. it will be looking for five or six additional scientists to add to its team and help it get to proof of concept. //



terrAVAB SeekS A ‘whoLe worLd’ SoLution to SuBduing MrSABy Marie Powers, Staff Writer

With the current ebola virus outbreak wreaking havoc in West africa and generating headlines across the world, it’s easy to forget that dozens of other pathogens cause even more illness and death around the world. one of those, antibiotic-resistant Staphylococcus aureus (mrsa), is no less a global scourge, infecting more than 50 percent of the hospitals in the U.s., Japan, south korea and certain other countries and 25 percent to 50 percent of the hospitals in much of the rest of the world, according to data published in 2013 in the Journal of Antimicrobial Chemotherapy.

in fact, infections with drug-resistant bacteria now represent the single most frequent cause of infectious diseases mortality in developed nations, including the U.s., Canada, europe, China and Japan.

Terravab llC, a 2-year-old Chicago start-up using technology licensed from the University of Chicago, aims to reverse that trend. The company is developing immunotherapeutics and therapeutic vaccines against mrsa and other drug-resistant bacteria, beginning with Terravab mvQ3, a humanized monoclonal antibody that neutralizes staphylococcal protein a, or spa, an immune evasive surface molecule of S. aureus.

mrsa is an unusually dangerous pathogen, because infection does not lead to protective immunity, and up to 60 percent of patients suffer from recurrent infections, explained vilasack Thammavongsa, a Terravab co-founder. spa – one of mrsa’s most abundantly expressed proteins and one of the most highly conserved genes in the bacterial genome – is the principal reason for that reinfection rate.

spa has two primary functions. The protein is expressed on the surface of the bacteria, where it binds to the Fcg domains of host antibodies. spa essentially flips the antibodies inside out so they cannot be recognized by the appropriate immune cells, Thammavongsa explained, thus inhibiting opsonic clearance of mrsa in infected tissue.

in addition, spa released from the bacteria can crosslink igm receptors on the surface of B cells, inducing B-cell apoptosis. That process leads to depletion of antibody-producing B cells, preventing the immune system from mounting an effective attack against spa.

The U-Chicago technology produced the first spa-specific

monoclonal antibodies, Thammavongsa said.

“We screened a large panel of monoclonal antibodies for the ability to neutralize spa activity, and we identified a lead candidate and humanized the antibody to generate mvQ3,” he told BioWorld Today. “This is the first time anybody has been able to do this.”

as the company’s lead candidate, mvQ3 is a humanized igG1 antibody that allows infected individuals to develop protective immune responses, improves the outcome of S. aureus infection and prevents recurrent disease. in proof-of-principle demonstrations, when mixed with blood from healthy human volunteers and cord blood from premature infants, mvQ3 promoted opsonophagocytic killing of mrsa.

preclinical studies also showed that mvQ3 protected neonatal mice from mrsa by neutralizing spa and allowing the immune system to generate a broad spectrum of anti-mrsa antibodies – another first, Thammavongsa said. When the mice were subsequently challenged with a lethal dose of mrsa to examine whether the anti-mrsa antibodies were protective, 60 percent or more of the animals treated with mvQ3 survived.

mvQ3 also may also be useful as a preventive measure, Thammavongsa suggested, for individuals at high risk for S. aureus infection, including those with indwelling catheters, endotracheal intubation, medical implantation of prosthetic joints and heart valves, surgical procedures, hemodialysis, peritoneal dialysis and immunosuppressive or cancer therapy.

The company has patents pending on the technology in the U.s., europe and China.

‘oUr aNTiBodY GeNeraTes Broad-speCTrUm proTeCTive immUNe respoNses’

Three biotechs – durata Therapeutics inc., Cubist pharmaceuticals inc. and The medicines Co. – gained Fda approvals in quick succession this year to treat patients with mrsa infections using their drugs, dalvance (dalbavancin), sivextro (tedizolid phosphate) and orbactiv (oritavancin), respectively. Those actions followed a long drought after Fda approval of vibativ (telavancin), developed by Theravance inc. and astellas pharma Us inc., in 2009. (see BioWorld Today, sept. 15, 2009, may 27, 2014, June 24, 2014, and aug. 7, 2014.)

mrsa has gobbled up other therapies on their way through


clinical trials, however, among them Nabi Biopharmaceuticals inc.’s staphvax and altastaph programs; Novartis aG’s aurograb, gained in its acquisition of Neutec pharma plc; inhibitex inc.’s veronate; and pagibaximab, developed by Biosynexus inc. (see BioWorld Today, Nov. 2, 2005, april 4, 2006, and June 8, 2006.)

These technologies did not address the complex nature of mrsa, whose multiple virulence factors infect a number of organs in the body and affect them at different times, Thammavongsa observed.

“our technology is different since our antibody generates broad-spectrum protective immune responses against all of these virulence factors,” he said.

Failures in mrsa – and the growing list of companies in the space – haven’t deterred newcomers, since the indication represents a global opportunity estimated at more than $1 billion and growing. aradis pharmaceuticals llC, arsanis Biosciences inc. and savara pharmaceuticals inc. are among the biotechs with trials under way for vaccines or antibodies targeting mrsa, according to Cortellis Clinical Trials intelligence.

operating virtually with just its four co-founders, who include

University of Chicago microbiology professors olaf schneewind and dominique missiakas, Terravab has generated a master Cho cell bank expressing mvQ3 to prepare for cGmp manufacturing, which could be conducted anywhere in the world. The company is self-funded, so far, but “right now we’re looking for partners or investors to move us along,” Thammavongsa said, with a goal of filing an investigational new drug application and entering a phase i trial within two years.

