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Neuronal Nicotinic Receptors

Neuronal Nicotinic Receptors. In Depth Analysis of Breaking Research, Drug Development News & Pipeline Activity. Next Edition: January 13 th 2008. UpdatesPlus: Subscription Information.

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Neuronal Nicotinic Receptors

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  1. Neuronal Nicotinic Receptors In Depth Analysis of Breaking Research, Drug Development News & Pipeline Activity Next Edition: January 13th 2008

  2. UpdatesPlus: Subscription Information • To subscribe to receive future editions of UpdatesPlus-Nicotinic Receptors: please fill in this page and fax back to us on +44 (0)870 7525685 or contact us for further details • Annual subscription cost £4000 (up to December 31st 2007); £5000 (2008 onwards). Subscription allows company wide distribution of 12 monthly editions. • Card#................................ • Expiry……………………... • 3 digit security #................ • For UpdatesPlus in your area: This file is intended to represent an example of the type of service provided by LeadDiscovery’s UpdatesPlus service • If you are interested in receiving UpdatesPlus in your therapeutic area please contact us (leaddisc@leaddiscovery.co.uk or +44 (0)1580831877)

  3. December 14th 2007Executive Summary of new activity – α7 ligands • MEM 3454 (Memory Pharmaceuticals/Roche; phase 2a):Data were presented from a phase 2a study evaluating the efficacy of MEM 3454 in Alzheimer’s disease patients. The primary efficacy end-point, an improvement in episodic memory, was met. However in contrast to earlier expectations, once daily dosing no longer seems to be acceptable. Emergent hurdles include a loss of effect at higher doses and the frequency of constipation. Memory pharmaceuticals have suggested that future studies may employ lower doses • TC-5619 (Targacept/AstraZeneca; phase 1): Targacept have announced that TC-5619 had been selected as a candidate treatment of cognitive disorders. This has triggered a milestone payment from AstraZeneca and suggests that advancement to phase 2 may be imminent

  4. December 14th 2007Executive Summary of new activity – α7 ligands • PHA-568487 (Pfizer, Preclinical): Pfizer are developing an α7 ligand with quite novel pharmacology. PHA-568487 has both allosteric modulatory and agonist activity. This is mirrored by efficacy in a model of schizophrenia. Activity was maintained over a broad range of doses contrasting with other molecules that show reduced activity at higher doses • S 24795 (Servier; Preclinical): Servier appears to be making a push to establish itself in the nicotinics arena. Attention is focussed on S 24795. A body of papers and Neuroscience posters demonstrate efficacy in models of contextual, discriminative and working memory in aging mice suggesting that Alzheimer’s will be the primary indication

  5. December 14th 2007Executive Summary of new activity – α4ß2 ligands • Chantix (Pfizer; Marketed): Report of suicidal ideation in an individual using Chantix have been received by the FDA who are now evaluating post marketing adverse event reports. Drowsiness has also been flagged as a adverse event. • Targacept: Considerable development has been reported by Targacept over the past few weeks • TC-2696 failed to meet its efficacy end-point in a phase 2 study of dental pain. The future of TC-2696 is unclear • Preclinical data have demonstrated efficacy of TC-6499 in multiple models of neuropathic pain. Phase 1 studies have now opened triggering a milestone payment from GSK • Attention has been shifted from mecamylamine to its S(+) isomer, TC-5214, as a candidate treatment of depression which is expected to enter phase 1 Q1 2008. This resulted from proof of concept studies of various isoforms of the α4ß2 receptor and the demonstration that inhibition of (α4)3(ß2)2 and positive modulation of (α4)2(ß2)3 may offer the best approach, a profile mirrored by the selectivity of S(+) mecamylamine

  6. December 14th 2007Executive Summary of new activity – α4ß2 ligands • ABT-894 (NeuroSearch/Abbott; Phase 2): NeuroSearch have stated that ABT-894 will enter phase 3 studies within the next 12 months for both neuropathic pain and ADHD • Unnamed molecules: (Solvay; Preclinical): In their September 2007 investors day presentation Solvay stated that a more focused pipeline will be sought with especial attention being paid to the neurosciences. As part of this focus α4β2 partial agonists are being developed.

