Nicotinic Receptor Therapeutics & Drug Dependence

1. Nicotinic Receptor Therapeutics & Drug Dependence In Depth Analysis of Breaking Research, Drug Development News & Pipeline Activity February 2011 Edition(Featuring information published: Feb 4th - Mar 10th) Next issue April 8th (approx)

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3. Executive summary of new activityFebruary 2011 - Key activity around the α7 receptor • TC-5619 - Phase 1 Alzheimer’s study now fully enrolled: Targacept has been evaluating TC-5619 in Phase 2a studies of ADHD and CIAS. Positive top line CIAS data were reported in the December issue of UpdatesPlus; ADHD data are expected very shortly. In February Targacept announced through clinicaltrials.gov that a Phase 1 Alzheimer’s disease study is also now fully enrolled and that data remains on track to read out in Q2 2011. • PAM assay from Abbott:Abbott has displayed an interest in PAMs. A recent Abbott patent claims screening tools for the identification of α7 PAMs (WO 2009/003074). Company researchers have now published one assay in detail. In particular the assay is compatible with HTS for Type II PAMs (ie those that increase peak response and slow desensitization). • α7 receptor agonists as potential treatments of thrombocytopenia: Chronic immune thrombocytopenic purpura (ITP) and drug induced thrombocytopenia require new treatment approaches. The potential market for new treatments may exceed $0.5 billion. New research has shown α7 antagonism blocks platelet differentiation; extending this finding by demonstrating agonist-induced differentiation would support further expansion of the nicotinics field into the treatment of platelet diseases. • Can α7 receptor agonists improve mortality and morbidity after cardiac arrest? Delayed mortality and morbidity after cardiac arrest is due in part to global cerebral ischemia. New research suggests that α7 agonists can limit cerebral inflammation and hippocampal cell damage.

4. Executive summary of new activityFebruary 2011 - Key activity around the α4β2 receptor • New Phase 1 study of TC-5214 announced: We have learned that Quintiles is looking for 32 patients to include in a Phase 1 study of TC-5214. The study will assess the safety, tolerability and pharmacokinetics of the candidate in elderly patients. We believe that this study simply reflects filling requirement, allowing data to be included on an eventual product label on special populations. Data in the elderly would however be useful given the prevalence of depression in this cohort. • GSK/Targacept alliance terminated as GSK realigns CNS activities: Targacept and GSK have been collaborating since 2007 in various CNS diseases. GSK has now terminated its alliance with Targacept due to GSK’s strategic changes in the neurosciences area in 2010. This is not expected to present a major problem to Targacept given its evolution as a company over recent years. Companies interested in in-licensing candidates emerging from the collaboration may stand to benefit; alternatively Targacept should hopefully be in a position to advance these candidates unilaterally if necessary.

5. Executive summary of new activityFebruary 2011 - Key activity around other nicotinic receptors • Researchers identify bupropion analogues with α3β4* affinity and smoking cessation potential:Researchers at the Research Triangle Institute have identified analogues of the smoking cessation product, bupropion. These analogues have been suggested to act through the modification of dopamine and norepinephrine uptake as well as stimulation of α3β4* receptor activity.

6. Executive summary of new activityJanuary 2011 - Key activity around smoking cessation • Varenicline study opens in paediatric patients: Smoking remains a serious problem in adolescents. In an attempt to help address this problem Pfizer has opened a study of 300 adolescents smokers. The primary end-point will read out in Aug 2013. This study has the additional advantage for Pfizer in that it could result in a paediatric extension. • Johnson & Johnson opens new nicotine replacement therapy study: The product being evaluated in the study (NCT01296698) is not disclosed. Of note the 1500 subject study is apparently a pharmacy based one. This design has been selected to make the study more naturalistic. Initial screening and data collection will be conducted by the pharmacist. • NicVax extension study opens: Nabi, in partnership with GSK, is currently conducting two Phase 3 registration trials of NicVax. This vaccine generates antibodies to nicotine which are hoped to prevent temporary lapses developing into full relapse by neutralizing nicotine. Both studies are now fully enrolled and should read out Q1 2012. An extension study (NCT01304810) has now been advanced. This is simply an observational study and will monitor antibody persistence. • Duke University evaluates new smoking cessation strategy: Individuals who appear unlikely to abstain on nicotine replacement therapy alone will be randomized to receive varenicline alone or combined with bupropion. The remarkably large study (NCT01303861) is recruiting 1500 people and is due to read out H2 2012.