To that end, Thammavongsa took the company’s show on the road earlier in 2014 to the Chinabio partnering Forum in suzhou to introduce Terravab to local biopharmas and investors, with the goal of seeking a collaboration for manufacturing, clinical testing and regulatory approval in China. mrsa is on a particularly rapid ascent in China, growing from an incidence of approximately 20 percent of S. aureus infections in 1980 to approximately 60 percent in 2010, he said.

To keep its options open, Terravab – which combines the latin root word for world or earth with vaccine antibody – also is considering the prospect of raising a $5 million to $10 million series a round. //



pAin in the BrAin? trigeMinA Seeking to BreAk the BArrierBy Marie Powers, Staff Writer

No matter what the cause – cluster headaches, migraines, cancer, nerve damage, temporomandibular joint disorder, trigeminal neuralgia or another disorder – chronic head pain remains among the most vexing of medical conditions for patients and the most daunting of challenges for scientists. over-the-counter remedies that may help acute conditions often are ineffective for chronic pain, and opioids that can relieve pain come with serious downsides.

Trigemina inc. is seeking to resolve chronic head pain while sidestepping the dependency of opioid drugs by administering a new application of oxytocin to the nasal mucosa, where the drug migrates along cranial nerves and is delivered directly to the central nervous system.

The moraga, Calif.-based company was founded in 2006 by david Yeomans, director of pain research and associate professor of anesthesia at stanford University school of medicine, and the company’s chief scientist. some months earlier, Yeomans had struck up a conversation at a conference with William Frey, founder and co-director of the alzheimer’s research Center at regions hospital, professor of pharmaceutics and a faculty member in neurology, oral biology and neuroscience at the University of minnesota. Frey had discovered a non-invasive, intranasal method for bypassing the blood-brain barrier to rapidly deliver and target therapeutic agents to the brain along the olfactory and trigeminal neural pathways – thus, the company’s name. Yeomans thought the method could prove an ingenious route for delivering large molecules to the brain to provide an analgesic effect.

The two began running experiments, which showed impressive results using oxytocin, according to Charles Yeomans, david’s brother, who now serves as Trigemina’s Ceo. The scientists filed patents based on david Yeomans’ work at stanford and continued to conduct preclinical and early clinical experiments. in the lab, they showed the application of oxytocin, using Frey’s delivery method, halted the effect of calcitonin gene-related peptide, or CGrp, the neurotransmitter for pain. The process worked even to tamp down migraine, with its constellation of symptoms.

in 2007, the company conducted a phase ii trial in australia, administering a single dose in acute migraine patients as soon

as possible after the onset of symptoms. The mechanism of action was not well understood at the time, however, according to Charles Yeomans, who explained that a certain amount of time was needed following the onset of migraine to up-regulate the receptor and induce inflammation, providing a target for the drug to do its job. Too, it was critical for patients to avoid the use of any substance that might potentially prevent that up-regulation process. long story short, the initial efficacy trial fell flat.

The scientists went back to the drawing board and, in 2009, conducted a smaller trial in 40 patients with chronic migraine, “who were more likely to be up-regulating all the time,” Charles Yeomans said. This time, the oxytocin delivery method worked better, but the company ran out of money before it could repeat the experiments and study the long-term effects of the drug.

Charles Yeomans, who had a background in banking and private equity investment and was an early investor in Trigemina, offered to step in so his brother could keep the research team together. The new Ceo attracted venture funding from Chilean-based investor aurus, through its aurus Bios Fund, supplemented by additional funding from high net worth individuals. in late 2011, Trigemina was “reconstituted,” Yeomans said.

‘We doN’T WaNT To haNd This oFF aNd Walk aWaY’

Work on the intranasal oxytocin candidate, Ti-001, has progressed rapidly ever since. in may 2013, the company began a randomized, double-blind, placebo-controlled, withdrawal- and enrollment-enriched phase ii safety and efficacy study using the nasal spray formulation. The study is expected to enroll 240 chronic migraine patients in Chile and australia.

The primary outcome measure is mean reduction in migraine headache days from baseline – the 28-day screening period before enrollment in the study, according to Thomson reuters Cortellis Clinical Trials intelligence (CTi). secondary measures include frequency of migraine episodes; change in migraine pain scores; frequency and severity of adverse events; frequency of nausea, phonophobia and photophobia; time to discontinuation due to any cause; and interleukin-6 levels as a marker of response, according to Cortellis CTi. The study also is


assessing several doses, from 15 to 60 iU, to determine the best dose for a phase iii study.

in June 2013, Trigemina completed a $4.5 million series a financing, led by aurus and supplemented by a grant from the government of Chile, to fund the phase ii study to completion. The company expects to report data late in the third quarter.

“if the early trends hold, we will have a very strong candidate to help chronic migrainers,” Yeomans said. “We think this will be a candidate to move into phase iii pretty fast.”

migraine is a large but challenging space dominated by Botox (onabotulinumtoxina, allergan inc.). in January 2013, allergan moved to secure its position in migraine treatment by purchasing map pharmaceuticals inc. in a cash deal, acquiring the company’s shares at $25 each. (see BioWorld Today, Jan. 24, 2013.)

in december 2013, depomed inc. added some interest to the space and boosted its pain portfolio with the purchase of Nautilus Neurosciences inc.’s migraine drug, Cambia (diclofenac potassium for oral solution) – the only single agent nonsteroidal anti-inflammatory specifically indicated for

migraine. (see BioWorld Today, dec. 19, 2013.)

But chronic migraine remains unchartered territory, though a growing number of companies is seeking to fill the void, with CGrp receptor antagonists among the leading mechanisms of action. once the Ti-001 phase ii is complete, Trigemina likely will seek another financing round to move post haste into phase iii, Yeomans said.

Trigemina has a second molecule, Ti-002, a polypeptide also delivered via the nasal-cerebral pathway that is designed to target a broad range of pain throughout the body, including neuropathic pain.

With multiple assets, the company’s long-term business strategy will depend on the circumstances.