  7. December 14th 2007Other information • Key new drug development report has been published on nicotine addiction markets and pipelines: A report has just been published analyzing patient potential, unmet needs and clinical trial design in nicotine dependence. The report provides an overview of the current nicotine dependence market, covering both prescription and OTC products; an overview of drugs in late stage clinical development for nicotine dependence, and profiles of key compounds in development for use in nicotine dependence, with forecasts of drug revenues to 2016 and insight from key opinion leaders • A second report provides a broader view of the future CNS market: This reportprovides a detailed epidemiological analysis of major indications within the CNS disorders market, and examines the factors impacting their prevalence. The current opportunities and threats facing the market are assessed and the most promising potential growth areas across all indications are highlighted. The report also profiles the key trends influencing treatment sales and analyses the competitive dynamics of leading brands within each indication. Segments discussed include: Depression; Alzheimer’s; Epilepsy; Migraine; Parkinson’s and Schizophrenia;

  8. This Month’s activity around the α7 receptor

  9. Pipeline Overview – α7 ligands Phase 3 Phase 2 Preclin Phase 1 NeuroSearch - NS-1738 Bayer - ABBF Abbott- 582941 Mitsubishi – Unnamed cpds Memory Pharma – Unnamed cpds Servier - S 24795Pfizer - PHA-568487Xytis – XY 4083Targacept – Unnamed cpds Memory Pharma/Roche – R4996Abbott – ABT-107AstraZeneca - AZD-0328 Targacept - TC-5619 En Vivo - EVP-6124 Sanofi-Aventis - SSR-180711 Alzheimer’s Alzheimer’s/CIAS Alzheimer’s Alzheimer’s/CIAS Alzheimer’s Alzheimer’s/CIAS Alzheimer’s/ADHD/CIAS CoMentis GTS-21 Memory Pharma - MEM 3454 Alzheimer’s/CIAS

  10. Pipeline Overview – α7 ligands • Pipeline changes for November • Memory announces that further late stage preclinical compounds are in development • Servier disclose data on partial agonist, S 24795 • Pfizer develop PHA-568487, a mixed agonist/allosteric modulator of the α7 receptor

  11. Memory Pharmaceuticals Present MEM 3454 data Summary of new data • Data were presented from a phase 2a study evaluating the efficacy of MEM 3454 in Alzheimer’s disease patients • The primary efficacy end-point, an improvement in episodic memory, was met • Once daily dosing no longer appears to be sufficient as efficacy was lost after 8hrs • Potential hurdles include a loss of effect at higher doses and the frequency of constipation • Further studies are expected at lower doses • Share Prices (Source Google Finance): • J: Positive phase 2a MEM 3454 data • Note that the price slide towards the end of November was unrelated to development activity

  12. Memory Pharmaceuticals presents investor updates during November • Since the last edition of NicotinicMonthly, Memory pharmaceuticals have presented updates at a number of investor conferences. • Most recently data were provided at the Lazard Capital Markets 4th Annual Healthcare Conference [Click here for presentation]. • Key announcements were: • A Phase 2a study of MEM 3454 in CIAS is to start Q4 2007 with data becoming available year end 2008. The study will randomize 40 patients to 4 arms (5mg, 15mg, 50mg, placebo) each 8 weeks in duration. Primary end points will be selected from: MATRICS; UPSA; PANSS; BPRS • Data were presented from a phase 2a study evaluating the efficacy of MEM 3454 in Alzheimer’s disease patients

