CNS Drug News

Issue No. 169 6th September 2007

R&D Highlights The continued benefits of statins

Statins have been available for a number of years, however new
Phase III post hoc analysis more positive for safinamide in research suggests that their benefits are not yet fully understood. In
PD separate studies, two research groups have found evidence supporting
Page 3 the use of statins for Alzheimer's disease (AD) and suggesting their
continued use after a stroke.
Neurochem reports negative results from North One study, by researchers at the University of Washington and
American Alzhemed trial colleagues, has provided evidence of an association between
Page 4 statin use and a lower risk of neuropathologic changes in the brain
that are associated with AD. Meanwhile, a second group, which
Study suggests cancer drugs may have use for HD included researchers from the University of Santiago de Compostela
in Spain, has found that people who stopped taking their statins
Page 9 while hospitalised after a stroke were more likely to have died or be
dependent on others for their care three months after the stroke than
Lilly’s LY2140023 shows antipsychotic activity in humans people who kept taking the drugs.
Page 14 This news will be welcomed by those in healthcare due to the relative
PRODUCT Highlights low cost of statins, however, there have been concerns about the side
effects of the drugs' use. Indeed, University of North Carolina (UNC) at
Chapel Hill researchers reported at the end of last year that people with
Aricept approved for severe AD in Japan low levels of LDL cholesterol are more likely to have Parkinson's disease
Page 6 (PD) than those with high LDL levels, despite the fact that low levels of
LDL-C are considered an indicator of good cardiovascular health.
Biopartners submits Biferonex in Europe
This theory is backed by the fact that people with PD have a lower
Page 8 occurrence of myocardial infarction and stroke than those who do
not have the disease. Furthermore, PD patients are also more likely to
Risperdal receives FDA approvals in children and carry the gene, APOE-2, which is linked with lower LDL-C, and smoking,
adolescents which increases a person's risk for cardiovascular disease, is also
Page 16 associated with a decreased risk of PD.

AGREEMENT Highlights Despite the link demonstrated by the UNC research, it was cautioned
at the time that people should not change their eating habits, nor
their use of statins and other cholesterol-lowering drugs because of
Teva partners with Compugen for CGEN-54 the results. Nevertheless, the research did raise concerns among statin
Page 8 users. On the other hand, the new research, particularly the AD study,
has been widely reported and may mean an increase in statin use.
Cephalon acquires rights to Amrix
In other news, Phase II data have demonstrated the antipsychotic
Page 19 activity of Eli Lilly's LY2140023 in humans. This news has received
particular attention, as most currently-approved antipsychotic
EDITOR medications work by affecting dopamine or serotonin, but for
Lucy Vann LY2140023, the active substance, LY404039, is thought to work by
CONTRIBUTING EDITORS reducing the presynaptic release of glutamate in brain regions where
Ros Smallman, Fiona Cowie, metabotropic glutamate 2/3 (mGlu2/3) receptors are expressed.
Matthew Dennis, Johanna Shiu, Sam Turner Indeed, according to Dr Steven Paul, Lilly's Executive Vice President
PUBLISHER of Science and Technology: "These data provide compelling new
evidence that mGlu2/3 receptor agonists have antipsychotic properties
Eric Wigart
and may provide a completely new therapeutic approach for treating
Conditions of Sale schizophrenia and, perhaps, other neuropsychiatric disorders."
• CNS Drug News must not be reproduced, abstracted, stored in a retrieval system
or transmitted in any form or by any means without the written permission of the
publisher.