“if we complete our trial, we could look for a partner that would be supportive and help us to get this into the market,” Yeomans said. “But with the expertise we’ve developed internally, we don’t want to hand this off and walk away. We have a lot of passion for this drug, and we want to see it get to people whom it could help.” //



tunitAS fuSion proteinS tAke douBLe AiM At ALLergic diSeASeBy Marie Powers, Staff Writer

although Tunitas Therapeutics inc. has its namesake in California’s Tunitas Creek, which meanders from the santa Cruz mountains to the pacific ocean, the company’s progress has been anything but a long and winding road.

established early in 2009 by Nolan sigal, president and Ceo, and andrew saxon, acting chief scientific officer, the san Francisco-based biotech is developing a family of fusion proteins that interact with two receptors on a number of key allergic cells.

The technology inhibits the release of both mediators, such as histamines and leukotrienes, as well as cytokines produced by those cells. over a longer period of time, the proteins turn off ige production, the key trigger for allergic disease.

epsi-gam, the company’s lead candidate, is composed of the Fc portions of human ige and igG1, linking the receptors for ige on basophils, mast cells and B cells with the Fcgriib receptor on those cells to inhibit their function. advanced to investigational new drug-enabling studies, the technology directly inhibits basophil and mast cell function – the primary cellular mediators of allergic disease – by turning off their signaling through the ige receptor and then suppressing ige production.

Because epsi-gam is not allergen-specific, the platform offers the potential advantage of treating multiple food and/or inhalant allergies with a single therapeutic, according to sigal, who said phase i studies seeking initial proof of principle could begin late this year. The company, which also has earlier-stage programs in cat and peanut allergen vaccines, previously demonstrated both mechanisms in nonhuman primates.

saxon, a professor and former chief of clinical immunology and allergy at the University of California los angeles (UCla) school of medicine, developed the fusion protein platforms in the early 2000s but was frustrated by foot-dragging at the institution’s technology transfer office. sigal, a colleague who began his career as the University of Toronto studying pediatric immunodeficiency and bone marrow transplantation, had since moved to industry. For a decade, he served as head of immunology research at merck & Co. inc. before co-founding pharmacopeia inc., which was taken public in 1996. in 2000, sigal joined Cytokinetics inc., where he spent several years as head of r&d, before taking the helm of Trellis Bioscience inc.

around 2007, saxon contacted sigal, looking to jumpstart the fusion protein technology.

“i’m sure i wasn’t the only person he contacted,” sigal admitted. “i’m sure he went through his entire rolodex. But we reconnected.”

The reacquaintance was providential. after meeting nearly weekly for several months, sigal recognized in saxon’s technology the potential to leapfrog allergy compounds in development at the time. Taking a license to the technology from UCla, Tunitas was born.

With experience in raising capital from venture financings and initial public offerings (ipo), sigal thought the next step would be the easy part.

“From my track record of building two successful companies, i had assumed – maybe a little naively – that i would call my friends in the venture community and in a couple of months i’d have $10 million in the bank,” he said.

Needless to say, that didn’t happen. in addition to the crisis in the capital markets, Tunitas confronted a wall of uncertainty about the allergy space, with prospective investors snubbing an indication “that wasn’t rheumatoid arthritis, wasn’t cancer and wasn’t alzheimer’s disease,” sigal recalled. “Their view was that the medical need wasn’t clear.”

The trained academics turned to a funding source they knew intimately. “We rolled up our sleeves and started writing grants,” he said.

Tunitas since has attracted $10 million in grant funding, mostly from the National institutes of health, and eschewed venture capital altogether. The company has spent only half of that war chest advancing its lead protein into preclinical development, with the remainder providing a potential runway of two to three years.

“We still have a lot of research money to take other products in our platform and move them to the point where we will nominate molecules for formal preclinical development,” sigal said. “having been born and bred at merck, i think of this in a little bit more formal way than a lot of biotech companies. it’s a very rigorous nomination process.”

in the meantime, the allergy space has witnessed “a sea change” in the potential commercial opportunities associated


with unmet medical need, while pharmas and investors have grown curious about the company’s technology in light of its eight-figure grant funding, he added.

Tunitas has plenty of company in allergy development. a search on Cortellis Clinical Trials intelligence shows that nearly 150 allergy compounds are in development, most at biotechs and pharmas rather than academic centers. of those, only 15 are reported to have progressed to phase iib or beyond. Circassia ltd., alk-abello a/s, Cytos Biotechnology ltd., Circassia ltd. and stallergenes sa are among the biggest names in allergy development, but promising newcomers include dBv Technologies sa, immunomic Therapeutics inc., sitari pharmaceuticals inc. and immusant inc. (see BioWorld Today, dec. 14, 2011, march 8, 2013, oct. 21, 2013, and Nov. 22, 2013.)

Because the epsi-gam platform, targeting allergic asthma, will require large trials, “we know we will partner that out,” sigal said, “but we’d like to keep it as long as possible to increase its value.”

With that goal in mind, sigal is considering venture funding as the next step in the financing plan. although he’s “fairly agnostic” about fundraising options, sigal suggested an ideal scenario would be a $5 million to $6 million venture round – “with the right syndicate of investors who would add value to the company” – to provide initial clinical data that would attract a more advantageous pharma or venture deal

to fund phase ii studies.

either way, “the most important thing right now is to get our initial drug into trials and see whether it works,” he added. “We have enormous confidence that it’s going to work, but you never know until it actually does.”

The company has a timetable for the phase i study, but execution is “dependent on financing,” sigal said. The initial trial, in australia, could begin as early as the fourth quarter 2014, with top-line data reporting in early 2015.

a member of the University of California san Francisco’s California institute for Quantitative Biosciences, or QB3, network, Tunitas keeps a low burn rate by accessing shared lab space and other research facilities. The company employs eight scientists and uses collaborators for other development and manufacturing work. in december 2013, Tunitas inked an agreement with dsm pharmaceutical products, of parsippany, N.J., the manufacturing and technology business of royal dsm, to begin process development for its lead Fc fusion protein.

long term, Tunitas will consider a variety of options, including partnering other assets in the pipeline or taking the company public through an ipo.