  13. Data from MEM 3454 phase 2a Alzheimer’s study reported • MEM-3454 demonstrates nanomolar affinity for α7-nAChRs translating to agonist activity with an EC50 value of 0.5nM. MEM-3454 is a partial agonist with an Emax of 67% of the maximal response to Ach. • At the beginning of November 2007, Memory reported data from a randomized, placebo-controlled, multi-center Phase 2a proof-of-concept trial of MEM 3454. • The study randomized 80 patients with mild to moderate Alzheimer's disease into 3 treatment (5mg; 15mg; 50mg qd) and 1 placebo arm over an eight week treatment period. • The primary endpoint of the trial was improved QESM score from the CDR battery • CDR testing was performed at 4 time points on 6 measurements days throughout the 8 week trial Source: Memory Pharmaceuticals investor presentation

  14. Study meets end point with MEM 3454 improving QESM score • Raw data from the study revealed considerable variation with time in the placebo group as well as intergroup baseline variability. Further data analysis required correction for this variation • Even from the raw data it was apparent that efficacy was achieved at 2 and 4 hours post-treatment but not at 8 hours. Dose dependency was “bell shaped” with efficacy being lost at 50mg These data suggest that qd dosing is unlikely to be sufficient removing a potential advantage suggested by LeadDiscovery during earlier communications It should also be noted that it was not stated at which visit data were collected and probably more important whether efficacy was consistent across the 8 week study period Source: Memory Pharmaceuticals investor presentation

  15. MEM 3454 - Efficacy • Adjusted data demonstrate a clear and significant effect on the primary end point (QESM) and as suggested by the raw data this effect was lost at higher doses • Quality of Working Memory (one of the secondary end-points) was also significantly improved at the two lower doses. • Power of Attention and Continuity of Attention were unaltered by MEM 3454 suggesting that improvements in other indices were not secondary to attention LeadDiscovery notes that CoMentis’ GTS21 is being developed for ADHD. The lack of effect of MEM 3454 on measures of attention prompts further evaluation of ADHD as a relevant indication for α7 ligands Source: Memory Pharmaceuticals investor presentation

  16. MEM 3454-Adverse Effects • The major adverse effect of MEM 3454 was constipation which was well managed. • It was commented that dose will probably be reduced in further studies • Roche has an option for further development which will be triggered based upon the final report which will be delivered mid-2008 Source: Memory Pharmaceuticals investor presentation Memory have suggested that the loss of activity at higher doses was due to desensitization. Presumably what is meant is long-term desensitization rather than the rapid desensitization that characterizes the receptor and is responsible for some physiological activity. The dose effect along with adverse events argues for the use of lower doses in future studies

  17. Servier enters the nicotinics arena with S 24795 Summary of data • Servier appears to be making a big push to establish itself in the nicotinics arena • Attention is focussed on S 24795. Servier claim this molecule is a partial agonist although the Emax is very low and activity may instead be due to antagonism • Contextual, discriminative and working memory were reduced in aging mice but recovered in the presence of S 24795

  18. Servier enters the nicotinics arena with S 24795 • Servier was founded in 1954. Headquartered in France the company is Frances largest independent pharmaceutical company. • Company sales come primarily through sales in cardiovascular disease. Diseases of the CNS currently represent a minor fragment of Servier’s revenue stream however there is a current emphasis on the CNS pipeline Source: Servier Website • In particular, over the past year Servier has been strengthening its position in the nicotinics arena through both full publications and a body of research presented at Neuroscience • This activity centers on the development of a partial agonist, S 24795

  19. S 24795 acts as a partial agonist with emphasis leaning towards antagonism • In July 2007 researchers reported preclinical data on Servier’s α7 partial agonist S 24795 (Lopez-Hernandez et al). These data were also reported at Neuroscience (see below). • The Emax for S 24795 was low (14% of electrophysiological response of oocytes to Ach; panel A) while inhibition of Ach was achieved with an EC50 of 34μM (panel B) Source: Gretchen et al, Neuroscience 2007

