1 POLITICS, POLICY & LAW:CONFERRED IMMUNITY IN IPR

7 PRODUCT DEVELOPMENT:RUNNING INTERFERENCE

10 EMERGING COMPANY PROFILE:SELECTIVE SUPPRESSION

11 FINANCE:CHASING ZAI

13 EBB & FLOW:MINING FUNGI

CONFERRED IMMUNITY IN IPRBY STEVE USDIN, WASHINGTON EDITOR

The outcome of Allergan plc’s gambit to shield its Restasis cyclosporine patents from inter partes review could determine the fate of the IPR system and upset the balance of power between generic and brand drug companies under the Hatch-Waxman Act.By transferring rights to six patents for the dry eye drug to the Saint Regis Mohawk Tribe in a Sept. 8 deal, Allergan is trying to buy access to the tribe’s sovereign immunity. On Sept. 22, the tribe filed a motion asking the U.S. Patent and Trademark Office’s Patent Trial and Appeal Board (PTAB) to dismiss an IPR challenge brought by Mylan N.V. in 2016.Reactions from the public, the media and lawmakers when the deal was announced Sept. 8 were predictably swift and angry, as the industry already faces criticism of anticompetitive tactics and concern about the high cost of drugs.“This move rips off consumers who need these drugs and closes the market to innovative new generics, and we can’t let this go-around become the new normal,” Sen. Sherrod Brown (D-Ohio) said in a statement provided to BioCentury. Allergan Chairman, President and CEO Brent Saunders, who has championed the concept of the drug industry’s contract with society, defended the maneuver as an ethically sound defense of the right to a fair process for adjudicating patent validity.His interpretation of the social contract, widely publicized as a promise to cap price increases, actually rests on shared obligations: of industry to develop and ensure access to medicines, and of society to provide incentives and regulatory protections for innovation.He argues Congress violated the social contract by creating IPR, so Allergan and other companies should do what they can to evade IPR.

WEEK OF SEPTEMBER 25, 2017

Allergan’s deal to use sovereign immunity to shield Restasis from IPR challenges could kill the IPR system and upset Hatch-Waxman’s balance.

Patisiran settles the question of whether an RNAi therapeutic can be used safely, but the results may or may not translate to the rest of Alnylam’s pipeline.

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Lessons other innovator Chinese biotechs can learn from Zai’s fast ascent to its NASDAQ IPO.

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“The social contract is a two-way street,” Saunders told BioCentury. “We need to be able to rely on the rule of law and the predictability of the patent system to be incentivized to invest in innovation and meet the social need.”He also pointed out that, under the deal, the tribe has agreed not to use its sovereign immunity to block a suit that is ongoing in the federal courts concerning the Restasis patents. The tribe, however, appears to be considering doing exactly that in an unrelated suit involving high tech patents. In addition, in the motion filed to PTAB, the tribe asserted that it is immune from litigation in federal courts. Both Allergan and the law firm representing the tribe provided BioCentury with copies of the motion, which is not yet available online.In response to the deal between Allergan and the tribe, Brown told BioCentury he “will be looking into what Congress can do to close loopholes that drug companies exploit to avoid competition.”While a legislative resolution is not impossible, political gridlock makes the chances of getting any bill through Congress slim. The viability of the strategy will more likely turn on the courts’ interpretation of the sovereign immunity of Native American tribes. Given the economic stakes of eliminating or weakening IPR, along with the potential for the sovereign immunity strategy to more broadly alter Hatch-Waxman litigation, it is likely the controversy will be decided by the Supreme Court. That is, unless Allergan loses a pending district court case over its Restasis patents, or a separate case the Supreme Court will hear this fall sweeps IPR off the table.

POSSIBLE PRECEDENT

Allergan didn’t discover the sovereign immunity IPR defense.That honor belongs to the University of Florida, which argued in Covidien LP v. University of Florida Research Foundation Inc. that patents held by a state government — a sovereign entity — are immune to IPR challenges under the Eleventh Amendment to the U.S. Constitution. In January PTAB ruled in the university’s favor and dismissed the IPR challenge filed by Covidien, a unit of Medtronic plc.

The University of Maryland subsequently used the sovereign immunity defense to fend off an IPR challenge from NeoChord Inc.The universities’ success in defending inventions discovered by their employees did not ripple the waters of public opinion.Allergan, however, is trying to shield its patents behind sovereign immunity from a tribe that had no connection to the discovery. The Saint Regis Mohawk Tribe confirmed in FAQs posted on its website that the deal was suggested by attorneys working for the tribe.Allergan paid the tribe $13.8 million up front and agreed to pay $15 million in annual royalties for as long as the patents are valid. The patents expire in 2024, valuing the deal at up to $118.8 million. Restasis is Allergan’s second-biggest product, behind Botox onabotulinumtoxinA. Revenues last year were $1.5 billion — 10% of the company’s total — with the vast majority from the U.S. During a PTAB hearing held by telephone on Sept. 11, an attorney for the Saint Regis Mohawk Tribe requested that PTAB issue a stay in the IPR cases pending the tribe’s forthcoming motion to dismiss the case. “The tribe does not and will not waive its sovereign immunity to the IPRs,” its attorney told PTAB.

A SHAM?

Patent law scholars are divided about the prospects for Allergan and the Saint Regis Mohawk Tribe to get the IPR cases dismissed.There is little doubt among attorneys that the tribe’s claim of sovereign immunity is at least as strong as the state universities’ claims.“I don’t see how tribes could possibly be treated differently from state universities,” Joanna Shepherd, professor of law at Emory University School of Law, told BioCentury.The question is more likely to come down to whether or not sovereign immunity can be licensed or sold to protect patents, and whether the Allergan deal in particular is a “sham” transaction with no purpose other than avoiding a legal commitment.Previewing arguments that are likely to be made in briefings to PTAB, and in the courts if PTAB’s decision is appealed, Mylan’s attorney, Richard

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Torczon of counsel at Wilson Sonsini Goodrich & Rosati, said “there’s a lot of reasons for concern that this transaction is a sham transaction.”He also accused the tribe of marketing a “protection scheme” to “patentees who they think have weak patents at risk of cancellation” through IPR.Michael Shore, an attorney representing the tribe, told the PTAB the briefs it plans to file in the case will alleviate concerns raised by Mylan’s attorney. Responding to Torczon’s contention that the patent assignment was a sham, Shore told the PTAB that “there’s no racketeering here or anything like that going on.” It was a “legitimate transaction,” he said.Shepherd said it is unlikely that Allergan’s agreement with the tribe was drafted in a manner that the courts would determine makes it a sham. Jacob Sherkow, associate professor of law at the New York Law School, doesn’t think PTAB will be swayed by Mylan’s sham argument. “You can assign your patent to whoever you want to,” Sherkow said. “It is perfectly permissible to assign a patent to someone else but also retain rights to practice the invention and receive the bulk of the royalties. That’s the way a lot of spin-off companies operate.”