• CNS Drug News must not be circulated to staff outside the address to which it is sent. Lucy Vann
ISSN 1462-656X Editor
©
Espicom Business Intelligence. All rights reserved. pharma_editorial@espicom.com

Monitoring central nervous system drug developments worldwide

TABLE OF CONTENTS
TABLE OF CONTENTS
The continued benefits of statins..........................................................................................1
NEURODEGENERATIVE DISORDERS.......................3
Parkinson's Disease - R&D Update........................................................3
Phase III post hoc analysis more positive for safinamide in PD.............................................3
Ovary removal before menopause linked to decreased neuroprotection..........................3
Alzheimer's Disease - R&D Update........................................................4
NYU vaccine combats AD tangles...........................................................................................4
Neurochem reports negative results from North American Alzhemed trial.......................4
Baxter/ADCS to pursue Phase III study of Gammagard Liquid for AD..................................5
Phase I studies completed with ELND-005/AZD-103............................................................6
Study supports statin use for AD............................................................................................6
Product News........................................................................................6
Aricept approved for severe AD in Japan...............................................................................6
Ranbaxy receives tentative FDA approval for galantamine tablets.....................................6
Multiple Sclerosis - R&D Update..........................................................7
Tysabri demonstrates significant HRQoL improvements for MS patients...........................7
PDL to focus on Ab discovery and development...................................................................7
Recruitment completed for Sativex Phase III trial in MS neuropathic pain.........................8
Product News........................................................................................8
Biopartners submits Biferonex in Europe..............................................................................8
NICE recommends Tysabri for use in highly-active RRMS....................................................8
New Rebif formulation approved in Europe..........................................................................8
Questcor approves new strategy for HP Acthar Gel..............................................................8
Agreement News...................................................................................8
Teva partners with Compugen for CGEN-54..........................................................................8
Other Neurodegenerative Disorders - R&D Update...........................9
McMaster study suggests kinase inhibitor use for HD..........................................................9
Protox acquires HUMxin research programme from Medicenna........................................9
Study suggests cancer drugs may have use for HD...............................................................9
Allergan/ExonHit compound to begin clinical trials.............................................................10
FSMA/Tikvah establish collaboration to develop TIK-201 for SMA......................................10
Ketasyn improves memory in AAMI study............................................................................10
Study suggests new targets for neurodegenerative diseases.............................................10
Neuralstem forms collaboration to advance SCs into ALS patients.....................................11
Agreement News...................................................................................11
Option to IPL455,903 not exercised by Inflazyme.................................................................11
Cerebrovascular Disorders..........................11
R&D Update.............................................................................................11
Data confirm NXY-059's inefficacy for AIS.............................................................................11
Sinobiomed completes evaluation of preclinical studies on first rhK..................................11
Study suggests continued use of statins after stroke...........................................................12
ReGen provides results of small-scale zolpidem study.........................................................12
ImaRx proceeds with Phase I/II trial of SonoLysis+tPA therapy in AIS................................12
Anxiolytics/Sleep Disorders..........................13
Product News........................................................................................13
FDA sets PDUFA action date for indiplon capsules................................................................13
Agreement News...................................................................................13
Tikvah signs licensing deal with P2D for LY156735...............................................................13
Antidepressants.............................................13
R&D Update.............................................................................................13
Have You Cost effective Multi-User solutions?
Contact Clare Mills for more information
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TCA discovery may lead to more effective drugs..................................................................13
Agreement News...................................................................................14
Tikvah signs licensing deal with P2D for LY156735...............................................................14
Psychotic Disorders.......................................14
R&D Update.............................................................................................14
Lilly's LY2140023 shows antipsychotic activity in humans..................................................14
Duke study uncovers clues about possible OCD mechanism................................................14
Corcept raises funds to advance Corlux.................................................................................15
AstraZeneca initiates Phase IIb trial of AZD3480 for cognitive deficits in schizophrenia...15
Product News........................................................................................15
AstraZeneca's Seroquel XR approved in the Netherlands....................................................15
Risperdal receives FDA approvals in children and adolescents............................................16
Analgesics/Anaesthetics................................16
R&D Update.............................................................................................16
Cymbalta reduces pain in fibromyalgia patients; sNDA submitted to FDA.........................16
Acura secures funds for Phase III trial of OxyADF Tablets.....................................................16
Meda completes acquisition of MedPointe...........................................................................17
Neuromed raises funds to accelerate development of pain treatments.............................17
Cannasat to commence Phase I study of CAT 310.................................................................17
Icagen raises funds via Pfizer investment.............................................................................17
TorreyPines initiates multiple-dose tezampanel trial..........................................................18
Zolmitriptan nasal spray effective for cluster headache......................................................18
Anesiva completes enrolment for Phase III Zingo trial in adults..........................................18
Cadence completes enrolment in Phase III trial of iv acetaminophen.................................18
Recruitment completed for Sativex Phase III trial in MS neuropathic pain.........................19
Allergan/ExonHit compound to begin clinical trials.............................................................19
Product News........................................................................................19
Daiichi Sankyo obtains additional indication for fentanyl injection in Japan.....................19
FDA approves Watson and Actavis' generic Duragesic products.........................................19
Agreement News...................................................................................19
Cephalon acquires rights to Amrix.........................................................................................19
Anti-Epileptics................................................19
R&D Update.............................................................................................19
Study provides clues to origin of Lafora disease...................................................................19
Product News........................................................................................19
Questcor approves new strategy for HP Acthar Gel..............................................................19
Eating Disorders.............................................20
R&D Update.............................................................................................20
Data support Histalean's use in obese women under 50 years of age.................................20
Product News........................................................................................20
FDA approves Caraco's generic Adipex-P...............................................................................20
General Development News...........................20
R&D Update.............................................................................................20
Memory commences Phase I programme for R4996/MEM 63908......................................20
ImaRx receives grant to study BBB permeability..................................................................21
Conference Listings........................................21
COMPANY INDEX.................................................22
COMPOUND INDEX..............................................23
6th September 2007
CNS Drug News
NEURODEGENERATIVE DISORDERS
Parkinson's Disease - R&D Update
Phase III post hoc analysis more positive for
safinamide in PD
Merck Serono (Merck KGaA) and Newron Pharmaceuticals have
released the preliminary results from a 12-month extension study of
a six-month, Phase III trial of safinamide as an add-on treatment to
dopamine agonist therapy in patients with early-stage Parkinson's
disease (PD). Merck Serono has exclusive worldwide rights to develop,
manufacture and commercialise safinamide in PD, Alzheimer's disease
and other therapeutic applications, under an agreement signed with
Newron.