  20. Servier evaluate S 24795 in a contextual memory model • In vivo behavioral data were reported for the first time in November. Beracochea et al report the effect of S 24795 on two assays of memory in young and older mice. The first assay modeled spatial memory and failed to identify an effect of either age or S 24795 on spatial memory. • The second model was a contextual serial discrimination (CSD) task. This model involved setting mice two distinct bait finding tasks in rapid succession during the acquisition phase. The two tasks differed in context (color and texture of the floor in the task chamber) • 24 hours later one task was repeated. A correct response was defined as exploration in the correct location for that task. An interference response was defined as searching in the correct location but in the context of the second task. The difference between the two represented the level of contextual memory and was suggested to be indicative of episodic memory. The sum of the two indicated spatial memory Source: Beracochea et al Psychopharmacology in press

  21. S 24795 shown to improve contextual memory in aged mice • The ability to perform the CSD task was severely impeded in older mice. This deficit was reversed by 9-day oral dose of S 24795 (0.3-1.0 mg/kg) such that the difference between correct and interference responses was enhanced (see inset). • The authors concluded that S 24795 improves flexible forms of memory which is indicative of episodic memory, one of the first cognitive parameters to be affected in Alzheimer's disease. In contrast Mermentine improved spatial memory LeadDiscovery notes that there appears to be an inverse/bell shaped dose relationship as is the case in general with nicotinic receptor ligands. Overcoming the loss of effect at higher doses probably reflects desensitization and may introduce problems in therapeutic use. This issue is faced by most stakeholders in the nicotinics field Source: Beracochea et al Psychopharmacology in press

  22. S 24795 improves discriminative memory…. • Marighetto et al presented further data demonstrating efficacy in additional models of declarative memory and in particular discriminative memory. • Mice were exposed individually during a training phase to 3 positive and 3 negative arms on a radial arm maze. • A subsequent test phase simultaneously challenged mice with positive and negative arms • S 24795 increased the rate at which aged mice successfully discriminated between the arms. • Donepezil, included as a positive control was also able to increase discrimination Marighetto et al, Neuroscience

  23. ….and working memory • Working memory was assessed by presenting mice with pairs of arms on a radial maze. One baited, the other not. The same pair was then represented and ability to remember which arm was baited determined. Short term memory was “taxed” by presented increasing challenges with different pairs • S 24795 gradually improves working memory of aged mice back towards control levels over a progressive number of sessions (one session/day). S 24795 also limited the effects of memory taxing

  24. Pfizer develop a mixed agonist/allosteric modulator of the α7 receptor Summary of data • Pfizer are developing an α7 ligand with quite novel pharmacology • PHA-568487 was demonstrated at Neuroscience to have both allosteric modulatory and agonist activity • Functional studies have demonstrated efficacy in a model of schizophrenia. Activity was maintained over a broad range of doses contrasting with other molecules that show reduced activity at higher doses

  25. Pfizer develop PHA-568487, a mixed agonist/allosteric modulator of the α7 receptor • In 2006 Walker et al reported an α7 agonist, PHA-568487. • Hurst et al profiled PHA-568487 in detail at Neuroscience • PHA-568487 was shown to have multiple effects on α7 receptor in hippocampus neurons. • At low concentrations PHA-568487 potentiated responsiveness to pulses of high dose PNU-282987; at higher concentrations, responsiveness was reduced. In addition to this modulatory activity PHA-568487 was an agonist at the highest concentrations tested

  26. PHA-568487 attenuates amphetamine induced dopamine release • Although it had no effect alone, PHA-568487 was shown to attenuate amphetamine induced dopamine release in the striatum of conscious rats.