LAPIDES

Stephen Vladeck, professor of law at the University of Texas School of Law, thinks Mylan may be able to argue that by voluntarily wading into an IPR dispute, and thereby subjecting itself to the authority of the federal government, the Saint Regis Mohawk Tribe waived its sovereign immunity.At the Sept. 11 PTAB hearing, Torczon took pains to note the tribe “has not been dragged into this proceeding against its will. It has deliberately by its own admission targeted these proceedings for exactly this kind of revenue-generating opportunity.” The tribe’s undated FAQ document was posted to describe a “new research and technology (patent) business” that it began in April. The tribe’s “only role is to hold the patents, get assignments, and make sure that the patent status with the US Patent Office is kept up to date.”

Vladeck noted that in 2002 the Supreme Court ruled in Lapides v. Board of Regents of University System of Georgia that “sovereign immunity can be waived when parties are consciously trying to manipulate litigation outcomes.”In Lapides the Supreme Court was asked to consider a suit against the Georgia Board of Regents alleging that university officials violated state law when they placed allegations of sexual harassment in an employee’s personnel file. The state successfully petitioned to have the case transferred from state to federal court and then argued that the federal case should be dismissed because the state had sovereign immunity from such cases.The Supreme Court ruled that when Georgia moved a case from state court to federal court it voluntarily invoked the federal court’s jurisdiction and, in the process, waived its sovereign immunity. The unanimous decision cited precedents that the court said have “made clear in general that ‘where a State voluntarily becomes a party to a cause and submits its rights for judicial determination, it will be bound thereby and cannot escape the result of its own voluntary act by invoking the prohibitions of the Eleventh Amendment.’”While Lapides did not involve patents or a Native American tribe, Vladeck said Mylan could use it to convince courts to toss out the Saint Regis Mohawk Tribe’s attempt to invoke sovereign immunity to block IPR challenges.

BROADER IMPLICATIONS?

Some attorneys have argued that Allergan’s strategy opens the door for other companies to use sovereign immunity to block some kinds of litigation in federal courts, even though Allergan said it will not do so.Allergan is defending the Restasis patents licensed to the tribe in the U.S. District Court for the Eastern District of Texas to prevent Mylan, Teva Pharmaceutical Industries Ltd. and Akorn Inc. from launching generic versions of Restasis. “The tribe has consented in this case not to assert sovereign immunity in federal district court,” Allergan spokesperson Mark Marmur told BioCentury.

“THE SOCIAL CONTRACT IS A TWO-WAY STREET.”BRENT SAUNDERS, ALLERGAN

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The tribe appears to confirm this. The motion seeking to dismiss the IPR proceedings states, “The Tribe will not assert sovereign immunity in the Eastern District of Texas case.”Christopher Evans, an attorney at Shore Chan DePumpo, told BioCentury, “The tribe doesn’t want its patents tested at the PTAB, only at district court,” Shore Chan DePumpo is the firm representing the tribe.However, it isn’t clear what the tribe’s intentions are in its deal with SRC Computers LLC. SRC transferred 40 patents to the tribe in August. According to the tribe’s FAQ document, it expects to “earn a significant amount of money” as a result of defending those patents in federal court.Evans noted no litigation has been filed yet on SRC’s patents and said suggestions that the tribe might assert sovereign immunity in federal district court are “speculative.”He added, however, that the tribe could use sovereign immunity to have a declaratory judgment action dismissed if the action were filed “in a forum they don’t want to be in.” He declined to explain further.In its motion to the PTAB, the tribe also asserted that it is “a sovereign government that cannot be sued unless Congress unequivocally abrogates its immunity or the Tribe expressly waives it.”If applied to drugs, sovereign immunity could undermine Hatch-Waxman, tipping the balance of power in favor of brand manufacturers and bigger generic companies, according to Sherkow. Specifically, she thinks Native American tribes might be able to use their immunity to preclude declaratory judgment actions. Hatch-Waxman gives generic manufacturers the option to seek declaratory judgments invalidating drug patents when brand manufacturers do not file suit to defend their patents.Eliminating the option for a declaratory judgment would leave generic manufacturers a difficult choice. They could wait for the brand manufacturer to sue them for patent infringement, which could delay revenues indefinitely. Or they could launch at risk of litigation from the brand company, potentially exposing themselves to penalties that can be as high as double the revenues the branded manufacturer lost as result of generic competition. Payouts in such cases can top $1 billion.

“For some generic companies, especially smaller companies, launching at risk is not an option because if they lose it would bankrupt them,” he said.Rachel Sachs, an associate professor at the Washington University in St. Louis School of Law, has also raised this possibility in a blog post. Sachs also hypothesized that it might be possible to use sovereign immunity to block generics companies from challenging the validity of a patent’s claims and asking the court to require correction or deletion of patent information from the Orange Book. The Orange Book is the official listing of patents used to determine when a generic can be marketed.Shepherd, however, said the scenario Sherkow and Sachs have painted is “speculative.”Allergan Chief Legal Officer Bob Bailey also dismissed such concerns. “We are focused on what we’ve done and not what might happen if someone did something different,” he told BioCentury. “We’ve made it clear our patents remain subject to challenge in Hatch-Waxman proceedings.”The same arguments could have been raised about state universities claiming sovereign immunity to fend off IPR challenges, Bailey said. “If sovereign immunity can be used to circumvent Hatch-Waxman, there is nothing Allergan can do to walk it back.”

POLITICAL AND PUBLIC RESPONSE

If it decides the situation has gotten out of hand, Congress could pass a law exempting patents from sovereign immunity, Sherkow said. Because it would be unlikely to single out Native American tribes, this would probably also prevent state universities from using sovereign immunity to deflect IPR challenges, he said.Sen. Brown has vowed to do that, but so far there is no evidence that he could attract enough political support.Saunders told BioCentury he has spoken with members of Congress, including a member of the Senate Committee on Health, Education, Labor and Pensions, to explain Allergan’s action. Allergan declined to name the HELP member or provide any information about its interactions with members of Congress, other than to say it “has reached out to [Brown’s] office to provide the facts and context around this agreement with the Saint Regis Mohawk Tribe.”