7. Executive summary of new activityJanuary 2011 - Key activity around drug dependence (excluding nicotine) • Omeros expands its drug addiction portfolio by in-licensing PDE7 inhibitors from Daiichi: Omeros has an addiction program, initially focused on the development of PPARγ agonists. Last year Omeros received an exclusive licence to develop Daiichi's PDE7 inhibitors as treatments for movement disorders, such as Parkinson's disease. Now Omeros has now announced that it is investigating these inhibitors for the treatment of addiction. • NK1 antagonists for the potential prevention of relapse in recovering alcoholics: Relapse is a common event in recovering alcoholics. This can be induced by alcohol cues or stressful life events. NK1 antagonists have been developed for anxiety and depression. Data has now shown that this class may be of use in preventing stress induced relapse in alcoholics. • Muscarinic M4 receptor agonists as candidates for cocaine addiction? Genetic deletion of the M4 receptor has been shown to increase cocaine self-administration. This suggests that the development of agonists as candidate treatments of addiction is warranted.

8. This Month’s activity around the α7 receptor

9. Pipeline Overview – α7 ligands Phase 3 Phase 2 Preclin Phase 1 Xytis – XY 4083 Alzheimer’s - Xytis no longer trading? Asthma/Diabetes ADHDAsthmaCIASCIAS/ADHD/Alzheimer’s(?)Alzheimer’s/CIASAlzheimer’s Targacept – TC-6987 Neuroderm - ND0801 Asmacure - ASM-024Novartis - AQW051 Targacept - TC-5619 EnVivo - EVP-6124 Roche - RG3487 (RO-5313534) Ph 2 Opened: Q1 2011 Ph 2 Opened: Q2 2010 Ph 2 Opened: Q2 2010 Ph 2 opened 2010 Ph 2a Completion Q1 2011 (CIAS; ADHD) Ph 2b Completion: Q1 2011 (AD) Ph 2b Completion: Q3/Q1 2011 (AD/CIAS) Positive Allosteric Modulators Agonists

10. Pipeline Overview – α7 ligands • Pipeline changes for February 2011 • No Changes

11. Targacept discloses a few further details on Phase 2 TC-6987 studies • The January issue of UpdatesPlusfeatured the initiation of Targacept’s Phase 2 studies of TC-6987 in asthma and diabetes. • The asthma study has now been posted on clinicaltrials.gov (NCT01296087). • As previously reported, mild to moderate asthmatics are being enrolled into this US randomized placebo controlled trial. • During an initial 4 week run-in period, patients will receive low-dose inhaled corticosteroid and cease taking their current asthma medication. • On top of this baseline, patients will receive TC-6987 at 100mg for the first day of dosing followed by 50mg for a further 4 weeks. Placebo will be dosed in a control arm. As is standard for asthma studies, improved FEV will be the primary end point. • We now know that TC-6987 will be dosed orally contrasting with ASM-024, an inhaled nicotinic agent in development for asthma. In addition, individuals using strong P450 3A4 (CYP3A4) inhibitors are being excluded suggesting this enzyme is responsible for the metabolism of TC-6987. • The diabetes study has also been posted (NCT01293669). • On the entry TC-6987 is described as an open channel stabilizer. In vivo data were also disclosed and particularly that TC-6987 improved both metabolic parameters (plasma glucose, triglyceride, and Hb1Ac) and reduced inflammatory mediators (TNF-α). • Patients will receive TC-6987 or placebo as a monotherapy after a 4 week wash-out. Dosing will be with 20mg for the first day dropping to 10mg for the remainder of the dosing period (note that the dose is considerably lower than for the asthma study). • Fasting plasma glucose will be the primary measure.