  27. PHA-568487 also reduces gating defects • Functionally, amphetamine produces a gating defect. This was reversed by PHA-568487 • Importantly the effects of PHA-568487 were seen over a very wide dose range. • This suggests, perhaps surprisingly, that despite its complex pharmacology PHA-568487 lacked the “bell shaped” dose responsiveness seen with other α7 ligands in behavioural tests • Efficacy of PHA-568487 was maintained following twice-daily administration (1 mg/kg, sc) over six days. LeadDiscovery notes that GTS-21 provided therapeutic benefit in schizophrenia patients in a phase 2 study. This effect was however lost at higher doses. It is tempting to speculate that the broad effective dose range seen with PHA-568487 in the gating study above may translate to a simple dose response in the clinic

  28. Targacept and AstraZeneca advance TC-5619 Summary of activity • Targacept announced that TC-5619 had been selected as a candidate treatment of cognitive disorders. This has triggered a milestone payment from AstraZeneca and suggests that advancement to phase 2 may be imminent • Share Prices (Source Google Finance): • F:TC-5619 selected as a candidate for CIAS triggering milestone payment from AstraZeneca • B: TC-2696 Fails To Meet endpoint (see later) • A:Phase 1 of TC-6499 opened (see later)

  29. Targacept and AstraZeneca advance TC-5619 • AstraZeneca has secured an option for an exclusive license to Targacept’s product candidate TC-5619 triggering a $2.0 million payment to Targacept.  • AstraZeneca is Targacept’s partner for cognition indications. Agreement was initially penned in December 2005 for the development and commercialization of TC-1734 (AZD3480) an α4ß2 ligand currently in phase 2b for Alzheimer’s disease and cognitive deficits in schizophrenia. • The announcement on TC-5619 therefore further advances the collaboration between the two companies for a second molecular target • A second partnership is in place with GSK (July, 2007) for other indications including pain, smoking cessation, obesity, addiction and Parkinson's disease.

  30. Development path of TC-5619 • In July, 2007 Targacept opened a phase 1 study of TG-5619. In November they announced that it had been selected as a candidate treatment of cognitive disorders Phase 1 (started Q3 ’07) Phase 2 Phase 3 Targacept advance TC-5619 for cognition Q4 ‘07 triggering $2 million milestone payment AstraZeneca has exclusivity option for cognition indications triggering $40 million Targacept will be responsible for phase 2 development Onward development could trigger up to $226 million plus stepped double-digit royalties LeadDiscovery believes that phase 1 data is imminent opening the way to rapid initiation of phase 2 study

  31. This Month’s activity around the α4ß2 receptor

  32. Pipeline Overview – α4ß2 ligands Phase 2 Phase 3 Preclin Phase 1 Pfizer - Unnamed cpdsServier - Unnamed cpds Wyeth – Unnamed cpds Solvay – Unnamed molecules Targacept - TC-5214Targacept - TC-6499 Abbott – ABT-560Targacept - TC-2216 Depression/Anxiety Targacept - TC-2696 Pain (?) Targacept - AZD3480 (TC-1734)* Alzheimer’s/CIAS Abbott - ABT-894 Pain/ADHD ADHD Abbott - ABT-089 Dianicline (Sanofi-Aventis) Nicotine Dependence *Also known as ispronicline

  33. Pipeline Overview – α4ß2 ligands • Pipeline changes for November • Targacept’s TC-6499 enters phase 1 trials Targacept’s TC-5214 expected to enters phase 1 trials Q1 2008

  34. FDA evaluating adverse effects associated with Chantix Summary of data • The FDA has received a report of suicidal ideation in an individual using Chantix. It is currently evaluating post marketing adverse event reports. FDA also advises that, due to reports of drowsiness, patients should use caution when driving or operating machinery until they know how using Chantix may affect them. • Share Prices (Source Google Finance): • A:Chantix under safety review • The price rise towards the end of November related to news on Celebrex

  35. Targeting α4ß2 for addiction • Two recent market research reports featured by LeadDiscovery describes the smoking cessation arena: • Smoking Cessation and Addiction Treatments: A World Market Analysis • Pipeline Insight: Substance Dependence - Nicotine • There are 1.4 billion smokers in the world. Zyban was the dominant prescription product in the market. • Pfizer’s α4ß2 partial agonist Chantix rapidly captured top spot when it became the first new prescription medication approved for smoking cessation in nearly a decade. There is still room for addition new entrants. • The launch of new innovative therapies will cause the nicotine dependence prescription drug market to grow by approximately 4-fold to $4.6 billion across the seven major markets by 2016.