“IT IS SILLY FOR US TO EXPECT COMPANIES TO LITIGATE CASES IN WAYS WE THINK ARE NICE.”JACOB SHERKOW, NEW YORK LAW SCHOOL

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The deal also was condemned by groups that are campaigning for lower drug prices.John Arnold, co-founder of the Laura and John Arnold Foundation, tweeted on Sept. 10, “Allergan patent scam shows how US has built an unnecessarily complex system of pharma regs that industry will always figure way to outsmart.” The Arnold Foundation provides funding to the Institute for Clinical and Economic Review (ICER), Memorial Sloan Kettering Cancer Center’s Evidence Driven Drug Pricing Project and other programs aimed at lowering drug costs.David Mitchell, president and founder of Patients for Affordable Drugs, sent a public letter to PhRMA calling on the trade group to “disavow Allergan’s disgusting legal dance to transfer corporate patents to tribal governments in order to circumvent the law.” Mitchell said Allergan should have allowed generic competition to Restasis starting in 2014, when the company’s original formulation patent expired. Restasis did not have composition of matter protection, because it is a formulation of an antibiotic that was first approved in the U.S. in 1983.Allergan was granted additional method of use patents that have extended its exclusivity through 2024. These are the patents that are subject to the IPR petitions Allergan is attempting to shield, as well as the pending federal district court litigation. Saunders rejects this argument. “The first tenet of our social contract is focused on investing in innovation. We did that when we discovered Restasis, and we were granted six patents to 2024. We are not trying to go beyond” the 2024 patent expirations, he said. He added that Allergan has a right to prevent competitors from filing IPR petitions because the “IPR process is flawed. It has no precedential value, there is no consistency of opinions” and “particularly when you have Hatch-Waxman, it uniquely creates a second forum, which it was not intended to do.”The biotech and pharmaceutical industries have tried and failed to persuade Congress to eliminate IPR, or to exempt their companies from the process.PhRMA declined to comment on Mitchell’s letter or Allergan’s deal with the Mohawk tribe. In a statement provided to BioCentury, it did register the industry’s distaste for IPR: “The threat of inter partes reviews (IPRs), coupled with having to defend patents in multiple venues under different standards, creates significant business uncertainty for biopharmaceutical companies that rely on the assurance of their patents to justify long-term investments needed to discover new treatments and cures.”“The IPR system is completely broken and I am sympathetic to Allergan,” John Maraganore, CEO of Alnylam Pharmaceuticals Inc. and chair of BIO, told BioCentury. “A company in the face of an environment that has a flawed system needs to think about what it can do to protect an important medicine and its shareholders.”He said IPR is unfair, because it gives generic companies a never-ending opportunity to challenge patents, even after they have been upheld by federal courts.

He believes the public is right to be outraged by some of the “gamesmanship” drug companies have used to extend patents, such as pay-for-delay deals and blocking access to drug samples that are required to conduct testing of generics and biosimilars. While he is concerned about public perception of the Allergan deal, he thinks it is fundamentally different because it doesn’t prevent generics from challenging patents in federal court. Speaking privately, other biopharma CEOs and industry lobbyists told BioCentury that while they loathe the IPR system, they are dismayed by Allergan’s move because it perpetuates the public’s sense that the industry uses devious practices to fend off competition. “Saunders has given the industry a black eye just when it doesn’t need it,” said one biotech CEO who did not want to be identified.

Although he strongly opposes the use of sovereign immunity as a shield against IPR, Sherkow told BioCentury he is sympathetic to the industry’s arguments against IPR. “The whole process is incredibly stupid. There is good reason to make federal litigation cheaper, but IPR is not the way to do it. It was stupid when it was created in 2012 and it is stupid now,” he said.Sherkow also said some of the criticism of Allergan is overwrought.“The stakes are so high for these Hatch-Waxman cases that we can’t possibly expect people to do anything other than play as many games as they can to help themselves,” he said. “It is silly for us to expect companies to litigate cases in ways we think are nice. You can have companies that are good citizens that are bad sportsmen.”PTAB has given the tribe and Mylan until Oct. 20 to present arguments for and against dismissing the IPR case. Whichever party loses at PTAB is almost certain to appeal the case to the federal courts, according to Vladeck.“I’d be surprised if the PTAB had the last word, either way,” he said. “This question has all the hallmarks of something that would get the Supreme Court’s attention.”If Allergan loses the district court case, however, Mylan’s IPR challenge would no longer be relevant. The trial was completed on Sept. 8. Allergan expects a ruling this fall.In the meantime, the Supreme Court will be considering a completely separate case that could sweep IPR off the board. In Oil States Energy Services LLC v. Greene’s Energy Group LLC the Supreme Court will decide whether the IPR system violates the U.S. Constitution by allowing the government to confiscate a valuable

“WE CAN’T LET THIS GO-AROUND BECOME THE NEW NORMAL.”SHERROD BROWN (D-OHIO)

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property right — a patent — through a proceeding that does not give the property owner the right to present the case to a jury. The court will hear oral arguments after the 2017 term starts on Oct. 1, and will rule before the term ends in June 2018.

COMPANIES AND INSTITUTIONS MENTIONED

Akorn Inc. (NASDAQ:AKRX), Lake Forest, Ill.

Allergan plc (NYSE:AGN), Dublin, Ireland

Alnylam Pharmaceuticals Inc. (NASDAQ:ALNY), Cambridge, Mass.

Biotechnology Innovation Organization (BIO), Washington, D.C.

Emory University, Atlanta, Ga.

Institute for Clinical and Economic Review (ICER), Boston, Mass.

Laura and John Arnold Foundation, Houston, Texas

Medtronic plc (NYSE:MDT), Dublin, Ireland

Memorial Sloan Kettering Cancer Center, New York N.Y.

Mylan N.V. (NASDAQ:MYL; Tel Aviv:MYL), Canonsburg, Pa.

NeoChord Inc., St. Louis Park, Minn.

New York Law School, New York, N.Y.

Patients for Affordable Drugs, Washington, D.C.

Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C.

Teva Pharmaceutical Industries Ltd. (NYSE:TEVA; Tel Aviv:TEVA), Petah Tikva, Israel

University of Georgia Research Foundation, Athens, Ga.

University of Florida, Gainesville, Fla.

University of Maryland, College Park, Md.

University of Texas, Austin, Texas

Washington University in St. Louis, St. Louis, Mo.

REFERENCES

Usdin, S., “SCOTUS to the rescue?” BioCentury (2016)

Usdin, S. “IPR battles.” BioCentury (2015)

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DISTILLERY

This week in therapeutics This week in therapeutics includes important research findings on targets and compounds, grouped first by disease class and then alphabetically by indication.

This week in techniques This week in techniques includes findings about research tools, disease models and manufacturing processes that have the potential to enable or improve all stages of drug discovery and development.

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RUNNING INTERFERENCEBY EMILY CUKIER-MEISNER, SENIOR WRITER

Phase III data for Alnylam Pharmaceuticals Inc.’s patisiran resolve one big question: It’s now clear that not all RNAi therapeutics will have unacceptable safety issues.The company also thinks it has elucidated the reasons for hepatotoxicity associated with previous programs, and has devised solutions to avoid that particular toxicity in the future. But it is not yet known what caused the cardiovascular adverse events that derailed revusiran. As a result, oligonucleotide researchers who spoke to BioCentury are divided on whether and how the company can avoid toxicity in future programs before they get into the clinic.Questions about the safety of Alnylam’s platform arose last fall when Alnylam discontinued two programs within a week of each other because of two different types of adverse events. On Sept. 28, 2016, Alnylam ended development of ALN-AAT, an siRNA targeting alpha-1 antitrypsin (AAT; A1AT; SERPINA1), after transient liver enzyme elevations occurred in a Phase I/II study. Seven days later, it discontinued revusiran, an RNAi targeting the transthyretin (TTR) gene, after the Phase III ENDEAVOUR trial showed an imbalance of cardiac-related deaths. After that, all eyes were on the Phase III APOLLO study of patisiran (ALN-TTR02), which also targets TTR but uses both a different sequence and a different formulation technology designed to achieve the same level of efficacy with less drug. The favorable safety and efficacy data reported on Sept. 20 should lay to rest concerns that either the TTR target or the RNAi approach are fundamentally flawed.