Results from the initial six-month trial were presented at the 59th
Annual Meeting of the American Academy of Neurology in May (see
CNS 162). The objective of the study was to assess the long-term
safety and efficacy of safinamide as an add-on treatment to dopamine
agonist therapy. In this study, the primary efficacy endpoint, time to
intervention, did not reach statistical significance when data from
both safinamide dose groups (50-100mg and 150-200mg) were
pooled, although a delay of 93 days in median time-to-intervention
was observed; it was thought that the lack of a significant effect might
be explained by the lack of response with the high-dose group. A post
hoc analysis, however, showed that the addition of safinamide 50-
100mg once daily to dopamine agonist therapy significantly reduced
the number of patients who experienced an intervention, maintained
improvement in motor symptoms and improved quality of life (QoL)
compared with dopamine agonist monotherapy (MT). Additional
Phase III studies are planned to further assess the efficacy of this dose
of safinamide.
The 18-month, double-blind, placebo-controlled, international, Phase
III trial enrolled patients with early-stage PD (less than five years of
disease), treated with a stable dose of a single dopamine agonist.
Patients were randomised to receive safinamide 50-100mg/day,
safinamide 150-200mg/day or placebo, as an add-on treatment to
dopamine agonist therapy. Of the 270 patients originally enrolled in
the trial, 227 entered the 12-month extension period and 187 patients
completed it, with the main reasons for discontinuation including side
effects, lack of efficacy and withdrawal of consent.
The primary efficacy endpoint of the 18-month trial was time
from baseline to intervention (defined by the onset of one of the
following events: increase in dose of dopamine agonist; addition
of another dopamine agonist, levodopa or another PD therapy; or
discontinuation due to lack of efficacy). The post hoc analysis of events
beyond the initial phase (>240 days) indicated that patients receiving
safinamide 50-100mg/day experienced a significantly lower rate of
events compared with patients receiving dopamine agonist MT (25 vs
51 per cent; p=0.049).
A post hoc analysis of the mean change in motor symptoms, as
measured by the UPDRS III Motor Score, the secondary efficacy
endpoint, demonstrated that the addition of safinamide 50-100mg/
day resulted in a statistically significant improvement in motor
symptoms over the 18-month treatment period (-4.7+/-9.34 vs -1.95+/-
7.41; p=0.019) and this improvement was accompanied by a statistically
significant improvement in QoL, as measured by the EuroQoL scale
(tertiary endpoint), both in the pooled dose group (safinamide: 0+/-
1.85, placebo: 0.42+/-1.69; p=0.0046) and in the individual dose groups
6th September 2007 ©
Espicom Business Intelligence
NEURODEGENERATIVE DISORDERS
versus dopamine agonist MT (safinamide 50-100mg: 0.03+/-1.95;
safinamide 150-200mg: -0.03+/-1.73; placebo: 0.42+/-1.69 [low dose vs
placebo, p=0.017; high dose vs placebo, p=0.011]). As observed in the
initial six-month trial, the higher safinamide dose range of 150-200mg/
day did not offer any incremental advantage over placebo over an 18-
month period.
Side effects, ECG changes and vital sign abnormalities were reported
with similar frequency in patients receiving safinamide and in those
receiving dopamine agonist MT, with the most frequent adverse
events including back pain, peripheral oedema, cataract, scotoma and
dizziness.
A Phase III trial evaluating safinamide 50-100mg/day as an add-on to
levodopa therapy is ongoing in patients with mid- to late-stage PD,
and additional Phase III trials evaluating this dose range either as an
add-on to dopamine agonist or as an add-on to levodopa therapy are
expected to be initiated in 2007, in early- and mid- to late-stage PD,
respectively.
Ovary removal before menopause linked to
decreased neuroprotection
A study by Mayo Clinic researchers has indicated that women who
have one or both ovaries removed before menopause face an
increased long-term risk of Parkinson's disease (PD) and parkinsonism
compared to women who retain their ovaries. The research, which was
published in the 29th August online edition of Neurology (10.1212/01.
wnl.0000280573.30975.6a), suggests that to protect against these
conditions, oestrogen-replacement therapy (ORT) may be warranted
for women who have their ovaries removed before menopause.