“as a young company, you can’t rule out any avenue,” sigal said. //



‘uniVerAL’ picture, SAyS ceo

VerSAtiLe Actr: pLAtforM gArnerS $12M in SerieS A for unuM therApeuticS

By Randy Osborne, Staff Writer

With cell therapy showing more promise lately, Unum Therapeutics inc.’s series a funding will help advance its platform for cancer treatment based on an antibody-coupled T-cell receptor (aCTr), in which T cells are genetically programmed so that they can go after a variety of cancers via targeting antibodies, and are not restricted by a particular antigen.

The aCTr approach differs from others that are limited to a single target and thus can treat only a narrow set of tumors. That is where the firm’s name comes from – latin, meaning “one,” most commonly heard in the phrase “e pluribus unum,” meaning “out of many, one.”

aCTr “takes advantage of Cd16, which is really part of the therapy itself,” said Unum Ceo Charles Wilson. “The way it works is essentially to create a modified T cell that expresses a chimeric receptor. Those engineered T cells are then combined with a tumor-targeting antibody like a rituxan [rituximab, roche aG] or a herceptin [trastuzumab, roche aG].” Cd16 on the surface of the T cells “arms” them and the antibody steers the medicine, he said.

“so, in a patient, basically you would dose the modified T cells and, let’s say, herceptin together. in the body, the herceptin would find the breast cancer tumor cells, and would serve as a beacon to target the modified T cells to attack the tumor,” Wilson told BioWorld Today. “in some ways, it is similar to what’s being done with [chimeric antigen receptors, or Cars] and high-affinity T-cell receptors. What sets it apart is that it really is a universal approach. There’s nothing specific about the T cell itself that limits it to one cancer type.”

Chief scientific founder of the company, dario Campana, is known as a leader in cancer cell therapy and at the National University of singapore developed the aCTr technology. at st. Jude Children’s research hospital in memphis, Campana created the much-talked-about Car approach now being pursued by various drug developers. (see BioWorld Today, June 23, 2014.)

“at last count, there were probably something like 30 to 40 different tumor-specific antibodies that have gone into the clinic,” Wilson said. “our idea would be that aCTr T cells could be a combination partner for all of those, if you wanted to ultimately create a T-cell therapy that would be antibody directed.” The

approach calls to mind antibody-drug conjugates (adCs), another increasingly popular strategy. But “some of the limitations that are known to be out there for adCs we don’t think should be issues for our T cells. For example, with adCs it’s known you need a pretty high concentration of the antigen on the surface of the tumor cell in order to get enough [of the toxic agent] into the cell to kill it. in contrast, with all the T-cell receptor-based approaches like aCTr, you need many fewer copies, probably on the order of tens to hundreds per cell, as opposed to the millions you need for conjugates. similarly, you don’t need to have those markers internalizing. For adCs, you need to basically drag the cytotoxin into the cell. We don’t need to do that with a T cell,” he noted.

lastly, with the conjugates, you always had this issue that the toxin comes off the antibody and, ultimately, that limits how much of a dose you can put into the body.” in all, aCTr promises a “much cleaner and more potent effector function” than adCs, he said.

Unum plans to use the series a money to advance its lead candidate. Wilson said Unum will enter the clinic with the frontrunner “sometime this quarter,” and the available funds “should be more than sufficient to demonstrate proof of concept. part of what we’re going to be doing in parallel is work with partners to generate data that would show that taking our T cell plus their antibody is creating a potent therapy in preclinical models. once we’ve clinically shown that our cells are safe and effective, then we’d be able to very rapidly start testing new combinations using antibodies.”

GoiNG aFTer solid TUmors

The company is “exploring options right now. We’re in discussions with a number of players that are antibody innovators,” Wilson said. “obviously, we’re at a point where we don’t want to give up too much value. as we think about how this is going to look five years in the future, we’re really intending to focus on the cell therapy piece of it. We’re going to be building out the capabilities for doing manufacturing, and all the regulatory work associated with making the cells, and ultimately bringing the cells to patients directly. Then we’ll work with partners who will provide the antibody piece.”

Within two years, “if everything goes right, it should be feasible to take some of these antibodies [under development by others] into clinical trials with our T cells,” Wilson said. “There are a number of antibodies that have already been made according to current


good manufacturing practices, and investigational new drug [iNd] applications may have already been filed.” once the safety data are established for the T cells, starting a combination clinical experiment – with the antibody under one iNd and Unum’s T cells under another – seems possible, he said.

“all of us with the key founding team have had a role in the Car space,” Wilson said. “What we’d really like to do is move beyond the current focus, which is very much on Cd19, going after a couple of blood cancers, and start to explore what could these types of cell therapy do in particular, i think, in the solid tumor space, where there is enormous unmet medical need.”

dosing flexibility may help a lot there. “Car T-cell therapies are very potent,” Wilson noted. “often, the activity of the T cell itself

can cause dangerous side effects, like cytokine release, which can be life threatening. one of the advantages that we have comes from the fact that we have a separate targeting moiety from the effector function. We can set the ‘thermostat’ on the T cells to a desirable range. We can turn up or down the activity by simply adjusting the antibody dose. That will be important, especially as we go into solid tumors, where very often, the markers you’re trying to hit are expressed on tissues other than the tumor.”