In 225 patients with TTR familial amyloid polyneuropathy (TTR-FAP), patisiran met the primary endpoint of change in mean modified Neuropathy Impairment Score +7 (mNIS+7) from baseline to 18 months (p<0.00001 vs. placebo). Patisiran also met all secondary endpoints. Adverse events occurred in 96.6% of the patisiran group vs. 97.4% for placebo. Serious adverse events were less common for patisiran (36.5% vs 40.3% for placebo), and fewer patients given the drug candidate died (4.7% vs. 7.8%). The only common adverse events that occurred more frequently in the patisiran arm were peripheral edema (29.7% vs. 22.1% for placebo) and infusion-related reactions (18.9% vs. 9.1%).The company did not break out other AEs. It plans to report full data at the European ATTR Amyloidosis Meeting for Patients and Doctors on Nov. 2, and to submit regulatory applications in the U.S. this year and the EU early next year.Alnylam CEO John Maraganore thinks patisiran may have fared better than revusiran at least in part because its formulation has a lower effective dose, which could contribute to lower toxicity. It is also true that patients in APOLLO had less severe cardiovascular disease than those in ENDEAVOUR. In addition, the placebo group in ENDEAVOUR had a lower mortality rate than natural history would predict.The company said mortality rates in both arms of the APOLLO study were consistent with the natural history of ATTR.As for the liver elevations that sank ALN-AAT and have appeared in at least six other programs, Alnylam has proposed a possible common

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mechanism: off-target RNAi interference driven by sequence similarity to non-target mRNAs.The hope is that the company’s formulation and liver-targeting technologies could help prevent that activity from producing clinically relevant side effects.A third adverse event that arose on Sept. 7 in the Phase III ATLAS study of fitusiran (ALN-AT3) appears unlikely to be related to the platform. Alnylam halted the ATLAS study in hemophilia after a patient in a Phase II open-label extension study died of cerebral venous sinus thrombosis. Fitusiran targets anti-thrombin III (AT3; SERPINC1) mRNA.The company has since determined that the death in ATLAS was likely related to a diagnosis error and subsequent treatment decisions. Specifically, the physician misdiagnosed a thrombotic event as a bleeding episode, and therefore continued treatment with coagulation factors and fitusiran instead of discontinuing the medications. The company hopes to resume ATLAS this year with a revised protocol specifying how to manage bleeds with factor replacement and monitor thrombotic risk.

ITERATING INTERFERENCE

Alnylam has put candidates into the clinic that use three different generations of liver-targeting technology, and a fourth is set to enter the clinic this year.Each iteration of the delivery technology has been intended to improve safety, either by reducing the amount of drug that must be delivered to achieve a therapeutic effect, or by reducing the potential for off-target activity.ALN-AAT and revusiran used Alnylam’s standard template chemistry (STC)-GalNAc conjugate delivery system, and patisiran uses lipid nanoparticle (LNP) technology from Arbutus Biopharma Corp. STC-GalNAc and LNP are intended to improve delivery to the liver, increasing potency and reducing systemic exposure of Alnylam’s RNAi therapeutics. But LNP confers much greater potency, enabling the delivery of much lower doses of the RNAi.The company has reported elevations in liver enzymes for all three programs; however, in the study where the patisiran elevation occurred, the company said there were no “clinically significant” changes in liver function tests.

The remaining candidates in Alnylam’s pipeline use a third delivery technology called enhanced stability chemistry (ESC)-GalNAc. ESC-GalNAc is expected to have the same potency as LNP, but with fewer injection-site reactions and greater ease of manufacturing.In an October 2016 R&D day presentation, Alnylam reported that the dose exposure of revusiran in one year is equivalent to 70 years’ exposure of patisiran delivered by lipid nanoparticles, and to 12-140 years’ exposure of ESC-GalNAc conjugated pipeline products.Maraganore said the results of the 497-patient Phase II ORION-1 study of inclisiran in patients with elevated LDL cholesterol support the safety of the ESC-GalNAc platform. Adverse events occurred in 75.3% of patients receiving a one-dose regimen of inclisiran vs. 70.8% of patients dosed with placebo on a similar schedule. The figures were 77.2% for a two-dose regimen of inclisiran and 80.6% for the corresponding placebo group.Serious adverse events occurred in 9.1% of the one-dose group vs. 4.6% for placebo. And SAEs occurred in 13% of the two-dose group vs. 9.7% for placebo.Rates of liver enzyme elevations were similar between inclisiran and placebo, and not considered related to treatment. Two deaths among patients receiving inclisiran were considered related to underlying disease, and not to treatment.Inclisiran is a subcutaneous formulation of siRNA against PCSK9. The Medicines Co. conducted ORION-1 and has worldwide rights to develop and commercialize inclisiran to treat hypercholesterolemia under a 2013 deal.The next generation of products will use an updated version of Alnylam’s Enhanced Stability Chemistry technology called ESC+. ESC+ uses chemically modified nucleotides within the “seed” region of the antisense strand to lower the propensity for off-target seed-sequence binding.According to Steven Dowdy, sequence-dependent off-target effects are driven predominantly by two portions of an siRNA: the seed sequence, which consists of the first 2-8 nucleotides, and to a lesser extent the 3’ end.Dowdy is a professor of cellular and molecular medicine at the University of California San Diego. He is a co-founder of RNA company Solstice Biologics LLC and a board member of the Oligonucleotide Therapeutics Society.In an August roundtable discussion, Alnylam reported data from a rat model of hepatotoxicity that showed ESC+ improved by sixfold the therapeutic index of an RNAi sequence known to cause toxicity compared with the corresponding ESC version.Maraganore said an ESC+ product using the same sequence as the discontinued ALN-AAT program will enter the clinic next year.“We fully expect the molecule will have continued efficacy without the liability of liver function test changes. That will be the proof point in humans,” he said.

REMAINING QUESTIONS

Four oligonucleotide experts who spoke to BioCentury agreed that APOLLO data show RNAi is not hampered by platform-wide effects;

“WE FULLY EXPECT THE MOLECULE WILL HAVE CONTINUED EFFICACY WITHOUT THE LIABILITY OF LIVER FUNCTION TEST CHANGES.”JOHN MARAGANORE, ALNYLAM

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however, they disagreed about whether the RNAi field has advanced far enough to reliably avert off-target activity.John Rossi’s comments about APOLLO were representative of the group: “The success of this trial provides a strong indication that the RNAi machinery can be safely engaged for long-term clinical applications.”

