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Nicotinics
Monthly
Neuronal Nicotinic Receptors
In Depth Analysis of Breaking Research, Drug Development News &
Pipeline Activity
Next Edition:
January 13th 2008
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Nicotinics
Monthly
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14th
Nicotinics
Monthly
December
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
14th
Nicotinics
Monthly
December
2007
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
14th
Nicotinics
Monthly
December
2007
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
14th
Nicotinics
Monthly
December
2007
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.
14th
December
2007
Other information
Nicotinics
Monthly
• 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;
This Month’s activity around the α7
receptor
Nicotinics
Monthly
Nicotinics
Monthly
Pipeline Overview – α7 ligands
Preclin
Phase 1
Phase 2
Phase 3
NeuroSearch - NS-1738
Bayer - ABBF
Abbott- 582941
Mitsubishi – Unnamed cpds
Memory Pharma – Unnamed cpds
Servier - S 24795
Pfizer - PHA-568487
Xytis – XY 4083
Targacept – Unnamed cpds
Memory Pharma/Roche – R4996
Abbott – ABT-107
AstraZeneca - AZD-0328
Targacept - TC-5619
En Vivo - EVP-6124
Sanofi-Aventis - SSR-180711
CoMentis GTS-21
Memory Pharma - MEM 3454
Alzheimer’s
Alzheimer’s/CIAS
Alzheimer’s
Alzheimer’s/CIAS
Alzheimer’s
Alzheimer’s/CIAS
Alzheimer’s/ADHD/CIAS
Alzheimer’s/CIAS
Pipeline Overview – α7 ligands
Nicotinics
Monthly
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
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
Nicotinics
Monthly
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
Memory Pharmaceuticals presents investor
updates during November
Nicotinics
Monthly
•
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
Data from MEM 3454 phase 2a
Alzheimer’s study reported
Nicotinics
Monthly
•
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
Study meets end point with MEM 3454
improving QESM score
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
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
MEM 3454 - Efficacy
•
•
•
Nicotinics
Monthly
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
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
Nicotinics
Monthly
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
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
Nicotinics
Monthly
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
Nicotinics
Monthly
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
S 24795 acts as a partial agonist with
emphasis leaning towards antagonism
Nicotinics
Monthly
•
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
Servier evaluate S 24795 in a contextual
memory model
Nicotinics
Monthly
•
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
S 24795 shown to improve contextual
memory in aged mice
Nicotinics
Monthly
•
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
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
Nicotinics
Monthly
Marighetto et al, Neuroscience
….and working memory
Nicotinics
Monthly
•
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
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
Nicotinics
Monthly
Nicotinics
Monthly
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
PHA-568487 attenuates amphetamine
induced dopamine release
•
Nicotinics
Monthly
Although it had no effect alone, PHA-568487 was shown to attenuate
amphetamine induced dopamine release in the striatum of conscious
rats.
PHA-568487 also reduces gating defects
Nicotinics
Monthly
•
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
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)
Nicotinics
Monthly
Targacept and AstraZeneca advance TC5619
Nicotinics
Monthly
•
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
Phase 1 (started Q3 ’07)
Targacept advance TC5619 for cognition Q4
‘07 triggering $2 million
milestone payment
•
Phase 2
Phase 3
Targacept will be
responsible for phase 2
development
AstraZeneca has
exclusivity option for
cognition indications
triggering $40 million
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
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
This Month’s activity around the α4ß2
receptor
Nicotinics
Monthly
Nicotinics
Monthly
Pipeline Overview – α4ß2 ligands
Preclin
Phase 1
Phase 2
Phase 3
Pfizer - Unnamed cpds
Servier - Unnamed cpds
Wyeth – Unnamed cpds
Solvay – Unnamed molecules
Targacept - TC-5214
Targacept - TC-6499
Abbott – ABT-560
Targacept - TC-2216
Targacept - TC-2696
Targacept - AZD3480 (TC-1734)*
Abbott - ABT-894
Abbott - ABT-089
Dianicline (Sanofi-Aventis)
*Also known as ispronicline
Depression/Anxiety
Pain (?)