  36. FDA issues early communication for Chantix • The FDA announced in November a report of suicidal ideation in an individual who had used Chantix. The FDA is currently evaluating post marketing adverse event reports to establish risk • The FDA’s Center for Drug Evaluation and Research is working to complete an analysis of available data prior to communicating its conclusions and recommendations to the public. • In the meantime, FDA recommends that health care providers monitor patients taking Chantix for behavior and mood changes. Patients taking Chantix should contact their doctors if they experience behavior or mood changes. • FDA also advises that, due to reports of drowsiness, patients should use caution when driving or operating machinery until they know how using Chantix may affect them. LeadDiscovery notes with interest that Brown University are currently recruiting depressed smokers to a study (NCT00525837) designed to evaluate the antidepressant effects of Chantix

  37. Further proof of concept to support the targeting of α4ß2 for addiction • Despite adequate proof of concept data from Chantix clinical studies the exact role of the α4ß2 receptors in tobacco addiction in humans remains unclear • In a paper soon to be published in the journal Neuroscience LettersWüllner et al visualized brain α4ß2* receptors of smokers and non-smokers with PET and demonstrated a significant increase in smokers. • Subtraction analysis was performed and as can be seen from the inset the most prominent regional differences were found in cerebellum and brainstem • The up-regulation of α4ß2* receptors may therefore play an important role in nicotine addiction. Moreover identifying ways of preventing this upregulation could offer alternatives to partial agonists as an approach to addiction Source: Wüllner et alNeuroscience Letters

  38. α5 subunits may prevent the over-expression of α4ß2 in chronic nicotine administration • Of interest a second paper identified in November (Mao et al) described how the α5 subunit is associated with alpha4beta2*. Importantly, in contrast to α4ß2 which is increased by 37-85% after chronic administration of nicotine, α4ß2α5 receptors is not increased by nicotine treatment. Identifying the mechanism through which the α5 prevents receptor upregulation could lead to novel approaches to addiction

  39. Solvay enter the α4ß2 field Summary of data • In their September 2007 investors day presentation Solvay stated that a more focused pipeline will be sought with especial attention being paid to the neurosciences. • A paper in press suggests that α4β2 ligands may be one such focus as a series of partial agonists were reported with potential for the treatment of cognition and smoking cessation.

  40. Solvay enter the α4ß2 field with a series of 7-azaindoles derivatives • Solvay has long been involved in the neuroscience arena and indeed the company’s anti-depressant Luvox was the first SSRI to reach the market in 1983. To date activity has not been reported in cognitive or addiction disorders • In their September 2007 investors day presentation Solvay stated that a more focused pipeline will be sought with especial attention being paid to the neurosciences. The company also stated their intention to expand their pipeline through acquisitions and in-licensing • In an upcoming edition of BMCL, Stoit et al from Solvay describe a series of 7-azaindoles as potential partial agonists of α4β2. Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affinity and functional activity. • High affinity (10nM) molecules have been identified and one representative has demonstrated both moderate binding affinity and partial agonist potency. This is being advanced as a promising lead for the indications of cognition and smoking cessation.

  41. Targacept Reports mixed fortunes Summary of activity • On December 3rd, 2007 Targacept announced that TC-2696 failed to meet its efficacy end-point in a phase 2 study of dental pain. The future of TC-2696 is unclear • Preclinical data have demonstrated efficacy of TC-6499 in multiple models of neuropathic pain. Phase 1 studies have now opened triggering a milestone payment from GSK • Targacept suggest that the initial label to be sought for AZD3480 (TC-1734) will be improved symptoms of Alzheimer’s rather than reduced neurodegeneration • α4ß2 receptors exist in two stoichiometries: (α4)2(ß2)3 and (α4)3(ß2)2. The two receptors behave differently electrophysiologically and respond to S and R isomers of mecamylamine in a differential manner. Inhibiting (α4)3(ß2)2 and facilitating (α4)2(ß2)3 with TC-5214 (the S isomer) offers a promising antidepressant profile in animal models. These data underpin Targacept’s decision to advance this molecule into phase 1 development. • Share Prices (Source Google Finance): • F:TC-5619 selected as a candidate for CIAS triggering milestone payment from AstraZeneca (see earlier) • B: TC-2696 Fails To Meet endpoint • A:Phase 1 of TC-6499 opened