12. Thrombocytopenia: A group of platelet diseases potentially treatable by α7 agonists? • Thrombocytopenia is defined as an abnormally low platelet level and is associated with clotting disorders. • The common autoimmune disease, immune thrombocytopenic purpura (ITP) is caused by platelet antibodies. ITP presents as: • Acute self-limiting ITP which is primarily a paediatric condition. • Chronic ITP, an orphan disease affecting 3-5/100,000 adults. • Thrombocytopenia can also arise as a side effect of cytotoxic agents and ribavirin (used in HCV treatment) • Treatment of thrombocytopenia has changed in the past decade with the current focus on two new thrombopoietin mimetics (TPO): romiplostim (Nplate; an injectable peptide) and eltrombopag (Promacta; an orally small molecule). • Romiplostim is disadvantaged by its peptidic nature while eltrombopag carries a black box warning of hepatotoxicity. • Rodman & Renshaw has forecast sales of $510 million by 2012 for Promacta assuming approval for oncology and HCV. So far sales remain at $50 million with indications limited to ITP. • With Promacta having failed to live up to expectations there is potentially space for new platelet stimulation agents and recent data suggests nicotinic agents could fill this niche. Few pipeline candidates target thrombocytopenia Veltuzumab (Immunomedics) S-888711 (Shionogi) 2285921 (GSK) No Phase 3 candidates Phase 2 Phase 3

13. Platelets as a new target for α7 nicotinic agonists? • In addition to thrombopoietin receptors, components of the cholinergic system have been detected in platelet precursors (megakaryocytes), and platelets themselves. • Moreover cholinergic agonists have been shown to modulate megakaryopoiesis and stimulate megakaryocyte proliferation. • In 2010 Schedel et al reported the expression of α7 receptors on platelets. • The same group has now reported that MLA, used at concentrations known to antagonize α7, blocks megakaryocyte differentiation (Thornton et al. 2011; see inset). • This suggests that α7 agonists may enhance differentiation offering a new approach to the treatment of thrombocytopenia. Megakaryoblasts were stimulated by the differentiation factor, TPA. This caused increased expression of the megakaryocyte marker, CD61. This was reduced by both nicotine and MLA The next obvious study would be to determine whether an α7 agonist is able to stimulate platelet generation and to compare this to the effect of a TPO.

14. New data suggests α7 agonists may limit post resuscitation cerebral ischemic damage Effect of GTS-21 on hippocampal inflammation and neural death following CA/CPR • In the US, according to the AHA, emergency medical personnel treat ≈300,000 victims of out-of-hospital cardiac arrest each year. • Sasson et al, 2009 reported that 24% of those treated survived to hospital admission. • However, <8% of victims survived to discharge. Delayed mortality and morbidity is due in part to global cerebral ischemia following successful resuscitation. • Using a rodent model, Norman et al have now reported the involvement of α7 receptors in cerebral ischemia. • The authors report that cardiac arrest/cardiopulmonary resuscitation (CA/CPR) increased hippocampal proinflammatory mediators. Elements of the cholinergic system were also down-regulated. • Treatment with GTS-21 reversed the elevation in hippocampal IL-6 and microglial number (top panel) suggesting anti-inflammatory activity. This was reflected in reduced hippocampal neural cell damage (lower panel). Each of these changes was inhibited by mecamylamine Microglia marker, MAC1 was reduced in rodents subject to CA/CPR and treated with GTS-21 daily post arrest Fluro-Jade levels were also reduced by GTS-21 reflecting reduced neural damage

15. This Month’s activity around the α4ß2 receptor

16. Pipeline Overview – α4ß2 ligands Phase 2 Phase 3 Preclin Phase 1 Abbott- A-969933/NS9283 AntagonistsPartial Agonists Targacept/GSK - TC-5653 (dual α4ß2/α6) Targacept - AZD3480 Backups PAM Amgen - Unnamed cpds Suven - SUVN-911 Suven - SUVN-F90101; SUVN-F90201 Smoking Cessation (patch)CognitionIBS Pfizer – Varenicline (LCM) Abbott/NeuroSearch – ABT-560 Targacept – TC6499 Depression Pfizer - CP-601927 Alzheimer’s Targacept/AstraZeneca (AZD1446/TC-6683 Ph 2a ADHD AstraZeneca – ispronicline (AZD3480/TC-1734) Ph 2b ? Starting in Q1 2011 ADHD Abbott/NeuroSearch - ABT-894 (Sofinicline) Ph 2b Completed 2008 ADHD/Alzheimer’s Ph 2b Completed 2008 - presumed terminated Abbott - ABT-089 (Pozanicline) AMD CoMentis – ATG-3 (Mecamylamine)* Alzheimer’s AGI - AG-004 (Mecamylamine)* Diarrhea Pfizer – Varenicline • Depression • NDA H2 2012 • MAA 2015 Targacept - TC-5214 Ph 2 (mono) & Phase 3 (add on) Started Mid-2010 *Mecamylamine is considered a poorly selective nicotinic ligand

