Nicotinics Monthly Neuronal Nicotinic Receptors In Depth Analysis of Breaking Research, Drug Development News & Pipeline Activity Next Edition: January

Nicotinics Monthly

Neuronal Nicotinic Receptors

In Depth Analysis of Breaking Research, Drug Development News & Pipeline Activity

Next Edition: January 13th 2008

Nicotinics Monthly

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Nicotinics MonthlyDecember 14th 2007

Executive 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


Executive 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


Executive 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


Executive 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.


Other 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 report provides 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;

Nicotinics MonthlyThis Month’s activity around the α7

receptor

Nicotinics Monthly

Pipeline Overview – α7 ligands

Memory Pharma/Roche – R4996Abbott – ABT-107AstraZeneca - AZD-0328 Targacept - TC-5619 En Vivo - EVP-6124 Sanofi-Aventis - SSR-180711

Preclin Phase 1 Phase 2 Phase 3

CoMentis GTS-21 Alzheimer’s/ADHD/CIAS

Memory Pharma - MEM 3454 Alzheimer’s/CIAS

NeuroSearch - NS-1738 Bayer - ABBF Abbott- 582941 Mitsubishi – Unnamed cpds

Alzheimer’s/CIAS

Alzheimer’s/CIAS

Alzheimer’s

Alzheimer’s

Alzheimer’s

Alzheimer’s/CIAS

Memory Pharma – Unnamed cpdsServier - S 24795Pfizer - PHA-568487Xytis – XY 4083Targacept – Unnamed cpds

Nicotinics Monthly

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

Nicotinics MonthlyMemory 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

Nicotinics MonthlyMemory Pharmaceuticals presents investor

updates during November

• Since the last edition of Nicotinic Monthly, 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

Nicotinics MonthlyData 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

Nicotinics Monthly

• 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

Study meets end point with MEM 3454 improving QESM score

These data suggest that These data suggest that qdqd dosing dosing is unlikely to be sufficient removing is unlikely to be sufficient removing a potential advantage suggested by a potential advantage suggested by LeadDiscovery during earlier LeadDiscovery during earlier communications communications

It should also be noted that it was It should also be noted that it was not stated at which visit data were not stated at which visit data were collected and probably more collected and probably more important whether efficacy was important whether efficacy was consistent across the 8 week study consistent across the 8 week study periodperiod


Nicotinics Monthly

LeadDiscoveryLeadDiscovery notes that notes that CoMentis’ GTS21 is being CoMentis’ GTS21 is being developed for ADHD. The lack of developed for ADHD. The lack of effect of MEM 3454 on measures effect of MEM 3454 on measures of attention prompts further of attention prompts further evaluation of ADHD as a relevant evaluation of ADHD as a relevant indication for indication for αα7 ligands7 ligands

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


Nicotinics MonthlyMEM 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

Memory have suggested that the loss of activity at higher doses was due to 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 desensitization. Presumably what is meant is long-term desensitization rather than the rapid desensitization that characterizes the receptor and is responsible for some 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 physiological activity. The dose effect along with adverse events argues for the use of lower doses in future studieslower doses in future studies


Nicotinics MonthlyServier 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

Nicotinics MonthlyServier 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

• 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

Source: Servier Website

Nicotinics MonthlyS 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

Nicotinics MonthlyServier 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

Nicotinics MonthlyS 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

Source: Beracochea et al Psychopharmacology in press

LeadDiscovery notes that there appears to be an LeadDiscovery notes that there appears to be an inverse/bell shaped dose relationship as is the inverse/bell shaped dose relationship as is the case in general with nicotinic receptor ligands. case in general with nicotinic receptor ligands. Overcoming the loss of effect at higher doses Overcoming the loss of effect at higher doses probably reflects desensitization and may probably reflects desensitization and may introduce problems in therapeutic use. This issue introduce problems in therapeutic use. This issue is faced by most stakeholders in the nicotinics fieldis faced by most stakeholders in the nicotinics field

Nicotinics MonthlyS 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

Nicotinics Monthly

….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

Nicotinics MonthlyPfizer 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

Nicotinics MonthlyPfizer 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

Nicotinics MonthlyPHA-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.