The round was led by Fidelity Biosciences and atlas venture, with participation from sanofi-Genzyme Bioventures. Unum’s board consists of Wilson, Ben auspitz, partner at Fidelity, and Bruce Booth, partner at atlas venture. //



third rock’S VoyAger BLASting off with $45M for cnS gene therApyBy Randy Osborne, Staff Writer

Fueled by $45 million in series a money, gene therapy player voyager Therapeutics inc. was expected to make public in February 2014 the details of its adeno-associated virus (aav) approach in central nervous system (CNs) disorders.

Formed by Third rock ventures llC, the Cambridge, mass.-based firm – which will use gene replacement or gene knockdown techniques, depending on the disease – has a parkinson’s disease (pd) program in an ongoing phase ib study with collaborators at the University of California san Francisco.

preclinical programs are investigating a monogenic (a mutation in the sod1 gene) form of amyotrophic lateral sclerosis (als), and Friedreich’s ataxia (Frda).

The company has been in the works for “well over a year and a half,” said interim chief medical officer, phil reilly. “as part of that process, i and the team examined scores, if not a hundred, monogenic disorders that involve the central nervous system” and narrowed them down to three.

size of patient population and severity of the disorder were factors in the choices, as well as “the ability to reach some of the key cells that we wanted to reach,” reilly told BioWorld Today. Frda and als are “primarily, but not exclusively, diseases of the spinal cord and related nerves,” so access to that tissue “seemed like reasonable targets in a relatively new field,” he said.

“The fluid around the spinal cord and the brain represent, you could say, a quasi-privileged space from an immune point of view,” too, he said.

although still considered fresh, aav work has been picking up, with “quite a dramatic increase” in academic work and new companies formed around the technology, reilly said.

“at this point, aav has quite a good safety record,” he pointed out. “one always has to be careful about saying that, but aav has been in clinical trials with about 1,300 patients already,” though not necessarily in CNs disorders.

“aav does not integrate normally into the host dNa, so it theoretically reduces some of the risks that have been associated with earlier use of other viruses,” he said.

idiopathic als, the commoner kind, leads to death “in about five years,” reilly said, whereas the monogenic variety can kill in as little as 18 months.

“i would say [als caused by] sod1 represents on the order of 2

percent to 3 percent of all als patients, so that would only be a few hundred patients in the U.s. and a few hundred more in europe,” he said. “But – and i don’t want to make too much of this – there is, in the extensive als literature, a suggestion that sod1 may be an important pathological feature of idiopathic als,” so that research into the monogenic form could lead to “learnings that might be applicable to the broader population,” he added.

The company is checking out promising new vectors as well.

“That’s an important leg of the tripod of our company along with the clinical programs – vector engineering and development,” reilly said. “also, there’s much still to be learned about producing, at an industrial scale, vector that would meet the kind of requirements that we expect the Fda to impose on us.”

voyager can do it, he contended.

“We do not want to diminish the challenge, but we have hired appropriate people and we’re diverting resources into a project to make, in-house, a high-quality production facility,” he said. “The amount you need depends on the disease you go after,” and with an illness such as pd, the quantity is high.

“also, if one is going to deliver systemically as opposed to locally – and we are not planning to do that, at this time – one would have to totally rethink production demands for the virus,” reilly said.

interim chief business officer Jim Geraghty said voyager has “all the funds that we’re going to need to develop those for the next three years,” and has been talking with pharma firms and large biotech concerns. Geraghty cited a “high level of inbound interest expressed in collaborating with us in different areas” with “room for so-called non-dilutive financing” as an option to widen capabilities and add partners.

“if you look at the model of other Third rock companies, at some point there might be a crossover round leading to a public offering, with the combination of funds that can provide over a three to five-year period,” he said.

he and reilly, “along with many others at Third rock, were very involved with the company that’s now called Bluebird Bio,” also of Cambridge, mass., which researches lentiviral vectors, Geraghty told BioWorld Today. in the summer of 2013, Bluebird


conducted an above-the-range initial public offering, selling about 5.9 million shares at $17 each to raise $101 million. (see BioWorld Today, June 20, 2013.)

organizers of Bluebird decided it would not try the aav

strategy, which left it for voyager, which is working with patient-advocate groups as well as academic and industry sources to move its CNs efforts forward. //



VyoMe AddS $8M to AdVAnce pipeLine AgAinSt Skin conditionSBy T.V. Padma, Staff Writer

NeW delhi – indian biopharma company vyome Biosciences raised almost $8 million in a second round of fundraising as part of a push to develop treatments for hard-to-treat skin conditions such as acne, persistent dandruff and bacterial and fungal skin infections.

sabre Capital led the investment into that series B fundraising, while kalaari Capital and aarin Capital, both existing investors, also participated. kalaari and aarin had invested $3.5 million in a first funding round.

vyome, set up four years ago in New delhi, has completed clinical research on two products. Two lead compounds are in the preclinical stage.

The company was co-founded by shiladitya sengupta, co-chair at the Center for regenerative Therapeutics at Brigham and Women’s hospital at harvard medical school in Boston; rajesh Gokhale, director of the institute of Genomics and integrative Biology in New delhi; N. venkat, former president of the hyderabad-based firm shantha Biotechnics; and rajiv mantri, executive director of Navam Capital.

vyome focuses on hard-to-treat dermatology conditions where relapse rates are high and there are no effective solutions, venkat, the firm’s Ceo, told Bioworld Today. its leading-edge biotechnology products include molecules to kill dandruff-causing fungus and new antibiotics to kill resistant acne-causing bacteria.

Two dandruff products, vB0001 and vB2421, have completed clinical trials and are ready for commercialization.

The company also has come up with a new molecule that could help in acne treatment. That compound has undergone preclinical research.