Rossi is a professor and chair of the Department of Molecular and Cellular Biology at City of Hope. He is co-founder of RNA companies Dicerna Pharmaceuticals Inc. and MiNA Therapeutics Ltd. and an honorary member of the Oligonucleotide Therapeutics Society. He has been a clinical investigator in a trial testing vector-delivered siRNAs to treat HIV, but not for Alnylam’s therapies.Art Krieg is still concerned that chemical modifications or sequence-dependent protein binding could cause side effects by mechanisms that are not well understood. “We’ve seen a lot of weird effects with oligonucleotides that are very sequence dependent,” he said.Krieg is CEO of immuno-oncology company Checkmate Pharmaceuticals Inc. and president of the Oligonucleotide Therapeutics Society.

David Corey acknowledged RNAi off-target activity does arise from the specific sequences and chemical modifications of individual RNAi therapies. “Those are probably going to be the predominant causes of side effects, especially the unexpected ones,” said Corey, a professor of medical science at the University of Texas Southwestern Medical Center.Corey’s group has collaborated with Ionis Pharmaceuticals Inc. to study single-stranded RNA silencing mechanisms. He is on the board of the Oligonucleotide Therapeutics Society.He said those effects can resolve with a sequence tweak or minor chemical modification — but that the challenge lies in predicting the toxicity ahead of human trials. But Dowdy said RNA sequencing has become cheap enough to perform regularly in preclinical development, which lets companies easily screen for off-target RNAi activity and weed out promiscuous candidates. “Five to eight years ago off-target effects were a big problem, but today they’re not much of an issue,” Dowdy told BioCentury.

COMPANIES AND INSTITUTIONS MENTIONED

Alnylam Pharmaceuticals Inc. (NASDAQ:ALNY), Cambridge, Mass.

Arbutus Biopharma Corp. (NASDAQ:ABUS), Burnaby, B.C.

Checkmate Pharmaceuticals Inc., Cambridge, Mass.

City of Hope, Duarte, Calif.

Dicerna Pharmaceuticals Inc. (NASDAQ:DRNA), Cambridge, Mass.

Ionis Pharmaceuticals Inc. (NASDAQ:IONS), Carlsbad, Calif.

The Medicines Co. (NASDAQ:MDCO), Parsippany, N.J.

MiNA Therapeutics Ltd., London, U.K.

Oligonucleotide Therapeutics Society, San Diego, Calif.

Solstice Biologics LLC, San Diego, Calif.

University of California San Diego, San Diego, Calif.

University of Texas Southwestern Medical Center, Dallas, Texas

REFERENCES

Hansen, S. et al. “Program or Platform?” BioCentury (2016)

“SUCCESS OF THIS TRIAL PROVIDES A STRONG INDICATION THAT THE RNAI MACHINERY CAN BE SAFELY ENGAGED FOR LONG-TERM CLINICAL APPLICATIONS.”JOHN ROSSI, CITY OF HOPE

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SELECTIVE SUPPRESSIONBY EMILY CUKIER-MEISNER, SENIOR WRITER

Kezar Life Sciences is targeting the immunoproteasome to selectively suppress the hyperactive immune cells that drive autoimmunity. The company expects its biologics to have the rapid onset and broad activity of steroids, but without their toxicity.Like other proteasomes, immunoproteasomes process antigens for major histocompatibility complex (MHC) presentation. But immunoproteasomes also regulate the differentiation, function and survival of immune cells. The immunoproteasome is uniquely expressed by immune cells that have been stimulated by pro-inflammatory cytokines.Lead program KZR-616 is an optimized version of ONX-0914, an immunoproteasome inhibitor originally developed by Proteolix Inc. Proteolix was acquired in 2009 by Onyx Pharmaceuticals Inc., and Onyx was acquired by Amgen Inc. in 2013. CEO John Fowler said Amgen chose not to advance the programs, and spun Kezar out in 2015 with a worldwide exclusive license to the platform in exchange for undisclosed equity, plus potential milestones and royalties.Data on the predecessor molecule showed activity in mouse models of autoimmune diseases including rheumatoid arthritis, lupus, multiple sclerosis and Type I diabetes.“In all the disease models,” Fowler told BioCentury, “this immunoproteasome inhibitor was profoundly immunomodulatory without being immunosuppressive.”He said it did not decrease viral clearance in infection models or prevent antibody production in vaccination models, suggesting it acted selectively in overactive immune cells and could pose a lower infection liability than more broadly acting immunosuppressants. Fowler added that Kezar’s molecules may be more effective than agents that target a single cytokine because they quell multiple immune processes.“If you could go to the headwaters of the river and block all of those inflammatory cytokines,

and up-regulate regulatory T cells, and down-regulate plasma cells, you would have a powerful across-the-board immunomodulatory effect,” said Fowler.While ONX-0914 inhibits only the beta 8 subunit of the proteasome (PSMB8; LMP7), Kezar optimized KZR-616 in silico to target multiple active sites of the immunoproteasome and improve selectivity.Fowler said data from an Australian Phase Ia trial showed KZR-616 inhibits the immunoproteasome in humans at equivalent levels to the effective dose in animal models, and is well tolerated upon repeat administration. Results will be presented at the American College of Rheumatology’s annual meeting in November.Kezar plans to submit an IND to begin a U.S. Phase Ib/II study early next year in autoimmune indications involving swollen joints. Its first Phase II will be in lupus nephritis.

A $50 million series B announced in July brought the company’s fund-raising total to $73 million, which will let Kezar hire additional employees, fund KZR-616 through two Phase II studies and advance up to two preclinical projects into IND-enabling studies.Kezar is collaborating with co-founder Jack Taunton’s lab at the University of California San Francisco to optimize protein secretion inhibitors to treat cancer and autoimmune disease; the partners will be co-inventors on patent applications.Taunton is a professor of cellular and molecular pharmacology at UCSF.At least one other company is targeting the immunoproteasome to treat autoimmune disease. Principia Biopharma Inc. is developing preclinical oral immunoproteasome inhibitors to treat immunological diseases under a deal with AbbVie Inc.Kirk said Principia’s patents suggest that the company’s molecules target only PSMB8, whereas Kezar’s inhibit all three subunit types in the immunoproteasome. Hitting only one site could lead to a less comprehensive anti-inflammatory effect, he said. Principia declined to comment.

COMPANIES AND INSTITUTIONS MENTIONED

AbbVie Inc. (NYSE:ABBV), Chicago, Ill.

American College of Rheumatology, Atlanta, Ga.

Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.

Kezar Life Sciences, South San Francisco, Calif.

Principia Biopharma Inc., South San Francisco, Calif.

University of California San Francisco, San Francisco, Calif.

REFERENCES

Groettrup, M., et al. “Proteasomes in immune cells: more than peptide producers?” Nature Reviews Immunology (2010)

Osherovich, L. “Proteasome progress.” SciBX: Science-Business eXchange (2009)

KEZAR LIFE SCIENCESSouth San Francisco, Calif.

