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1Pharmaprojects Update Analysis Informa UK Ltd January 2009

www.pharmaprojects.com

What are purinoreceptors?

Purinoreceptors are the cell-surface receptors for the nucleotides adenosine, ATP, ADP,UTP and UDP. This review will highlight drug discovery based on the receptors activatedby ATP a class known as the P2 purinoceptors. From the initial description of purinergicnerves by Geoffrey Burnstock in 1972, to the cloning of the first P2 purinoreceptors in theearly 1990s, their existence had been a matter of hot debate. These receptors haveproved readily tractable, and as we further understand their function and expression indifferent tissues, they continue toprovide a point of therapeutic

intervention in an array of disorders.Pharmaprojects data shows thatdrugs targeting P2 purinoreceptorsare under development for a widerange of indications including cysticfibrosis, cardiovascular disorders,depression, rheumatoid arthritis(RA) and pain (Graph 1).

Purinoreceptors are divided into twobroad groups: P2X and P2Y. P2Xreceptors are multi-subunit ligand-gated ion channels activated by ATPand which non-selectively conductcations. Seven mammalian P2Xsubtypes have been cloned (P2X1-7),each forming homomeric receptorswith a number of known heteromeric assemblies (P2X2/3, P2X1/5 & P2X4/6). P2Y receptorson the other hand, are G-protein coupled receptors (GPCRs) of which eight subtypes areknown to exist (P2Y1,2,4,6,11,12,13,14). They are linked to a variety of G-proteins and areactivated in response to a number of nucleotides, including ATP, ADP and UDP.

History

Like so many other great scientific breakthroughs, the discovery of P2 purinoreceptors wasrather serendipitous. In the early 1960s, Geoffrey Burnstock and his two students at theUniversity of Melbourne, Australia, stumbled across autonomic neurotransmission which

they believed was mediated by a novel transmitter. The traditional view of the autonomicnervous system at the time was that it comprised adrenergic and cholinergic nerves.Whilst examining intestinal smooth muscle, Burnstock observed that a rapid hyperpolariza-tion of the muscle persisted in the presence of both cholinergic and adrenergicantagonists, indicating a third type of nerve, simply named non-adrenergic, non-cholinergic (NANC). This finding was strengthened by the detection of excitatory NANCtransmission in blood vessels and the bladder, and so the hunt for this mysterioustransmitter ensued.

It was in 1972 with Burnstocks landmark paper Purinergic Nerves that the world was firstintroduced to ATP as a neurotransmitter and it was not until some 20 years later that theconcept proposed by Burnstock was widely accepted. The idea that ATP could function asan extracellular transmitter was controversial due to the fact it was is ubiquitous in thebody. Some of Burnstocks peers at the time were so incensed that he could suggest such

a hypothesis that they vowed to devote their lives to destroying it. The majority of thescientific community continued to reject Burnstocks proposal until the first of manypurinoreceptors were cloned and characterized in the early 1990s.

Update AnalysisTarget Analysis - Potential of Purinoreceptors

January 2009, Volume 29, Issue 8

Please circulate to all Pharmaprojectsusers

ManagingEditor

Ian Lloyd

Editor Thomas Stirzaker

Subeditors Jonathan StephensAlix Biancardi

Writers Mohamed FarahNaila Shaw

Welcome to the monthly newsletter forPharmaprojects, the Update Analysis.In this issue you will find a Target

Analysis of purinoreceptors and a

review of the 38th Society forNeuroscience Annual Meeting. All the

usual Pharmaprojectshighlights follow,including details of one new target, anda selection of the free news storiespublished on our website in our NewsDigest section. This month's Search Tip

s h o w s y o u h o w t o s e a r c hPharmaprojectsfor drugs acting on thepurinoreceptor target family.