“our key objectives are to take some of our new innovative pharmaceutical products in dermatology through the U.s. Fda,” venkat said. The latest financing “was a major landmark” in vyome’s journey to translate cutting-edge science into differentiated products and innovative commercialization strategies.

venkat said in the past few decades there has “hardly been any innovation” or novel products in dermatology, a sector that could be worth $20 billion in the next three or four years. “most of

the molecules are old and at best there has been incremental progress, for example, using different percentages of blends used in a product,” he said. “our idea is to bring innovation, science and strategy and merge them together to develop a good platform for novel technologies and products. “There are lots of opportunities, with right ideas and right innovation,” he added.

vyome’s dandruff product, for example, is based on molecular replacement therapeutics in which some of the old molecules used in treatment products are replaced by existing but unused molecules. The products for acne caused by resistant bacteria use dual action rational therapeutics, or darTs, which use novel chemical entities that have dual mechanisms of action to kill bacteria.

There is a huge opportunity globally and an unmet need for acne, especially drug-resistant acne,” said sabre’s alok samantaney, who also pointed out that there are “very, very few companies in india doing innovative work or developing new molecules.”

vyome’s chairman, raghunath mashelkar, former director general of the india’s Council of scientific and industrial research, echoed that sentiment.

“something has been missing in india,” he said. “it is the cutting-edge science-led innovation that leads to products that are not just first to india, but first to the world. We, at vyome, with a dynamic young team of researchers, are going to achieve precisely this.”

vyome has a “world-class team, with a stellar management, an experienced board, real innovative work, potential for upsides for returns and relatively moderate risk in the area they are working in,” samantaney said.

Ceo venkat said the new series of financing would enable the company to complete the critical milestones of Fda filings and complete phase i and phase ii trials for some of its lead compounds.

sabre partners, founded by a group of investment professionals led by rajiv maliwal, has invested more than $300 million in india. it has an infrastructure fund and a health care-focused venture capital fund called spring healthcare, which has financed two hospital chains and a diagnostics firm.

Gokhale, another vyome co-founder, is also director of the


institute of Genomics and integrative Biology (iGiB) in New delhi. Gokhale’s group on chemical and systems biology at iGiB focuses on three main research areas: tuberculosis (TB), especially of organs other than the lungs; molecular networks that influence skin pigmentation; and systems biology approaches to understand vitiligo, a skin disorder in which white patches appear on the skin.

one of the iGiB group’s recent research projects, published in

the Proceedings of the National Academy of Sciences in February 2014 identified a new mechanism of skin pigmentation balance and proposed that the strength and durability of local skin immune response may be decisive factors to delineate outcome between skin tanning, which is a protective mechanism against sun’s harmful radiation, and cancer that can be caused by excessive exposure to the sun’s ultraviolet rays. //



xeriS rethinkS deLiVery technoLogy to iMproVe hypogLyceMiA treAtMent By Marie Powers, Staff Writer

steve prestrelski has a fascination with improving drug delivery. Two decades of experience in biotech convinced the research scientist and inventor that some of the biggest shortcomings associated with promising drugs were related largely to formulation and delivery mechanisms.

xeris pharmaceuticals inc., established in 2006 and operating virtually until a few years ago, is testing that thesis. The company is developing a soluble, stable formulation of glucagon as an alternative to existing glucagon emergency kits to treat hypoglycemia. Ultimately, xeris aims to provide additional products to address broader problems of hypoglycemia in the diabetic population and to improve the delivery of other rescue drugs, such as diazepam for epileptic seizures.

more than a decade ago, prestrelski was vice president of biopharmaceuticals at powderject Technologies plc, where he had helped to pioneer the delivery of solid biopharmaceuticals, when the oxford, Uk-based company was acquired by Chiron Corp. to expand its vaccine footprint. (see BioWorld Today, may 20, 2003.)

prestrelski moved on to amylin pharmaceuticals inc., now a wholly owned subsidiary of Bristol-myers squibb Co., as vice president of pharmaceutical r&d and executive director of the Bydureon (exenatide) program, where he became acquainted with the ins and outs of delivering peptide-based drugs such as glucagon and insulin.

sensitized to the unmet need to treat hypoglycemic attacks in patients with diabetes, prestrelski kept revisiting the potential of the formulation technology he developed at powderject, which was designed to create non-aqueous solutions and suspensions of dry powders, potentially improving the delivery of active pharmaceutical ingredients consisting of large molecules such as proteins, vaccines and monoclonal antibodies.

in 2004, Chiron spun out the dNa vaccines technology it acquired in the powderject purchase into powdermed ltd., which was headed by a team of former powderject executives. Two years later, pfizer inc. acquired powdermed, whose lead product against seasonal flu had just entered a phase i/iia challenge trial in london and a U.s. phase i trial. (see BioWorld

Today, may 18, 2004, and oct. 11, 2006.)

With the former powderject essentially “broken into pieces,” prestrelski was able to acquire the formulation technology.

operating under the radar, xeris – the Greek word for “dry” – refashioned prestrelski’s formulation process into two technologies, xeriject and xerisol, designed to improve the delivery and reduce the side effects associated with existing drugs by turning them into non-aqueous pastes and solutions. The technologies offer the additional advantage of extending the patent life for certain drugs.

For nearly five years, xeris was incubated by prestrelski and co-founder John kinzell. a key milestone for the company was receipt of a small Business innovation research (sBir) grant in 2011 to advance its glucagon rescue pen, or G-pen (glucagon injection), through phase i/ii studies as a rescue treatment for severe hypoglycemic emergencies in diabetics. xeris’ glucagon formulation is pre-mixed, allowing for administration in only two steps as a ready-to-inject glucagon that is stable at room temperature. Currently marketed glucagon emergency kits contain the active ingredient as a dry powder in a sealed vial, which must be reconstituted with a water-filled syringe in a multi-step process before injection, prestrelski explained.

at the end of 2011, xeris moved to austin, Texas, and launched in earnest with a $1.5 million series a financing led by the Central Texas angel Network. around that time, prestrelski joined the company as chief scientific officer.

moviNG ToWard ’a CommerCial-readY asseT’

since then, xeris has attracted more than $3 million in additional sBir grants as well as funding from the JdrF, the helmsley Charitable Trust and several epilepsy research organizations. all told, the company has raised about $12 million.