Technology: Immunoproteasome inhibitors and protein secretion inhibitors

Disease focus: Autoimmune, cancer

Clinical status: Phase I

Founded: 2015 by Christopher Kirk, John Fowler and Jack Taunton

University collaborators: University of California San Francisco

Corporate partners: None

Number of employees: 12

Funds raised: $73 million

Investors: Cowen, Pappas Ventures, Qiming Venture Partners, Bay City Capital, Morningside Ventures, Omega Funds, EcoR1 Capital, Cormorant Asset Management, Aju IB Investment, 9W Capital Management

CEO: John Fowler

Patents: 3 issued covering peptide epoxyketone-based selective immunoproteasome inhibitors

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CHASING ZAIBY STEPHEN HANSEN, ASSOCIATE EDITOR

The lightning ascent of Zai Lab Ltd. from start-up to NASDAQ darling can be attributed in part to the Shanghai company ticking several boxes that other Chinese companies looking to list in the U.S. would do well to replicate. Less than three years after its 2014 launch, the cancer, autoimmune and infectious disease company raised $150 million in a bumped-up offering of 8.3 million shares at $18. The deal valued Zai at $888.9 million on Wednesday and the stock accelerated to close Friday at $27.73, a 54% gain to a market cap just shy of $1.4 billion. Including the overallotment, Zai raised $172.5 million in the deal.One banker who asked not to be named told BioCentury the deal was 17-18x oversubscribed, with 3-4x oversubscription just in Asia before the roadshow even reached U.S. shores. U.S. investors grabbed two-thirds or more of the deal.The banker noted the demand meant the deal required minimal insider participation, an exception to the prevailing wisdom that as much as 50% of IPO books are still being built with existing investors, largely from the mezzanine round. Zai has a pipeline of five clinical candidates in-licensed from Western biopharma companies. The most advanced is the PARP inhibitor niraparib from Tesaro Inc. This year, Zai expects to start a Chinese Phase III trial to treat ovarian cancer in China, where it has exclusive rights. In March, Tesaro received FDA approval for the drug as Zejula for ovarian cancer.Zai’s valuation is in line with other late-stage companies with a China profile. FibroGen Inc. has roxadustat in Phase III testing to treat anemia in chronic kidney disease (CKD). The U.S. company has said it expects the molecule to receive its first approval in China. It plans to submit an NDA to CFDA this quarter.FibroGen raised $167.7 million in a 2014 IPO that valued the company at $1 billion, and now has a market cap of $4 billion.The small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH; EGLN) is partnered in both China and the U.S. with AstraZeneca plc. From the China side, BeiGene Ltd. has BGB-A317, an anti-PD-1 mAb, in two pivotal Phase II Chinese trials to treat urothelial cancer and classical Hodgkin’s lymphoma. BeiGene entered into a global deal for the compound with Celgene Corp., which included taking over the big biotech’s commercial operations in China. The partners plan to start global pivotal trials of BGB-A317 next year.

The cancer and autoimmune play went public on NASDAQ in February 2016, raising $182.2 million in a bumped-up IPO that valued the company at $757 million. Its market cap now is $3.6 billion. Hutchison China MediTech Ltd. — which Zai co-founder, Chairman and CEO Samantha Du helped to found — has its fruquintinib in registration in China to treat colorectal cancer. Hutchison added a NASDAQ listing last year and raised $101.3 million at a $1.6 billion valuation, which has since jumped to $3.1 billion.

LESSONS LEARNED

Buysider Oleg Nodelman of EcoR1 Capital, who invested in Zai’s IPO, said one of Zai’s main draws was the global experience of the management team, Du’s in particular.“I think for us to have made an investment in any of these companies, they’d have to have a team that can compete at the global level,” Nodelman told BioCentury. He said Du matched that criteria, citing her experience in global licensing at Pfizer Inc. and as founder and CEO of Hutchison MediPharma Ltd., one of China’s first innovator biotechs and a subsidiary of Hutchison China MediTech. Du also served as managing director for Sequoia Capital China.Zai’s CMO of Oncology, Qi Liu, is an AstraZeneca veteran and Harald Reinhart, CMO of autoimmune and infectious diseases, was at the U.S. unit of Shionogi & Co. Ltd.Both Nodelman and OrbiMed Advisors’ Carl Gordon noted Zai followed the plan that other foreign biotechs have when listing in the U.S.: spending time with investors well ahead of any road show. “The Zai management team and banking syndicate did a good job of getting out there and meeting with investors ahead of time,” Gordon said. OrbiMed invested in all three of Zai’s venture rounds, in which the company raised a total of $164.5 million, as well as the IPO.

“THE ZAI MANAGEMENT TEAM AND BANKING SYNDICATE DID A GOOD JOB OF GETTING OUT THERE.” CARL GORDON, ORBIMED ADVISORS

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Gordon noted Zai’s $30 million crossover series C round in June helped get management in front of U.S. investors. In addition to OrbiMed, investors in that financing included Vivo Capital, Cormorant Asset Management and Rock Springs Capital.The next Chinese innovator to jump into the NASDAQ queue could be Ascentage Pharma Group Corp. Ltd. The cancer company told BioCentury in January it was planning a U.S. listing this year.

COMPANIES AND INSTITUTIONS MENTIONED

Ascentage Pharma Group Corp. Ltd., Hong Kong, China

AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K.

BeiGene Ltd. (NASDAQ:BGNE), Beijing, China

Celgene Corp. (NASDAQ:CELG), Summit, N.J.

China Food and Drug Administration (CFDA), Beijing, China

FibroGen Inc. (NASDAQ:FGEN), San Francisco, Calif.

Hutchison China MediTech Ltd. (LSE:HCM; NASDAQ:HCM), Hong Kong, China

Pfizer Inc. (NYSE:PFE), New York, N.Y.

Shionogi & Co. Ltd. (Tokyo:4507), Osaka, Japan

Tesaro Inc. (NASDAQ:TSRO), Waltham, Mass.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.