17. Pipeline Overview - α4ß2 ligands • Pipeline changes for February 2011 • No changes

18. Phase 1 study of TC-5214 about to start in the elderly • The Phase 3 program, RENAISSANCE, studying TC-5614 as a candidate treatment for depression is now well underway. • We have recently learned that the CRO, Quintiles is looking for 32 patients to enrol into a Phase 1 study of TC-5214. • The trial, which will take place at a single site in Sweden, is expected to be completed by April this year and will assess the safety, tolerability and pharmacokinetics of multiple oral doses of TC-5214 in medically stable patients, more than 65 years old. This study probably reflects a filing requirement, evaluating the safety of TC-5214 in special populations including the elderly. It should be noted however that depression is an especial problem in the elderly. The generation of efficacy data subsequent to this study could help promote the sale of TC-5214 post-launch.

19. Targacept and GSK go their separate ways as GSK realigns its activity within the neurosciences • Targacept and GSK have been collaborating since 2007 in five therapeutic areas - pain, smoking cessation, addiction, obesity and Parkinson's disease. • The collaboration produced TC6499 for the treatment of pain however this development was stopped in 2009 due to an insufficient therapeutic margin. Targacept has since switched indications to IBS. • In addition the companies were developing a dual α4ß2/α6 agent which we believe was being targeted towards smoking cessation. Activities around this indication have drawn in milestone payments for Targacept in the past. • GSK has now terminated its alliance with Targacept due to GSK’s strategic changes in the neurosciences area in 2010. • While this is obviously not ideal for Targacept it has gained full rights to the programmes and related candidates that were within the alliance. This opens up the possibility of new partnering opportunities. • Since the alliance was opened Targacept has evolved as a company with market entry potentially on the horizon. Revenue generated by the launch of molecules such as TC-5214 means that Targacept should hopefully be in a good position to continue development of assets emerging from the GSK partnership even if it doesn’t find another partner to replace GSK.

20. This Month’s activity around other subtypes

21. Researchers identify bupropion analogues with α3β4*affinity and smoking cessation potential • Researchers at the Research Triangle Institute have been developing analogues of bupropion for the treatment of nicotine dependence. • These analogues have been suggested to act through the modification of dopamine and norepinephrine uptake as well as stimulation of cholinergic receptor activity. • Further activity has now been reported around a 2-(substituted phenyl)-3,5,5-trimethylmorpholine scaffold. • Analogues from this series were profiled in vitro and then evaluated in two animal models: nicotine induced antinociception and nicotine-conditioned place preference. These are assays for the acute and reward effects of nicotine. • Two molecules were selected as being of especial interest as smoking cessation candidates.

22. This Month’s activity around smoking cessation/nicotine dependencePharmacologic approaches

23. Pipeline Overview Smoking cessation/nicotine dependence Preclin Phase 1 Phase 2 Marketed Phase 3 Pfizer - Varenicline (LCM) Acrux - Nicotine MDTS Aradigm - ARD-1600 Cary Pharmaceuticals - QuitPak Cytos/Novartis - NIC002 Celtic Pharma -TA-NIC Independent Pharma - Niccine Nabi Pharma - NicVax Phase 3 studies to complete 2012 Pfizer - Chantix/Champix GSK - Niquitin CQ GSK - Bupropion

24. Pipeline Overview – Smoking Cessation • Pipeline changes for February 2011 • No Changes

25. Pfizer opens US paediatric varenicline study Adolescent smoking remains high in the US • According to data from 1999-2004 (CDC National Health Statistics Reports, 2009), 37% of adolescents who smoked were daily smokers and 33% smoked ≥6 cigarettes per day. • 2009 figures (CDC, Health, United States, 2010) show a remarkable fall in the rate of adolescent smoking however this trend has flattened out and there remains a clear need to address smoking cessation in younger individuals. • With these statistics in mind it is of interest to note that Pfizer has opened a new varenicline study in adolescents (NCT01312909). • The US study will enrol 300 adolescents who smoke at least 6 cigarettes/day. • The study is similar to varenicline registration studies. Of note however, a half dose of varenicline will be used in lighter individuals. • The primary end-point will read out in Aug 2013 Although success in this study would be of potential use in reducing the rate of adolescent smoking, it would also benefit Pfizer. Not only could it increase the size of the market, the study could also support a paediatric extension for varenicline.