That funding enabled xeris to move the G-pen as well as its G-pen mini and G-pump (glucagon infusion) candidates into phase ii studies. a “formulations-based” company, xeris partners with device manufacturers to develop a range of products. For example, the company is advancing a single glucagon formulation using not only an auto injector but also a pen injector and infusion pump applications.

The xeris formulation offers significant advantages to a


product that has been on the market for decades without any competition, said doug Baum, the company’s president and Ceo.

“Now that we have this liquid glucagon, we can not only compete against products on the market with a ready-to-inject glucagon but we can also put it into other devices and create products that aren’t currently available because they’re not conducive to dry powder,” Baum told BioWorld Today.

xeris is “device agnostic,” seeking the best delivery technology for each indication, Baum added. although the first few programs are rescue-oriented, the technology is applicable to drugs that may need refrigeration or cold chain distribution as well as intravenous applications that could be moved from the clinic to a patient’s home as a self-administered injection.

The company is pursuing Fda 505(b)(2) pathway for its drug-device combinations, with the lead application potentially reaching the market in 2016.

“The Fda has become fairly clear about the pathway for working with drug-device combinations,” prestrelski said. “The general challenge for drug-device combos is that the Fda divisions don’t talk with each other very well.” xeris works primarily with the Center for drug evaluation and research, since “the drug is the primary driver of the efficacy of the product.”

xeris is raising a $10 million series B that Baum hopes to close within 60 days. That money will move the lead G-pen program to a new drug application submission and advance the follow-on product candidates, “effectively getting us a commercial-ready asset to launch,” Baum said. at that point, the company will decide whether to pursue another private equity round, consider an initial public offering or partner with a big pharma.

“We still have a number of options to pursue and evaluate between now and then,” Baum said. //



Biotech VeterAn coLeS returnS to foLd with StArt-up yuMAnity By Jennifer Boggs, Managing Editor

a little more than a year after completing the sale of his company to amgen inc. in a $10.4 billion deal, the former Ceo of onyx pharmaceuticals inc., Tony Coles, is back in the biotech game, this time heading start-up Yumanity Therapeutics, which is aimed at neurodegenerative diseases and already boasts a potential new target for parkinson’s disease. (see BioWorld Today, aug. 27, 2013.)

it’s an opportunity that came about thanks to his “very old and dear friend” susan lindquist, whose pioneering work in protein misfolding previously founded Foldrx pharmaceuticals inc., a rare disease firm snagged by pfizer inc. in 2010. in fact, Coles and lindquist met while serving on Foldrx’s board.

“i gained immediate respect for her science, which is world class,” he said of lindquist, who works at the Whitehead institute at the massachusetts institute of Technology and is a 2009 National medal of science winner. Coles said he also was impressed with lindquist’s “values, ethics and integrity,” so when she contacted him several months ago about establishing a company around the technology in her lab, “i told her i would give her a hand.”

at first that was to entail setting up the firm and raising money, but “the more i studied the technology, the more compelled i was” to take a bigger role, he said.

a large part of the attraction was the technology itself. Yumanity’s discovery platforms comprise technologies to model and screen compounds in pathologies of protein misfolding, believed to underlie nearly all neurodegenerative diseases. a protein’s amino acids must fold in a particular way to ensure proper cellular function; misfolded proteins, on the other hand, “can really wreak havoc in the cellular processes,” Coles said.

“once that goes awry, it’s really hard to get the cellular processes back on track,” he added, with the result being the clumping of proteins by cells that have been damaged – beta-amyloid in alzheimer’s and lewy bodies in parkinson’s, for example.

The trick has been finding methods of studying those pathologies and testing compounds in ways that can be translated from the lab to humans. The “beauty” of Yumanity’s approach is that it involves a phenotypic rather than a target-based approach, Coles said.

Yumanity’s ultra-high-throughput phenotypic screening platforms are designed to model protein misfolding pathologies in yeast, then testing compounds “to see if you can rescue the yeast,” he explained. Then those compounds are tested in the firm’s stem cell-derived neuron platform, again, to see if those cells can be rescued. if they can, “then you know you have a compound that has biological activity,” he told BioWorld Today.

so far, the company already has taken those “two very promising steps” in parkinson’s, having identified a potential new target and is looking to advance a chemical series against it. Coles said it was too early to talk about clinical time frames – “we’ll let the science lead us” – but Yumanity, which currently has five employees in addition to its Ceo, is expected to grow its headcount to as many as 20 or 25 by the end of 2015.

The company was seeded by Coles – who walked away from 2013’s onyx deal with nearly $60 million, according to seC reports – and lindquist. it will seek to close a series a financing round in the first quarter of next year.

‘The proBlems oF This milleNNiUm’

along with the technology, it also was the focus on neurodegenerative diseases that drew Coles’ interest. Yumanity also plans to focus efforts in alzheimer’s disease and amyotrophic lateral sclerosis (als).

“These are the problems of this millennium,” he said, adding that an estimated 50 million people worldwide suffer from neurodegenerative disease. Costs for treating those diseases run about $650 billion and are expected to triple by 2050, “so we have a moral imperative.”

indeed, the company’s name itself is intended to reflect that imperative. Combining “humanity” with the “y” in “yeast,” it’s intended to reference the firm’s “yeast to human” technology. But it also refers to a “problem so big, so intractable and [one that] costs so much, that we just have to do something,” Coles said.