Zai Lab Ltd. (NASDAQ:ZLAB), Shanghai, China

REFERENCES

Hansen, S. “OrbiMed’s Asia angles.” BioCentury (2017)

Hansen, S. “Transforming BeiGene.” BioCentury (2017)

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MINING FUNGIBY VIRGINIA LI, STAFF WRITER

Through GV, LifeMine Therapeutics Inc. will have access to big data expertise as it builds out its fungal DNA mining capabilities.LifeMine raised $55 million in a series A round on Sept. 18 led by existing investor WuXi Healthcare Ventures. New investors GV, Foresite Capital, Arch Venture Partners, Boyu Capital, Blue Pool Capital, MRL Ventures Fund and Alexandria Venture Investments also participated.LifeMine’s drug discovery platform mines fungal genomes to identify small molecules against previously undruggable targets. “On average, each fungus has about 100 gene clusters, and each of those makes a different family of natural products. They’re just loaded with bioactive molecules,” said CEO Greg Verdine, who is also a venture partner at WuXi. LifeMine’s search algorithm aims to predict the structure and function of bioactive molecules based on these gene clusters. The company then induces gene expression to isolate the desired molecules. Verdine told BioCentury, “Given that this is fundamentally a search problem, it made sense to have GV as a financing and scientific partner.”GV is the venture arm of Google Inc. parent Alphabet Inc. (NASDAQ:GOOG). GV’s Krishna Yeshwant said the firm was intrigued by the untapped potential of fungi as a source of small molecules combined with LifeMine’s informatics-based approach to identifying drug candidates. “The argument that some of our most effective drugs are derived from fungi was compelling, and the next question was, why haven’t we looked for everything else that’s possible there?” said Yeshwant. “The whole vision and the informatics component was exciting for us, and we saw how we could help the company build the informatics platform.” According to Yeshwant, GV has helped several of its life science portfolio companies develop their computational infrastructure, including antibody discovery company Adimab LLC, cancer genome sequencing play Foundation Medicine Inc. (NASDAQ:FMI) and bioinformatics company Flatiron Health Inc. At LifeMine, Yeshwant said GV’s connections “across the Alphabet universe” could help the team recruit the technical talent needed to refine its search algorithm. LifeMine’s series A round will enable the company to continue building its discovery platform and bring its first oncology candidate to the clinic in four years.Verdine declined to disclose specific indications of interest, but told BioCentury, “We’re going after major cancers with large patient populations.” Verdine is also CEO of stapled peptide play FOG Pharmaceuticals Inc. and a chemistry professor at Harvard University.

“THIS IS FUNDAMENTALLY A SEARCH PROBLEM.”GREG VERDINE, LIFEMINE

IMMUNOCORE’S GATES INJECTIONBY STEPHEN HANSEN, ASSOCIATE EDITOR

A $40 million investment from the Bill & Melinda Gates Foundation will allow Immunocore Ltd. to pursue parallel development of multiple immunotherapies in infectious diseases, an area the T cell receptor company had already been expanding over the past 18 months.

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According to Kevin Pojasek, Immunocore VP and director of corporate strategy and co-head of its infectious disease unit, the Gates money will be ring-fenced for development of the biotech’s two infectious disease platforms: Immune mobilising monoclonal TCRs against virus (ImmTAV) and immune mobilising monoclonal TCRs against bacteria (ImmTAB). ImmTAV and ImmTAB are similar in design and function to Immunocore’s ImmTAC platform for cancer. Each is a bispecific biologic that combines an affinity-enhanced TCR with an anti-CD3 single-chain variable fragment (scFv) effector function to activate a T cell response against the target cell.Pojasek told BioCentury that Immunocore started building its platform for infectious diseases after it had produced clinical data for its lead cancer program, IMCgp100, in early 2016.“It was a natural place to expand because we are just leveraging the same molecular platform,” he said. “Rather than being engineered to recognize a cancer cell that is masked by the immune system, it recognizes an infected cell that is masked by the immune system.” Immunocore’s current TCR technology targets peptides expressed on major histocompatibility complex class I A (HLA-A), which is a common subset of HLA haplotypes among the general population.Pojasek said the Gates investment will focus some of Immunocore’s infectious disease programs against indications with a greater prevalence in developing countries, with the first two being tuberculosis and HIV. To that end, Immunocore will accelerate development of its platform against HLA-E, which is more broadly conserved across 98% of the population. He said this is critical for infectious disease therapies in developing countries where the ability to test patients for HLA status may be restricted.Immunocore had already been developing an ImmTAV to treat HBV.Pojasek added the collaboration with Gates may help address issues such as how to generate a return on investment for therapies predominantly used in developing nations. “We really wanted to go after tuberculosis, but it was something that without Gates on board at the outset, it would’ve been much harder for us to do.” He said he expects the first infectious disease program to reach the clinic in 2021-22.

DISARM AND DERISKBY VIRGINIA LI, STAFF WRITER

After replicating the effect of sterile alpha and TIR motif containing 1 gene knockout with small molecule SARM1 inhibitors, axon degeneration company Disarm Therapeutics Inc. passed the milestone needed to unlock series A funding from seed investor Atlas Venture.New investors Lightstone Ventures and AbbVie Ventures also participated in the $30 million A round, which closed on Sept. 19. Atlas’ modus operandi is to source newco ideas from its network of academic investigators, physician scientists and entrepreneurs-in-residence, and drip feed incubated newcos with seed funding to reproduce and ideally

MONEY RAISED IN 2017Last week, the biotech industry raised $1.1 billion, bringing to $52.5 billion the total raised year-to-date. In 2016, a total of $85.2 billion was raised, including $49.1 billion in debt, $10.3 billion in follow-ons, $3.8 billion in PIPEs and other equity, $7.4 billion in IPOs, and $14.6 billion in venture capital. Totals include overallotments and warrants, and are rounded to the nearest millions.

IPO$3,144

Venture$10,387

Debt$17,703

Follow-on$16,101

PIPEs & other equity

$5,208

Total YTD: $52,543 ($M)

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extend the science before committing to a series A (see BioCentury, Jan. 25, 2016). Disarm emerged from the work of Washington University in St. Louis professors and scientific co-founders Jeffrey Milbrandt and Aaron DiAntonio, who published a series of papers demonstrating that knocking out the SARM1 gene delayed or prevented axon loss in mouse models of neurodegenerative disease. In March, the investigators published a paper in Neuron characterizing a domain of the SARM1 enzyme that directly induces axonal degeneration, and suggested the domain could be targeted by therapeutics.Chairman and acting CEO Jason Rhodes said over the past year, Disarm used “a couple million” in seed funding from Atlas to reproduce the neuroprotective effects observed in SARM1 knockouts and generated unpublished data recreating those effects with small molecule inhibitors.

“We were able to repeat, confirm and extend the academic work, and develop a set of industrial assays, do small molecule discovery and enter preclinical models,” said Rhodes.Disarm co-founder and CSO Rajesh Devraj told BioCentury, “That provided confidence and a gating event that led to our whole discovery program.” Disarm has a portfolio of SARM1 inhibitors in different chemical classes that could address a broad range of indications including multiple sclerosis, amyotrophic lateral sclerosis, glaucoma and peripheral neuropathies, according to Devraj, who is also an entrepreneur-in-residence at Atlas.Rhodes declined to disclose which indications the company will pursue first, but said the series A would bring at least one SARM1 inhibitor to the clinic in the next few years. Disarm holds an exclusive license to IP covering its SARM1 inhibitors from Washington University in St. Louis.