CONTENTS

Therapy Analysis 1

Meeting Report 4

New Targets 5

New Companies 5

Mergers and Acquisitions 6

News Digest 7

Further Information 8

Search Tip of the Month 9

New Drug Development Strategies 6

To read our monthly analysis featurearticles, please visit our website:


Clopidogrel in its packaging, marketed by San-

ofi-Aventis as Plavix

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Painful purinoreceptors

Moving away from the circulatory system, and demonstratingthe wide expression of purinoreceptors throughout the body,expression of P2X3 receptors is also highly localized on sen-sory neurones involved in the perception of pain, and the pe-ripheral or spinal application of ATP and other agonists hasbeen shown to induce pain responses and enhance sensitivity

to noxious stimuli. The role of P2X3 receptors in pain has beenvalidated, with hypoalgesia being observed in gene knockoutand gene silencing studies. The localization of the receptorshas made them an attractive target for the development ofselective analgesics.

One company with a strong presence in purinoreceptor thera-peutics is Evotec, an emerging biotech company with a robustpipeline of drugs primarily for the treatment of CNS disordersand pain. Evotecs P2X3 and P2X2/3 antagonist program is inthe lead optimization stage of preclinical development withcompounds expected to enter the clinic in 2009. Evotec ispredicting that its drugs will achieve first- and best-in-class

status, with development of the only other P2X2/3 receptorantagonist (Abbotts A-317491) being dropped. While showingpromise in preclinical studies, A-317491 was shelved on ac-count of poor bioavailability and serves as an example of howthe pharmaceutical industry has faced difficulty in synthesizingclinically-viable drug-like molecules against these two targets.

The strange and wonderful P2X7 receptors

P2X7 receptors have been the most baffling to researchers buthave also attracted much interest from the pharmaceuticalindustry. The complex signalling and puzzling cellular effectsof P2X7 receptor activation have not deterred drug discoveryefforts. An important role for P2X7 receptors in the production

of cytokines has been recognized. This has prompted a num-ber of companies to begin development of P2X7 receptor an-tagonists for the treatment of inflammatory diseases includingRA and inflammatory bowel disease (IBD).

P2Y12 and the anti-platelet drugs

Among the first P2 purinoreceptor-targeted compounds syn-thesized were the antiplatelet drug ticlopidine and its ana-logue, clopidogrel. The role of ADP in the function of plateletshas long been known. Following activation, platelets secrete anumber of agonists including ADP and TXA2, which activate apathway for platelet aggregation and clot formation. There

are a number of diseases and medical procedures that leavepatients prone to development of life-threatening clots, forwhich blocking the action of ADP via P2Y12 receptors hasproved immensely important.

Clopidogrel (marketed as Plavix and Isover by Sanofi-Aventisand Bristol-Myers Squibb, respectively) is a potent P2Y12 re-ceptor antagonist indicated for the prevention of ischaemicevents in patients with atherosclerosis, the treatment of acutecoronary syndrome (ACS) and the prevention of thrombosisfollowing the placement of coronary stents. According to IMSHealth, in the period since its launch in 1998, it has ranked asthe second biggest selling drug in the world.

There are four novel P2Y12 receptor antagonists in clinicaldevelopment, which could potentially compete for this lucra-tive market as they boast a number of benefits over clopido-grel. The most advanced of these drugs is Daiichi Sankyosprasurgrel, which has been submitted for approval in the EUand the US. In a Phase III superiority trial against clopidogrelin ACS patients, prasugrel significantly reduced the risk ofcardiovascular death, non-fatal heart attack and non-fatalstroke by 19%. A staggering 40% reduction in risk of heartattack was observed in a subgroup analysis of patients withdiabetes. Another promising compound is Portolas PRT-060128 (elinogrel); it is the only reversible inhibitor of P2Y12 inclinical development, which may reduce the incidence of

bleeding compared with the likes of clopidogrel and prasugrel.It also has the benefit of an instant onset of action, as it hasno prodrug properties. Both iv and oral formulations are underdevelopment for acute (hospital) and chronic settings. It iscurrently in a Phase II trial comparing it to clopidogrel in pa-tients undergoing non-urgent percutaneous coronary interven-tion (PCI), to assess if these favourable chemical propertiestranslate into a safer and more efficacious drug.