Alzheimer’s/CIAS
Pain/ADHD
ADHD
Nicotine Dependence
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
Monthly
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
Nicotinics
Monthly
Targeting α4ß2 for addiction
•
Nicotinics
Monthly
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.
FDA issues early communication for
Chantix
Nicotinics
Monthly
•
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
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 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
Nicotinics
Monthly
Source: Wüllner et al Neuroscience Letters
α5 subunits may prevent the over-expression of
α4ß2 in chronic nicotine administration
•
Nicotinics
Monthly
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
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.
Nicotinics
Monthly
Solvay enter the α4ß2 field with a series of
7-azaindoles derivatives
Nicotinics
Monthly
•
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 7azaindoles 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.
Targacept Reports mixed fortunes
Nicotinics
Monthly
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 TC6499 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
Targacept Present at Lazard Capital
Markets Healthcare Conference
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
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
Targacept’s TC-2696 fails in phase 2 pain
study
Nicotinics
Monthly
•
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
Targacept profiles TC-6499 for the first
time at Neuroscience…
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•
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.
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: TC6499 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.
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…and then advances it into the clinic as
a clinical candidate for pain
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•
Very soon after announcing the failure of TC-2696 in the phase 2 postoperative 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
FocusOn peripheral neuropathy and
neuropathic pain
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• 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)
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
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Targacept evaluates benefit of targeting
α4ß2 receptors of specific stoichiometries
•
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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
– (α4)3(ß2)2 receptors which have low sensitivity to
nicotine and high Ca2+ permeability (LS receptors)
•
(α4)2(ß2)3
Targacept
have
mecamylamine
developed
– TC-5213 (R-(-)-mecamylamine)
isomers
of
Source: Fedorov et al; Neuroscience
– TC-5214 (S-(+)-mecamylamine)
•
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.
Dual LS inhibition/HS activation may offer
optimal approach to depression
•
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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
Will more selective targeting of α4ß2
subtypes offer an improved approach?
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•
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.
LeadDiscovery find these data provocative. The ability to improve the treatment of
depression through the use of α4ß2 receptor antagonists represents an underinvestigated approach. The present study represents one of the most comprehensive
series of experiments to establish proof of concept for the development of α4ß2
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
Chantix against HS and LS receptors. Blockade of HS receptors could limit the
antidepressant efficacy of Chantix and conceivably even unveil depression in susceptible
individuals. Equally it could be of importance to determine the optimal HS:LS profile for
smoking cessation as a means to improving available therapeutics
Source: Fedorov et al; Neuroscience
ABT-894 expected to advance into
phase 3 within 12 months
Summary of activity
• In their Q3 report NeuroSearch stated that ABT894 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.
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ABT-894 expected to advance into phase 3
within 12 months
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•
In their Q3 report NeuroSearch stated that ABT-894 which is being codeveloped 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
ABT-894 pain studies take on added
importance following the failure of TC-2696
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•
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
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And the other neuronal nicotinic receptors…..
α3β4 nicotinic receptor antagonism as an
approach to obesity
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•
Albany Medical College is investigating 18-methoxycoronaridine (18-MC), a
novel iboga alkaloid congener, for the treatment of drug dependence. 18MC 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 18MC 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 α3β4 ligands
may have cardiovascular activity
α6β2 nicotinic receptor as a novel
approach to addiction
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•
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.
α6β2 nicotinic receptor may activate GABAergic
neurons providing inhibitory input to dopaminergic
as a novel approach to addiction
•
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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
α6β2 nicotinic receptor as a novel
approach to addiction…..
•
•
•
•
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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
New Reports:
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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, 2007
Price: $7600
For further details contact LeadDiscovery or click here
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New 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:
Schizophrenia;
Depression;
Alzheimer’s;
Epilepsy;
Publication date: October, 2007
Price: $2875
For further details contact LeadDiscovery or click here
Migraine;
Parkinson’s
and
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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