26. Study opens to evaluate varenicline for smoking reduction in those not ready to quit • Nicotine replacement therapies were initially approved in order to help immediate smoking cessation. However in 2005 regulations in some regions changed to allow the use of such therapies as a stepping stone to quitting. • A 2007 systematic reviewsuggested that a substantial reduction in smoking improved several cardiovascular risk factors, and respiratory symptoms (Pisinger & Godtfredsen, 2007). • Consequently, regulatory authorities and particularly those in the UK have allowed the use of NRT to help reduce or temporarily stop smoking. Indeed a recent survey of English smokers has revealed that 28% of smokers use nicotine replacement therapy for this purpose. • Of interest New Jersey researchers have now opened a study (NCT01308736) of 60 individuals to determine whether varenicline can reduce smoking in individuals not wishing to quit. This study is of interest given that varenicline has a boxed warning. If the study does demonstrate a reduction in the number of cigarettes smoked without a significant reduction in abstinences we ask what the implications may be? The study is too small to bring about change on its own but a larger study could pressure regulators to approve varenicline as a smoking reduction strategy. We doubt whether this would occur unless high risk patients were to be studied, ideally with clinical outcomes measures.

27. Arbi Group and Italian Antismoking League complete E-cigarette studies • The Arbi Group, an Italian electronic cigarette retailer, in collaboration with the Italian anti-smoking league, opened a number of studies in 2010. • The studies (NCT01188239; NCT01194583; NCT01164072) were investigating the ability of E-cigarettes to reduce smoking. • These studies are no longer recruiting and we believe that data is now available. Smokers with no intention to quit wk2 Wk4 wk6 wk8 wk10 wk12 Study visitto monitor Base • 1O Outcome Measures • Sustained 50% reduction in cigarettes at each visit • Sustained smoking abstinence at wk12 • 2O Outcome Measures include • Sustained 80% reduction in cigarettes at each visit • Sustained smoking abstinence at wk24 • Withdrawal suppression • Cravings reduction • Adverse events

28. This Month’s activity around drug dependence (excluding nicotine)Pharmacologic approaches

29. Pipeline Overview Drug dependence (excluding nicotine) Phase 1 Phase 2 Marketed Phase 3 NanoBUP (Nanotherapeutics) AIKO-150 (AIKO) Omeros (PPARγ ligands) Lilly (LY-2456302) GSK (618334) BioDelivery (buprenorphine/naloxone) Orexa (Buprenorphine/Naloxone) Alkermes (ALKS 33) BioTie (Nepicastat; SYN-117) Lilly (OprA) Catalyst (CPP-109) Pivotal Phase 2b started; IND H2 2012? Lundbeck/BioTie (Nalmefene) MAA Expected H2 2011 Titan (Probuphine) Generic Suboxone (buprenorphine/naloxone) Generic Subutex (buprenorphine) Alkermes (VIVITROL) Reckitt Benckiser (Suboxone Film) Forest/Meram (CAMPRAL/AOTAL)

30. Pipeline Overview – Drug dependence (excluding nicotine) • Pipeline changes for February 2011 • No Changes

31. D&A Pharma is about to file reformulated treatments of alcohol and opiate addiction • Sodium oxybate has been marketed in Italy for several years as a liquid-formulation for alcoholism. This product is unfortunately also used as a street drug and therefore has significant misuse potential. • D&A Pharma is addressing this through the development of SMO-IR, an immediate-release, thin-pellet formulation. • The company expects to file in Europe in 2011 having demonstrated bioequivalence of SMO-IR with sodium oxybate. A granule formulation may follow on from SMO-IR • At the same time the company has reported that it also intends to file an “undisclosed dual µ/κopioid agonist” for the treatment of opiate addiction. This product is presumed to be a reformulation of suboxone.