Graph 1: Breadth of indications for which purinoreceptorshave been studied

Graph 2: Number of purinoreceptor-targeted drugs underdevelopment and launched 1995-2008

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The most advanced P2X7 receptor antagonist is Pfizers CE-224535, which is currently in the Phase IIa portion of a PhaseII/III trial in RA patients who are inadequately controlled withmethotrexate, the current standard treatment. It is yet to beseen what role, if any, P2X7 receptor antagonists will have inthe treatment of RA. P2X7 receptor antagonists have beentested for a number of indications, many of which have beendiscontinued; for example, a Phase II trial of the anti-

inflammatory and analgesic efficacy of CE-224535 in os-teoarthritis knee pain was terminated after an interim analysisshowed a lack of efficacy compared to placebo. Another ad-vanced P2X7 receptor antagonist is AstraZenecas AZD-9056,which is in Phase II trials for RA. Like CE-224535, its potentialfor osteoarthritis was investigated but subsequently discontin-ued. Additionally, development programmes for IBD andchronic obstructive pulmonary disease (COPD) were also ter-minated. AZD-9056 is currently under development for RAwith submissions for approval expected in 2012. Returning toEvotec, the company has launched a Phase I study for itsP2X7 antagonist. The trial will examine the pharmacokinetics,safety and tolerability of the compound following oral admini-

stration in healthy volunteers.

Recently, genetic variations in the P2X7 receptor gene havebeen studied in populations suffering from major depressivedisorder (MDD) and bipolar affective disorders. One variationhas been demonstrated to be strongly associated with bothMDD and bipolar affective disorders. This has provided animpetus to develop drugs for the P2X7 receptor to target de-pression. Affectis Pharmaceuticals, a German biopharmaceuti-cal company, is investigating potential drugs for the treatmentof depression and schizophrenia. AF-4025, its P2X7 receptoragonist for the treatment of depression has completed pre-clinical testing and is planned for clinical development. Thecompany also has P2X7 receptor antagonists in the late stages

of lead optimization.

P2Y2 New Hope for Cystic Fibrosis

Inspire Pharmaceuticals is a company with a strong presencein P2Y2 receptor drug discovery, based on technology licensedfrom the University of North Carolina (UNC), the US. Re-searchers working at UNCs Cystic Fibrosis Research Centerdiscovered that UTP improved mucociliary clearance and in-creased surface airway hydration. Inspire Pharmaceuticalscurrently has two P2Y2 agonists under development: denufo-sol tetrasodium, in Phase III clinical trials for cystic fibrosisand diquafosol tetrasodium, which has finished trials and is

awaiting approval in Japan and the US for Sjogren's syndromeand dry-eye syndrome, respectively. In pivotal Phase III trials,denufosol tetrasodium provided significant improvement overplacebo in the primary endpoint of the study and was safeand well tolerated. Diquafosol tetrasodium failed to meet itsprimary endpoint in an FDA-requested Phase III trial to con-firm efficacy. Inspire plans to initiate a further Phase III trialunder a Special Protocol Assessment from the FDA after vali-dating clinical endpoints in dry-eye studies. The only otherP2Y2 receptor-targeted drug in active development is EPIXPharmaceuticals EPX-16006, an orally-available agonist, forthe treatment of IBS. It stimulates chloride ion secretion inthe GI tract, and has been shown to improve GI motility in

preclinical studies.

Future of Purinoreceptors

Much of the research on P2 purinoreceptors has been carriedout over the previous 15 years and it is expected that theseimportant receptors will be implicated in the pathology ofmany more disorders. The ubiquitous expression of the recep-tors in many tissues makes the future of purinoreceptor re-search unpredictable but exciting. The first drugs targeting

purinoreceptors (ticlopidine and clopidogrel) were products oftraditional drug discovery and were launched around the timemany P2 receptor subtypes were being cloned and character-ized. With the first of the new wave of purinoreceptor drugsnow awaiting approval, it remains to be seen if these newcandidates can mimic the commercial success of these earlydrugs. With the steep increase in the number of purinorecep-tor-targeted drugs in development over the past 13 years(Graph 2) expected to continue, the future of this class ofdrugs does indeed look promising.