Nicotinics MonthlyPHA-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 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 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 tempting to speculate that the broad effective dose range seen with PHA-568487 in PHA-568487 in the gating study above may translate to a simple dose response in the clinicthe gating study above may translate to a simple dose response in the clinic

Nicotinics MonthlyTargacept 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)

Nicotinics MonthlyTargacept 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.

Nicotinics Monthly

Development path of TC-5619

Targacept advance TC-5619 for cognition Q4

‘07 triggering $2 million milestone payment

AstraZeneca has exclusivity option for cognition indications triggering $40 million

Onward development could trigger up to $226

million plus stepped double-digit royalties

Phase 1 (started Q3 ’07)Phase 1 (started Q3 ’07) Phase 2Phase 2

Targacept will be responsible for phase 2

development

Phase 3Phase 3

LeadDiscoveryLeadDiscovery believes that phase 1 data is believes that phase 1 data is imminent opening the way to rapid initiation imminent opening the way to rapid initiation of phase 2 study of phase 2 study

• 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

Nicotinics MonthlyThis Month’s activity around the α4ß2

receptor

Nicotinics Monthly

Pipeline Overview – α4ß2 ligands

Abbott – ABT-560Targacept - TC-2216

Preclin Phase 1 Phase 2 Phase 3

*Also known as ispronicline

Abbott - ABT-089

Pfizer - Unnamed cpdsServier - Unnamed cpds Wyeth – Unnamed cpds

Abbott - ABT-894

Targacept - TC-2696 Pain (?)

Pain/ADHDADHD

Targacept - AZD3480 (TC-1734)* Alzheimer’s/CIAS

Solvay – Unnamed molecules

Depression/Anxiety

Dianicline (Sanofi-Aventis) Nicotine Dependence

Targacept - TC-5214Targacept - TC-6499

Nicotinics Monthly

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

Nicotinics MonthlyFDA 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.


A: Chantix under safety review

The price rise towards the end of November related to news on Celebrex

Nicotinics MonthlyTargeting 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.

Nicotinics MonthlyFDA 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

Nicotinics MonthlyFurther 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 Letters Wüllner 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 al Neuroscience Letters

Nicotinics Monthlyα5 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

Nicotinics MonthlySolvay 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.

Nicotinics MonthlySolvay 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.

Nicotinics MonthlyTargacept Reports mixed fortunes


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

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.

Nicotinics Monthly

• 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

Targacept Present at Lazard Capital Markets Healthcare Conference

LeadDiscoveryLeadDiscovery believes that targeting a symptomologic label will believes that targeting a symptomologic label will reduce time-to-market. It remains to be seen whether eventual reduce time-to-market. It remains to be seen whether eventual pivotal studies will incorporate measures of neurodegeneration and pivotal studies will incorporate measures of neurodegeneration and a study extension or whether disease modification will be the subject a study extension or whether disease modification will be the subject of post-marketing phase 4 studies of post-marketing phase 4 studies

Nicotinics MonthlyTargacept’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 Targacept has shifting their pain focus towards neuropathic pain as TC-6499 has now entered the clinic for this indication. The failure 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 TC-2696 may be viewed by other companies as a lack of proof of concept for the development of of concept for the development of αα44ß2 ligands for the treatment of ß2 ligands for the treatment of post-operative pain. The future of TC-2696 is currently unclearpost-operative pain. The future of TC-2696 is currently unclear

Nicotinics MonthlyTargacept 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.

Nicotinics MonthlyTC-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.

Nicotinics Monthly…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 LeadDiscovery suggests that special attention should be paid to mention of dizziness, somnolence or edema when data emerges. These are common dizziness, somnolence or edema when data emerges. These are common side effects with Gabapentin occurring in approximately 20% of patientsside effects with Gabapentin occurring in approximately 20% of patients

Nicotinics MonthlyFocusOn 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)

Nicotinics MonthlyAntidepressant 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

Nicotinics MonthlyTargacept 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)2(ß2)3

(α4)3(ß2)2

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.