32. Omeros expands its drug addiction portfolio by in-licensing PDE7 inhibitors from Daiichi • Omeros has an addiction program, initially focused on the development of PPARγ agonists. Pilot human and preclinical data suggest that this class may be most effective in the treatment of addiction to opioids, alcohol and nicotine. Efficacy as a treatment of psychostimulant addiction (cocaine and methamphetamine) is expected to be less impressive. • Last year Omeros received an exclusive licence to develop Daiichi's PDE7 inhibitors as treatments for movement disorders, such as Parkinson's disease. • Now Omeros has now announced that it is investigating these inhibitors for the treatment of addiction, thus expanding their activities within the drug dependence field. • PDE7 appears to modulate the dopaminergic system and according to Omoros, PDE7 inhibitors have been shown to reduce cocaine self-administration, inhibit cue and stress induced relapse, and facilitate drug abstinence in models of cocaine addiction. • Under the amended deal, milestone payments from Omeros to Daiichi have increased from $23.5 million to $30.2 million.

33. NK1 antagonism reduces stress-induced reinstatement of alcohol intake • NK1 antagonism has previously been shown to prevent the rewarding effect of morphine. Schank et al now report the effect of this therapeutic class on alcohol consumption. • Previous studies have implicated the potential efficacy of NK1 antagonists in treating alcoholism however it is not clear if such agents would suppress ongoing excessive alcohol use, prevent relapse, or both. • In their paper published in Psychopharmacology, the NIH group reports that LY822429 fails to modify alcohol self-administration in rodents suggesting no effect on excessive alcohol use. • In contrast LY822429 blocked stress-induced reinstatement of alcohol consumption (inset). Cue-associated reinstatement was not however affected by NK1 antagonism. • NK1 antagonists have been developed for anxiety and depression. The present data suggests that this class may be useful in treating recovering alcoholics in times of stress. This class may complement Naltrexone that reduces cue induced re-instatement.

34. New data suggests that muscarinic M4 agonists may be of benefit to cocaine addiction • In 2010 we reported on a series of dual α7/M4 agonists with analgesic and anti-inflammatory properties. • To our knowledge the M4 class remains an underexploited therapy area; to date no M4 agonists have entered the clinic. • Now we report that this class may be of benefit in treating addiction as well as inflammation/pain. • Previous studies have shown M4 knock-out to enhance D1 receptor induced motor activity. • In the March issue of PsychopharmacologySchmidt et al have now reported that M4 receptor knock-out is associated with greater cocaine self-administration under fixed ratio 1 (FR1) and progressive ratio (PR) schedules of reinforcement . • Panel A of the inset demonstrates that cocaine self-administration was higher under a FR1 schedule in M4 knock-outs. • Panel B demonstrates that higher breaking points were reached in the PR schedule. Using this schedule, the number of responses required to earn a cocaine reward was gradually increased until the breaking point where mice no longer attempted to earn a reward. This measure provides an index of motivation. • In addition, this group demonstrated that cocaine induced dopamine efflux in the nucleus accumbens and hyperlocomotion was increased in knock-out mice. • Having established a proof of concept for targeting M4 receptors, the development of agonists as candidate treatments of addiction is warranted.

35. Annex: Content identified for this edition

36. Stakeholders tracked in UpdatesPlus • Abbott • Acrux • AGI • AIKO • Alza (J&J) • Reckitt Benckiser • American Snuff • Omeros • Aradigm • Asmacure • AstraZeneca • BAT • Bayer • BioTie • Cary Pharmaceuticals • Catalyst • Celtic Pharma

37. Stakeholders contd. • CoMentis • Cornerstone Therapeutics (Critical Therapeutics) – Portfolio licensed by Targacept • Cytos • EnVivo • Eli Lilly • Forest • GSK • Independent Pharma • Johnson & Johnson • Lundbeck • Mitsubishi • Neuroderm • NeuroSearch • Nabi Pharma • Nanotherapeutics

38. Stakeholders contd. • Niconovum • Novartis • Pfizer • Philip Morris Int • Philip Morris USA • ReceptoPharm • Reckitt Benckiser • Reynolds American • Roche (now including Memory Pharma) • Sanofi-Aventis • Swedish Match • Servier • Siena Biotech • Suven • Targacept • Titan • Wyeth (now Pfizer) • Xytis (website down in July – possibly ceased trading)

39. Key Papers 1Reprints available from LeadDiscovery

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