  42. Targacept Present at Lazard Capital Markets Healthcare Conference • Targacept presented at the Lazard Capital Markets 4th Annual Healthcare Conference in November 2007 [Presentation]. The entire Targacept pipeline was presented but particularly interesting were comments that help understand Targacept and AstraZenaca’s strategic direction of AZD3480 (TC-1734) • AZD3480 (TC-1734) is Targacept’s lead candidate. AstraZeneca initiated a Phase 2b trial in mild to moderate Alzheimer's disease in July 2007 and a separate Phase 2b trial for cognitive deficits in schizophrenia in August 2007.  • During the Lazard Capital presentation Donald deBethizy, CEO of Targacept described the potent neuroprotective properties of AZD3480 however it was commented that the companies would be chasing a symptomatic improvement label as the initial indication. A further disease modification label would be targeted as a post-marketing label LeadDiscovery believes that targeting a symptomologic label will reduce time-to-market. It remains to be seen whether eventual pivotal studies will incorporate measures of neurodegeneration and a study extension or whether disease modification will be the subject of post-marketing phase 4 studies

  43. Targacept’s TC-2696 fails in phase 2 pain study • While AZD3480 (TC-1734) continues to advance, Targacept have announced that agonist TC-2696 failed to meet its primary end-point in a phase 2 study of dental pain. • 181 patients were randomized to receive a single dose of TC-2696(10mg, 25mg or 50mg), ibuprofen or placebo following third molar extraction • The primary endpoint, superior pain relief 4 or 6 hrs after dosing compared to placebo, was not met. TC-2696 was generally well tolerated in the trial. • These results suggest that TC-2696 is not a viable therapeutic candidate for acute post-operative pain. Targacept has shifting their pain focus towards neuropathic pain as TC-6499 has now entered the clinic for this indication. The failure of TC-2696 may be viewed by other companies as a lack of proof of concept for the development of α4ß2 ligands for the treatment of post-operative pain. The future of TC-2696 is currently unclear

  44. Targacept profiles TC-6499 for the first time at Neuroscience… • Jordan et al profiled TC-6499 at Neuroscience. To our knowledge this was the first time that significant information has entered the public domain on this candidate. • TC-6499 has a high binding affinity for α4β2 (Ki =27 nM), and selectivity against other nicotinic receptors (α7; α3β2; α3β4) • Functionally, TC-6499 was shown to be a full α4β2 agonist both in receptor studies and in a dopamine release model. This agonist activity is demonstrable at both high and low sensitivity α4β2 receptors. • TC-6499 is readily absorbed following oral administration and has favorable pharmacokinetics. • The compound demonstrated a favorable safety margin in preclinical safety studies, including in vitro and in vivo cardiovascular studies, acute and 14-day repeat dose studies, definitive 90-day studies and a full complement of genotoxicity studies.

  45. TC-6499 demonstrates efficacy in various models of neuropathic pain…. • TC-6499 is active in animal models of neuropathic pain. • Diabetic neuropathy: TC-6499 significantly reversed tactile allodynia in a model of diabetic neuropathy when administered both acutely (0.1 and 1 mg/kg; po) and as shown in the inset following repeat administration (0.1-10 mg/kg po). In the acute model efficacy was similar to that of gabapentin • Chemotherapy-induced neuropathy: TC-6499 was also efficacious in reversing tactile allodynia in a chemotherapy-induced neuropathy model (paclitaxel-induced; 0.01-1 mg/kg po). TC-6499 exhibits a quicker onset of action (i.e., 30 min) and comparable efficacy and duration of action compared to gabapentin.