Currently, there are no disease-modifying therapies approved, though it hasn’t been for a lack of trying. drug development in the neurodegenerative space has been riddled with devastating failures. The past couple of years alone have seen clinical misses in alzheimer’s with crenezumab, an anti-amyloid beta antibody from aC immune sa and roche aG, and in als with Cytokinetics


inc.’s tirasemtiv and dexpramipexole, a drug developed by partners Biogen idec inc. and knopp Biosciences llC. (see BioWorld Today, Jan. 4, 2013, april 28, 2014, and July 17, 2014.)

Coles and his team, however, remain undaunted by the space’s reputation for difficulty.

“a lot of people said the same thing in the 1990s [about hiv],” he noted. Now hiv is down to a chronic, manageable illness. “Great things come out of some out-of-the-box thinking.”

Nor is he daunted by the prospect of running his first start-up. his resume includes stints at Bristol-myers squibb Co., vertex pharmaceuticals inc. and Nps pharmaceuticals inc. prior to taking the helm at onyx in 2008 – in addition to the amgen acquisition, his tenure at onyx included the purchase of proteolix inc. for multiple myeloma drug that would gain

approval as kyprolis (carfilzomib) and reaching a favorable end to a long-running dispute with partner Bayer aG over a next-generation multikinase inhibitor – but Yumanity will be Coles’ first foray into heading up an early stage firm. (see BioWorld Today, oct. 13, 2009, and oct. 13, 2011.)

Because of his onyx experience, “i do actually know what success looks like,” he said. “so we’ll work backward, using that as a template.”

Joining Coles on the executive team is kenneth rhodes, who will serve as chief scientific officer, who will oversee the work on Yumanity’s integrated platforms, which were developed in close collaboration with scientific co-founders vikram khurana, Chee-yeun Chung and daniel Tardiff. //



zAi hAS ArriVed; inkS deAL with SAnofi for precLinicAL copd drugSBy Shannon Ellis, Staff Writer

shaNGhai – Newly minted Zai lab ltd., of shanghai, has made its eagerly awaited debut announcement, obtaining global rights to two sanofi sa preclinical compounds for chronic respiratory diseases.

and, while the firm is only just finding its legs, the founder and Ceo, samantha du, is well regarded as one of China’s pioneering returnee biotech entrepreneurs, putting Zai labs on the radar of China’s industry insiders.

Zai will be responsible for global development for the two compounds, which are ready to enter the clinic as per Fda standards but still are being analyzed to meet CFda requirements for chronic obstructive pulmonary disorder (Copd), asthma and idiopathic pulmonary fibrosis (ipF). sanofi may potentially receive development, regulatory and approval milestones and tiered royalties from global sales, though specific terms were not disclosed.

Zai lab, meanwhile, is taking a clear stance that it will develop drugs not only to address major unmet medical needs in China, but also globally. Copd is a condition that fits that bill – exacerbated by factors such as air pollution and smoking – it is a chronic disease that is on the rise in China and globally. The Who expects Copd to be the third leading cause of death globally by 2030.

Zai lab intends to take advantage of certain aspects that make drug development in China attractive, including large treatment-naïve patient populations. in the case of Copd, for instance, the company estimated there are 40 million patients that suffer from the chronic condition in China.

“We feel that by effectively using the huge patient population to demonstrate proof of concept, and by working collaboratively, we can speed up the development process, not just for China but also to meet global needs,” du told BioWorld Today.

Few companies in China have the chops to target innovative drug development for global markets. however, Zai labs, with its Western-trained, China savvy team, might be one of the few to meet that high bar.

That team starts with du, who began her career in innovative drug development at pfizer inc., where she worked on two global programs that were commercially successful. she left

her secure career and followed her passion to China with the aim of making a difference.

she made a mark in 2001 helping to set up hutchison medipharma, considered China’s first biotech exploring new drug development.

There she led the charge on setting up important partnerships with international companies such as astrazeneca plc and Johnson & Johnson, agreements that demonstrated that a new level of trust could exist between a local company and multinational corporations (mNCs).

even from the beginning at hutchison medipharma, more than a decade ago, she said, quality “was our number one focus. We did not want to develop drugs just to develop them. We really cared about the data and compliance quality, the truth of the science and clinical outcomes.”

From there, du went on to sequoia Capital, where in two years she invested in four health care companies, including Jhl Biotech Co. ltd., of Taipei, a leader in biosimilars. (see BioWorld Today, dec. 11, 2013.)

But du had the desire to return to innovative drug development and her passion for China. she decided it was time to try her entrepreneurial hand again to set up Zai lab.

“i feel this is what i want to spend the rest of my life work on; that is why i decided to rebuild a company called Zai lab, which means, one more time and the last time,” she said.

TimiNG riGhT For iNNovaTioN

This time around, du added, progress has gone a bit quicker. Back in the days of starting hutchison medipharma, there were significant challenges in finding talent, and the concept of “doing innovative r&d was largely unheard of in China at that time.”

she has been able to surround herself with experienced colleagues culminated from her various career stops, wanting to work for her again, from pfizer and hutchison, as well as other contacts networked along the way, include contacts from sanofi.

she said she is confident Zai’s in-licensing strategy, following in the footsteps of companies like puma Biotechnology inc. and Clovis oncology inc., will win out.


The timing, in particular, is right, now that the Chinese government is committed to developing homegrown innovation, and mNCs are looking for local partners to help ease the way.

although Zai has yet to secure government support, it is likely just a matter of time. according to du, the firm has backing from a global venture capital fund, to be made official shortly, that will help ensure it can move forward.

The focus of Zai will be anti-inflammatory diseases, oncology

and certain antiviral conditions mainly for hepatitis B and human papillomavirus, areas where the new team has tremendous experience, du said.

For her, Zai’s competitive advantage rests in its people. “This kind of caliber team, with this level of quality people willing to start up a company together for the dream to make a difference in certain therapeutic fields in China, is what will set us apart.” //


A Bioworld speciAl report The NexT GeNeraTioN: BioWorld ...into other parts of the body, so we may...

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