Nicotinics MonthlyDual 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


Nicotinics MonthlyWill more selective targeting of α4ß2

subtypes offer an improved approach?


LeadDiscovery find these data provocative. The ability to improve the treatment of LeadDiscovery find these data provocative. The ability to improve the treatment of depression through the use of depression through the use of αα44ß2 receptor antagonists represents an under-ß2 receptor antagonists represents an under-investigated approach. The present study represents one of the most comprehensive investigated approach. The present study represents one of the most comprehensive series of experiments to establish proof of concept for the development of series of experiments to establish proof of concept for the development of αα44ß2 ß2 antagonists. Also of importance, it was noted earlier that Chantix is being evaluated as a antagonists. Also of importance, it was noted earlier that Chantix is being evaluated as a treatment of depression in smokers. It may be of interest to determine the profile of treatment of depression in smokers. It may be of interest to determine the profile of Chantix against Chantix against HS and LS HS and LS receptors. Blockade of HS receptors could limit the receptors. Blockade of HS receptors could limit the antidepressant efficacy of Chantix and conceivably even unveil depression in susceptible antidepressant efficacy of Chantix and conceivably even unveil depression in susceptible individualsindividuals. Equally it could be of importance to determine the optimal HS:LS profile for . Equally it could be of importance to determine the optimal HS:LS profile for smoking cessation as a means to improving available therapeutics smoking cessation as a means to improving available therapeutics

• Supported by these preclinical studies, Targacept announced in October, 2007 that development of mecamylamine is on hold and that attention will now switch to TC-5214.

• Targacept expects to initiate a Phase 1 trial of TC-5214 in Q1 2008 and to initiate Phase 2 development soon thereafter.

Nicotinics MonthlyABT-894 expected to advance into

phase 3 within 12 months

Summary of activity• In their Q3 report NeuroSearch stated that

ABT-894 which is being co-developed with Abbott will enter phase 3 studies within the next 12 months for both neuropathic pain and ADHD

• Data from the phase 2 ADHD study is currently being analysed while a second neuropathic pain study has recently been opened.

Nicotinics MonthlyABT-894 expected to advance into phase 3

within 12 months

• In their Q3 report NeuroSearch stated that ABT-894 which is being co-developed with Abbott will enter phase 3 studies within the next 12 months for both neuropathic pain and ADHD

• Data from the phase 2 ADHD study is currently being analysed while a second neuropathic pain study has recently been opened.

Source Q3 report, NeuroSearch, Nov 28th, 2008

Nicotinics MonthlyABT-894 pain studies take on added

importance following the failure of TC-2696

• The earlier phase 2 study of ABT-894 (M06-850) is comparing the safety and efficacy of ABT-894 with duloxetine and placebo in subjects with diabetic neuropathic pain. This study opened in August 2007.

• A second study (M10-014) opened in October 2007 and is also recruiting patients with diabetic neuropathic pain. The main difference between this and the earlier study is the absence of a positive control

• Positive data from either of these studies, as well as Targacept’s development of TC-6499 is likely to prompt further companies in the neuropathic pain arena turn to α4ß2 ligand

Nicotinics Monthly

And the other neuronal nicotinic receptors…..

Nicotinics Monthlyα3β4 nicotinic receptor antagonism as an

approach to obesity

• Albany Medical College is investigating 18-methoxycoronaridine (18-MC), a novel iboga alkaloid congener, for the treatment of drug dependence. 18-MC has previously been shown to alter dopamine release in the nucleus accumbens through the selective antagonism of α3β4 nicotinic receptors.

• Data presented at Neuroscience by Taraschenkov et al suggested that 18-MC could also modify feeding behavior. Pretreatment with a single dose of 18-methoxycoronaridine dose-dependently decreased the ingestion of various palatable liquids (saline, sucrose and saccharin).