Mohamed Farah

Image courtesy of Trounceunder the Creative CommonsAttribution ShareAlike 2.5 License

Search strategies

Graph 1In Drug Profile Search:

[Target Name Includes] = Purinoceptor

Graph by: Primary Indication

Graph 2In Trend Analysis Search:

Any Pharmacology Code = PU-P2+OR Any Pharmacology Code = PU-P2-

OR Any Pharmacology Code = PU-P2-X-OR Any Pharmacology Code = PU-P2-X23-OR Any Pharmacology Code = PU-P2-X3-OR Any Pharmacology Code = PU-P2-X7+OR Any Pharmacology Code = PU-P2-X7-OR Any Pharmacology Code = PU-P2-Y+OR Any Pharmacology Code = PU-P2-Y-OR Any Pharmacology Code = PU-P2-Y12-OR Any Pharmacology Code = PU-P2-Y2+

Graph by: Active, Ceased, Fully-launched

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Meeting Report - 38th Annual Meeting of the Society for Neuroscience

In the midst of President-elect Obamas triumphantwin, over 31,000 people from all four corners of theglobe gathered to exchange ideas as well as mingleand network in the capital of the USA, Washington,DC, for the 38th annual meeting of the Society for Neu-roscience. The Walter E. Washington Convention Cen-ter provided the setting for numerous presentations,poster sessions and symposia, all in the interest ofsharing knowledge between international researchers.

Neuroscience is a highly diverse and multifaceted field, whichwas reflected at the conference by the range of topics, frompotential treatments for Alzheimers disease to our facial per-ceptions to the application of make-up. In the interest of find-ing the truth and advancing current knowledge in these some-times still poorly-understood areas, world-renowned scientistsbrought forward their pioneering research while exercisingtheir intellect through intense debate with their colleagues. Anexample of this depth and variety was exemplified by Mark

Morris, founder of the Mark Morris Dance Group, who chaireda discussion on dance specifically, movement in time andspace. Society president Eve Marder was in attendance at thediscussion, which covered the provision of customised danceclasses for people with Parkinsons disease, highlighting howmeaning is encoded in time and space and on the importanceof proprioception for dance.

On the pharmaceutical side of things, a fairly new area ofresearch and recently-added indication to Pharmaprojects,levodopa-induced dyskinesia, was amply covered in the con-ference by postdoctoral fellows such as Dr. Recchia and oth-ers from Merz Pharmaceuticals. The company is actively test-ing a variety of discontinued, suspended and active glutamate

agonist and antagonist compounds in rat models for this indi-cation. Also working in the field of Parkinsons disease, KyowaHakko Kirin presented results from preclinical studies of itsorally-available A2a receptor antagonist, istradefylline (KW-6002). In medial prefrontal cortex-lesioned rats, istradefylline0.1-0.3mg/kg ameliorated cognitive impairments in objectrecognition testing and Kyowa Hakko Kirin is now seekingcollaboration partners for further development of KW-6002.

Another drug under development for Alzheimers disease, asimilarly prevalent degenerative disease extensively coveredat the conference, was Wyeths TO-901317, a liver X receptoragonist. In APP transgenic mice, it increased hippocampal

ApoE and ABCA1 levels.

The symposia consisted of an array of subjects varying from

the dynamics of sleep to the role of orbitofrontal cortex indecision-making. The symposium Functional neuroimagingevidence for a brain network underlying impaired insight intoillness in drug addiction, chaired by Rita Z. Goldstein, laid thefoundation for a hot discussion on the brains response toerrors in ones performance and the subsequent activity of themonitoring systems thereafter. Many a heated debate evolvedfrom the small gatherings of great minds!