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PRICE GAINSStocks with greatest % price increase in the week ended 9/22.(Priced above $2; 5,000 minimum share volume)

Company Ticker $Close $Chg % Chg Vol(00)AbClon1 174900 W26500 W16500 165% 145889Capricor Therapeutics CAPR 2.140 1.140 114% 481359Madrigal MDGL 34.180 15.370 82% 10770Aradigm ARDM 2.530 1.100 77% 72355Opiant OPNT 40.580 16.465 68% 9586Kiadis Pharma KDS €8.700 €3.200 58% 36132Zai Lab1 ZLAB 27.730 9.730 54% 71080Akari Therapeutics AKTX 8.180 2.770 51% 146664Alnylam ALNY 113.800 37.590 49% 269799Celcuity1 CELC 13.630 4.130 43% 14606

PRICE DECLINESStocks with greatest % price decline (criteria as above).

Company Ticker $Close $Chg % Chg Vol(00)Versartis VSAR 2.675 -15.675 -85% 434596Intercept Pharmaceuticals ICPT 61.590 -33.290 -35% 234903MediWound MDWD 4.800 -1.300 -21% 14447Supernus SUPN 39.000 -10.050 -20% 113250Kala Pharmaceuticals KALA 20.690 -4.580 -18% 9757Achieve Life Sciences ACHV 2.350 -0.420 -15% 1806Tyme Technologies TYME 5.320 -0.890 -14% 4652Novan NOVN 5.400 -0.900 -14% 3078Ionis Pharmaceuticals IONS 51.320 -7.910 -13% 91875NewLink NLNK 10.990 -1.680 -13% 155863Abeona Therapeutics ABEO 14.950 -2.250 -13% 62116Acceleron XLRN 34.830 -5.080 -13% 64066Aerie Pharmaceuticals AERI 50.950 -7.350 -13% 41293

VOLUME GAINSGreatest changes in volume above 5,000 shares.

Company Ticker Vol(00) %Chg $Close $ChgNabriva NBRV 356072 9560% 8.470 1.610Silence Therapeutics SLN 116932 6563% 184.1p 37.1pAradigm ARDM 72355 5591% 2.530 1.100MaxCyte MXCT 1031 4954% 247.5p 0pCapricor Therapeutics CAPR 481359 3060% 2.140 1.140Oxford BioDynamics OBD 4071 2095% 162p 2pMerus MRUS 4243 905% 18.320 2.390Versartis VSAR 434596 849% 2.675 -15.675MediWound MDWD 14447 828% 4.800 -1.300Akari Therapeutics AKTX 146664 735% 8.180 2.770

1 IPO during the week. Price change from IPO price.

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BIOCENTURY 100 PRICE & VOLUME TRENDCumulative weekly performance of 100 bioscience stocks. 12-week period. Line shows Price Level change (Left scale. Index base=1000 on May 10, 1996). Bars show cumulative volume in millions (right scale).

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BIOCENTURY LONDON INDEXWeekly change in the combined market capitalization for 14 bioscience stocks listed on the LSE or AIM, 12-week period. Index base =1000 on May 10, 1996.

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The Bridge to Innovation2017 Nov. 14-15

Shanghai, China

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Attendance at this VIP-only meeting is restricted to senior executives, scientists and investors. Seating is limited, so register today to reserve your seat.

HAVE CHINA’S POLICY REFORMS TRANSFORMED THE CROSS-BORDER LANDSCAPE?

Early-Bird Registration Extended to October 1st

As China draws closer to international standards, what new strategies are required for China and Western innovators to

take advantage of cross-border opportunities for product development, partnership and investment?

In this must-attend plenary roundtable, leading executives from Ascentage, BeiGene, CANBridge, Lilly Asia Ventures,

SciClone and YuanMing Capital discuss how these policy reforms have transformed the biopharma landscape in China.

Attendance at this VIP-only meeting is restricted to senior executives, scientists and investors. Seating is limited, so

register today to reserve your spot.

DAY 2 HIGHLIGHT

CHINA'S CROSS-BORDER PIONEERS: HAVE CHINA'S POLICY REFORMS TRANSFORMED THE LANDSCAPE?

TINA YU, Managing Partner, YuanMing Capital (Session Chair & Moderator)

FRIEDHELM BLOBEL, PH.D., CEO, SciClone Pharmaceuticals Inc.

JI LI, PH.D., EVP & Global Head of Business Development, BeiGene Ltd.

JUDITH LI, Partner, Lilly Asia Ventures

JAMES XUE, PH.D., Founder, Chairman & CEO, CANbridge Life Sciences Ltd.

DAJUN YANG, M.D., PH.D., Co-Founder, Chairman & CEO, Ascentage Pharma Group Corp. Ltd.

OR GO TO www.biocenturychinasummit.com

REGISTER HERE

SPECIAL THANKS TO OUR PARTNERS & SPONSORS

SUPPORTING ORGANIZATIONS

CAPITAL MARKETS PARTNER

SCIENCE & INNOVATION SHOWCASE PARTNER

BFC GroupChinaBio

GBILingmed Ltd

Alliance Bernstein

WuXi NextCode

3SBio Ally Bridge GroupBeiGeneBoehringer IngelheimC-Bridge Capital DXY I-Bridge Captial Jiangsu Hengrui Medicine KPCB China Lee's Pharmaceutical

Shandong Luoxin Pharmaceutical Group OrbiMed Pfizer Qiming Venture PartnersQuintilesIMS SanofiSciClone PharmaceuticalsTakeda Zai Lab Lychee Group

PharmaDJPhIRDARDPAC

INSIGHTS PARTNER SPONSORS

McKinsey & Company

As Europeʼs largest life science partnering conference,BIO-Europe is singularly regarded as the annual “must attend”event for leading dealmakers from biotech, pharma and finance along with the most exciting emerging companies.

WHAT YOU CAN EXPECT:• 21,000+ one-to-one partnering meetings• 5,000+ licensing opportunities• 3,800+ attendees (74% top/senior management)• 2,000+ companies representing 60+ countries

SEE YOUIN BERLIN!

FIND OUT MORE:ebdgroup.com/bioeurope

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2 3 R D A N N U A L I N T E R N A T I O N A L P A R T N E R I N G C O N F E R E N C E

BERLIN, GERMANY // NOVEMBER 6–8, 2017

October 17-18, 2017 | The Westin St. Francis, San Francisco, CA

INVESTORFORUM

The BIO Investor Forum is an international biotech investor conference focused on investment trends and opportunities in life sciences, with unbiased emphasis on venture-stage growth and emerging public companies as well as those poised to join the growth “watch list” in 2018.

Complimentary registration is available for investors. For more information and to register for the event, please go to

bio.org/investorforum

Accelerate Discovery. Amplify Returns.

Conference features:• Company presentations

given by over 150 early and late-stage private biotech companies and emerging public companies.

• Fireside Chats and expert-led panel discussions on the latest market and investment opportunities with emphasis on drug and technology development.

• More than 2,100 BIO One-on-One Partnering™ meetings.

• Buzz of BIO competition recognizing “Early Stage Entrepreneurs”, “Late Stage Leaders” and “Diagnostics and Beyond.”

BioCentury subscribers receive a $200 registration discount.

Use code: BIOBIF6