  46. …and then advances it into the clinic as a clinical candidate for pain • Very soon after announcing the failure of TC-2696 in the phase 2 post-operative pain study Targacept announced that it has initiated a Phase 1 clinical trial of TC-6499 as a candidate treatment of neuropathic pain. • The initiation of the trial triggers a $6.0 million milestone payment to Targacept under the terms of its alliance agreement with GlaxoSmithKline. • The Phase I study is designed to evaluate the safety, tolerability and pharmacokinetics of TC-6499. The trial is a double-blind, placebo-controlled study with escalating single doses of TC-6499 administered orally to healthy volunteers. • Targacept anticipates that its Phase I program for TC-6499 will include, in addition to the ongoing single dose trial, a multiple rising dose trial. LeadDiscovery suggests that special attention should be paid to mention of dizziness, somnolence or edema when data emerges. These are common side effects with Gabapentin occurring in approximately 20% of patients

  47. FocusOn peripheral neuropathy and neuropathic pain • In a recent report featured by LeadDiscovery (Peripheral Neuropathy and Neuropathic Pain, 2007), peripheral neuropathy and neuropathic pain was estimated to affect 170 to 270 million individuals globally. • The two related conditions are causally linked to a number of diseases, however diabetes, cancer and HIV alone are expected to increase the prevalence of peripheral neuropathy and peripheral neuropathy over the next few years • The number of people suffering peripheral neuropathy and neuropathic pain is expected to increase by more than 10% between 2007 and 2012 • By 2012 the global market will be worth about $6.5 billion. • The pipeline for peripheral neuropathy and neuropathic pain represents one of the most diverse and novel in the drug development sector and TC-6499 as well as Abbott’s more advanced ABT-894 (see later) promise to feature in this growing field. Note that LeadDiscovery is able to produce a full evaluation of the market and/or pipeline for these indications (please contact us for further information)

  48. Antidepressant activity reported for α4ß2 ligands • Increases in cholinergic tone are associated with depressive symptoms in humans and reducing this tone could potentially ameliorate symptoms. • Antidepressant drugs such as selective serotonin or norepinephrine reuptake inhibitors and tricyclic antidepressants also non-competitively antagonize neuronal nicotinic receptors at clinically relevant doses. • Targacept have demonstrated that the non-selective nicotinic receptor antagonist (and approved antihypertensive), mecamylamine provides benefit when used an add-on therapy in patients with major depressive disorders who are resistant to citalopram. • Andreasen et al from NeuroSearch reported studies at Neuroscience demonstrating that both α4ß2 and α7 antagonists may have antidepressant activity

  49. Targacept evaluates benefit of targeting α4ß2 receptors of specific stoichiometries • α4ß2 receptors exist in two stoichiometries • (α4)2(ß2)3 receptors which have high sensitivity to nicotine and low Ca2+ permeability (HS receptors) • (α4)3(ß2)2 receptors which have low sensitivity to nicotine and high Ca2+ permeability (LS receptors) • Targacept have developed isomers of mecamylamine • TC-5213 (R-(-)-mecamylamine) • TC-5214 (S-(+)-mecamylamine) (α4)3(ß2)2 (α4)2(ß2)3 Source: Fedorov et al; Neuroscience • Isomers have differential activity against two α4ß2 isomers • TC-5213 non-competitively inhibits both HS and LS receptors. • TC-5214 inhibits LS with greater efficacy than TC-5213 and facilitates HS.

  50. Dual LS inhibition/HS activation may offer optimal approach to depression • Despite variability across different labs using the same models of depression, the S(+) isomer, TC-5214 had greater antidepressant activity than the R(-) isomer. LS antagonists/HS agonists may offer a novel approach to depression Source: Fedorov et al; Neuroscience

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