The conference provided an interesting and insightful five-daylook at current topics in neuroscience, saturated with fun andinformative activities. The brain, being the most importantorgan in the body, by popular opinion, was celebrated to thefullest. After all without our brains we wouldnt have the ca-pacity to interpret the world around us smell, sight, taste all wonderful and ever so important senses! For these rea-sons, the many thousands of research fellows have dug deepand have investigated many of the cranial ailments that afflictso many people worldwide. From schizophrenia to drugabuse, mood disorders, pain, addiction to the molecular basisof human reasoning, the annual Society for Neurosciencemeeting continues to enlighten and educate us about thatmysterious and ever-elusive grey mass between our earswhich controls our bodies and houses our minds.

Naila ShawThe 39th Annual Meeting of the Society for Neuroscience will

be held on 17th-21st October 2009, Chicago, USA

The Walter E Washington Conference Center

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New Drug Development Strategies

The following new drug development strategies are new to the January edition ofPharmaprojects.

Factor Xa stimulant

Portola Pharmaceuticals is developing an antidote which neutralizes small molecule Factor Xa inhibitors, for use inpatients experiencing major bleeding.

Factor Xa stimulants are coded in Pharmaprojectsas FA-10-A+.

Galactosylceramide beta-galactosidase stimulant

Shire Human Genetic Therapies (Shire) and Zymenex are developing Galactosylceramide beta-galactosidase stimu-lants for the treatment of globoid cell leukodystrophy (Krabbes disease).

Galactosylceramide beta-galactosidase stimulants are coded in Pharmaprojectsas GALAC-G-B+.

Mergers, Acquisitions, Name Changes and Joint-Ventures

BioTie Therapieshas acquired Elbion

BTGhas acquired Protherics

Cytrxhas acquired Innovive

InvitrogenandApplied Biosystemshave merged to form Life Technologies

Lilllyhas acquired ImClone Systems, which will now operate as a wholly-owned subsidiary

Oxford Genome Scienceschanged its name to Oxford Biotherapeutics

PatrysacquiredAcceptysassets.

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PharmaprojectsNews Digest

The following are taken from our selection of news stories listed on the Pharmaprojects website. Go towww.pharmaprojects.comfor more of the same, and to subscribe to our free RSS feed.

First approval for next-generation fibrate

The US FDA has approved TriLipix (fenofibric acid), anext-generation micronized fenofibrate co-developed by

Abbott and Solvay, for cholesterol management. Abbottwill be responsible for marketing TriLipix in the US,while Solvay holds the rights to the rest of the world. Itis also being developed in a tablet form (ABT-143), incombination with rosuvastatin calcium, for the treat-ment of hyperlipidaemia. Filing for approval of ABT-143is expected next year.

Fibrates activate peroxisome proliferator-activated re-ceptors (PPARs), primarily PPARa, which modulate car-

bohydrate and fat metabolism. Fibrates act on three keylipids, increasing 'good' high-density lipoprotein (HDL)levels and decreasing triglyceride levels, while also low-ering 'bad' low-density lipoprotein (LDL) levels. LDLstransport cholesterol to arteries where it can be re-tained by proteoglycans to initiate the formation of arte-rial plaques associated with atherosclerosis.

While TriLipix has not been shown to prevent heart dis-ease or heart attacks, clinical trials have demonstratedthat when used in combination with the most commonlyprescribed statins, TriLipix managed levels of three key

lipids better than either of the corresponding therapiesalone. Because of this, TriLipix is indicated for use withstatins and diet. It is currently the first and only fibrateapproved for use in combination with a statin for cho-lesterol management.

Erbitux filed for nsclc in the US

ImClone Systems and Bristol-Myers Squibb have sub-mitted a US filing for approval of their anti-EGFR mono-clonal antibody therapy, Erbitux (cetuximab) for thefirst-line treatment of advanced non-small cell lung can-

cer (nsclc) in combination with platinium-based chemo-therapy.