• Of interest reduced sucrose ingestion prevented weight gain establishing proof of concept for the development of α3β4 antagonists as a novel approach to obesity

LeadDiscovery notes that LeadDiscovery notes that α3β4 ligands α3β4 ligands may have cardiovascular activitymay have cardiovascular activity

Nicotinics Monthlyα6β2 nicotinic receptor as a novel

approach to addiction

• Dopaminergic input from the ventral tegmental area (VTA) modulates nucleus accumbens (NAcc) activity, a region of known importance in addiction.

• ACh increases dopamine release by single action potentials but reduces release following multiple action potentials, an electrophysiological correlate of reward. Nicotine blocks the former thus enhancing dopamine release.

• Nicotinic ligands have attracted interest for addiction. Pfizer has successfully developed the α4β2 ligand Chantix as a smoking cessation treatment. Durable abstinence is however achieved in just 25% of individuals and moreover recent safety concerns are currently being evaluated.

• The efficacy of Chantix is attributed to its ability to modulate dopamine release. Targeting receptors other than α4β2 may offer an alternate approach to smoking cessation.

Nicotinics Monthly

α6β2 nicotinic receptor may activate GABAergic neurons providing inhibitory input to dopaminergic as a novel approach to addiction

• At Neuroscience Yang et al reported that α6β2 is functionally active on GABAergic boutons of VTA dopaminergic neurons. α6 may thus increase GABAergic inhibition of dopaminergic nerves. Conversely nicotine desensitizes α6 potentially leading to increased dopamine release within the NAcc

Nicotinics Monthlyα6β2 nicotinic receptor as a novel

approach to addiction…..

• α6 containing receptors are extensively present on axons running between the VTA and the NAcc. Given this localization, α6 containing receptors are emerging as a potential target for addiction. Exley et al has explored further the targeting of α6β2 as a new approach to addiction.

• Of interest this group has reported that in the NAcc, α-CbMII (a known α6 antagonist) reduces dopamine release (y axis in inset) in response to single pulses (1p) but enhances the response to multiple pulses (4p). DHβE did not affect this response suggesting that in the NAcc, α6 receptors alone are responsible for the regulation of dopamine release

• α6 agonists may therefore be expected to reduce dopamine release in response to repetitive stimulation of dopaminergic nerves as occurs in response to various addictive drugs including nicotine

• This effect was not seen in the adjacent caudate putamen, a region which is also subject to regulation of dopamine release by nicotinic receptor. This suggests the potential for highly specific regulation of dopaminergic control

Nicotinics MonthlyNew Reports:

Pipeline Insight: Substance Dependence – Nicotine

The high prevalence of nicotine dependence, strong uptake of Pfizer's Chantix (varenicline), and the launch of new innovative therapies will cause the nicotine dependence prescription drug market to grow to $4.6 billion across the seven major markets by 2016. Innovative therapies are set to offer patients a convenient dosing regimen and thereby carrying the potential for improved compliance.

Scope of this report

– Analysis of patient potential, unmet needs and clinical trial design in nicotine dependence

– Overview of the current nicotine dependence market, covering both prescription and OTC products

– Overview of drugs in late stage clinical development for nicotine dependence – Profiles of key compounds in development for use in nicotine dependence, with

forecasts of drug revenues to 2016 and insight from key opinion leaders

Publication date: November, 2007Price: $7600

For further details contact LeadDiscovery or click here

Nicotinics MonthlyNew Reports:

The CNS Market Outlook to 2012

•CNS disorders represent 35% of the disease burden within the 7 major pharma markets. Increased generic attack and low innovation in product launches has slowed market growth. Pharma and biotech companies are responding with a shift in R&D focus towards disease areas with relatively low levels of innovation, such as Alzheimer's and Parkinson's disease.

•Scope of this report

– This report provides 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.

– This report covers: Depression; Alzheimer’s; Epilepsy; Migraine; Parkinson’s and Schizophrenia;

Publication date: October, 2007Price: $2875

For further details contact LeadDiscovery or click here

Nicotinics Monthly

Disclaimer

This report has been produced by LeadDiscovery Ltd and strictly reflects the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider

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Nicotinics Monthly Neuronal Nicotinic Receptors In Depth Analysis of Breaking Research, Drug Development News & Pipeline Activity Next Edition: January