The filing application is based on data from the PhaseIII FLEX trial in 1124 patients with stage IIIb or IVnsclc. In this trial, Erbitux in combination with cisplatinand vinorelbine increased survival by 1.2 months com-pared to chemotherapy alone, meeting its primary end-point. In a second Phase III trial (BMS-CA225-099) in600 advanced nsclc patients, Erbitux in combinationwith carboplatin and taxane therapy failed to meet theprimary endpoint of progression-free survival.

Erbitux is already launched for both metastatic colorec-tal cancer (MCC) and head and neck cancer both in the

EU and the US, with recent launches for MCC in Canadaand Japan. If approved, nsclc would represent Erbitux'largest indication. Future approval may also offer hopeto squamous cell cancer patients who are at presentfaced with limited treatment options due to the risk ofpulmonary bleeding with Roche/Genentech's Avastin(bevacizumab).

Merck KGaA submitted a similar filing to the EMEA inSeptember 2008, while a decision by the US FDA onwhether to accept the new filing for review is expectedin February 2009.

Merck KGaA's Kuvan becomes first Europeantherapy for hyperphenylalaninaemia

Merck KGaA and its Merck Serono division have re-ceived EU approval for their monoamine biosynthesisenhancer Kuvan (sapropterin dihydrochloride) for thetreatment of hyperphenylalaninaemia (HPA), making itthe first and only drug available in Europe for HPA dueto phenylketonuria (PKU) or BH4 deficiency. Until now,the only option for PKU patients had been to restrictthemselves to a diet with low levels of the amino acid

phenylalanine, non-adherence to which could lead toirreversable mental damage.

The approval of Kuvan was based on data collectedfrom two multinational Phase III trials which demon-strated that Kuvan reduced plasma phenylalanine levelsand increased patients' phenylalanine dietary tolerance,reducing the need to limit their diet. Adverse eventsreported were mild to moderate and transient.

Kuvan had received Orphan Drug designation for HPAand as such will receive 10 years of protection for the

treatment of this disease. Launch is expected to com-mence in the first half of 2009. Kuvan has beenlaunched under the name Biopten for over a decade inJapan, where it was developed by Suntory (now AsubioPharma, part of Daiichi Sankyo).

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Thomas Stirzaker Editor, Pharmaprojects Update AnalysisTelephone +44 (0)20 7017 77660Facsimile +44 (0)20 7017 6898E-mail [email protected]

For further information on any aspect of the Pharmaprojects service, or if you would like to receive thePharmaprojects Update Analysisby e-mail to facilitate internal distribution, please contact your local agent or one ofthe following:

For editorial information contact:Ian Lloyd Managing Editor, PharmaprojectsTelephone +44 (0)20 7017 6886

Facsimile +44 (0)20 7017 6898E-mail [email protected]

For product information contact:Michael Aplin Marketing Manager, PharmaprojectsTelephone +44 (0)20 7017 6949

Facsimile +44 (0)20 7017 6985E-mail [email protected]

Further Information

Copyright in this issue ofUpdate Analysisis held by Informa UK Ltd 2009. You may copy this issue as many timesas you wish in whole or part and in any format provided this is for internal use at the same mailing address as theone to which Informa has sent the copy you are reading.

Otherwise this issue is supplied on the same terms as apply to Pharmaprojects: save as provided herein, materialmay not be sent to any other part of the subscribers organisation and save for any use authorised by those termsand conditions this material may not be reproduced, distributed, leased or resold or otherwise made available to anythird party.

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Search Tip of the Month - Searching for P2Y-targeted drugs

The powerful search facilities available on Pharmaprojects can be used for a variety of research purposes. Thismonth we show you how to search by Target Family to find drugs targeted to a P2Y purinoreceptor.

Visit the PharmaprojectsWeb site for Search Tips of the Month which have featured inprevious issues of the Update Analysis.

In the Target Data section, ex-pand the Target Families tab andselect Receptor from the list.

Then select GPCR from the expanded list,and select P2Y from the list of receptorson the right of the screen. This will allowyou to search for purinoreceptors of theP2Y family.

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