This study involved reviews of medical records and follow-up
interviews with approximately 4,600 women. The Mayo team
identified all of the women in Olmsted County, MN, who had one or
both ovaries removed (approximately 2,300) from 1950 through 1987,
and these women were matched by age with an approximately equal
number of women who did not have ovarian surgery. Researchers
then interviewed women in both groups (or their relatives if the
women had died), examined those women who were suspected of
having PD and reviewed their medical records to compare the risk of
PD or parkinsonism between the two groups, throughout their full life
spans.
Prior to this report, there was either limited or conflicting clinical and
epidemiological evidence about oestrogen's ability to protect brain
functioning in women. The Mayo research shows that not only did
women who had one or both ovaries removed before menopause
have an increased risk for PD or parkinsonism compared to other
women, but that the risk increased the younger the woman was at
ovary removal.
While further studies are needed to validate these findings and clarify
their clinical implications, this research is among the first to suggest
that there is an age-related therapeutic window of opportunity for
ORT. Before the age of 50 years, ORT may in fact be beneficial for
the brain function of women who have their ovaries removed. The
findings support the concept that there is a window of therapeutic
opportunity before the approximate age of naturally-occurring
menopause (50 to 55 years), when the benefits of neuroprotection
outweigh the risks of side effects of oestrogen therapy.
Page 
NEURODEGENERATIVE DISORDERS
However, based on the results of other studies, the Mayo researchers
have stated that after the age of 55 or 60 years, the balance of
advantages and disadvantages from starting oestrogen treatment is
still somewhat uncertain, and the risk of side effects, such as increased
cancers or strokes, from oestrogen therapy may increase progressively
with age.
In addition...
Mayo researchers have also found that women who had one or
both ovaries removed before menopause were nearly two-times
more likely to develop cognitive problems or dementia compared to
women who did not have the surgery. Furthermore, those women
who were younger when their ovaries were removed were more
likely to develop dementia than women who were older when this
procedure took place.
The study, which was also published in the 29th August issue
of Neurology (10.1212/01.wnl.0000276984.19542.e6), involved
approximately 1,500 women who underwent the removal of one or
both ovaries for non-cancer-related reasons, such as ovarian cysts,
endometriosis, or for the prevention of ovarian cancer. The women
were compared to an equal number of women who still had both
ovaries at the beginning of the study. All participants were followed
for a median of 27 years and were interviewed about their memory.
If the women could not be interviewed directly, the investigators
interviewed a family member.
The results indicate that there may be a critical age window for the
protective effect of oestrogen on the brain in women. It was found
that women who had both ovaries removed before the age of 49
years, but were given oestrogen treatment until at least 50 years of
age, did not have an increased risk of developing memory problems,
which suggests that oestrogen is protective for these women in
this age window. By contrast, past studies from the Women's Health
Initiative have shown that oestrogen use started at the age of 65 years
or later may have a negative effect on memory and could increase the
risk of developing dementia.
According to study author, Dr Walter A Rocca, it is possible that
oestrogen has a protective effect on the brain and that a lack of
the hormone due to ovary removal may increase a woman's risk of
developing memory problems. Furthermore, Rocca believes that
these findings have important clinical implications and should prompt
physicians to re-assess removing ovaries before menopause and the
use of oestrogen treatment following such surgery.
Alzheimer's Disease - R&D Update
NYU vaccine combats AD tangles
A new study by New York University (NYU) Medical Center researchers
has shown for the first time that the immune system can combat the
pathological form of tau protein, which is implicated in Alzheimer's
disease (AD).
The researchers, led by Dr Einar Sigurdsson, have created a vaccine in
mice that suppresses aggregates of tau. According to the study, which
was published in the 22nd August issue of the Journal of Neuroscience
(2007;27:9115-9129), the vaccine successfully slowed the deterioration
of motor abilities produced by excessive amounts of tau in the CNS of
mice. Sigurdsson plans to conduct follow-up studies using mice that
slowly develop tangles and cognitive impairments without movement
problems.
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CNS Drug News
The study used mice that were genetically engineered to produce
abnormal tau proteins early in life, which became entangled in
several regions of the CNS. The resulting loss of motor co-ordination
was significantly reduced in those immunised with a specific piece
of the detrimental tau protein. By producing antibodies (Abs) that
could enter the brain and bind to irregular tau, the immune system
prevented their harmful aggregation and associated behavioural
impairments. Sigurdsson believes that this approach may have
extensive therapeutic implications because the problematic protein
can be specifically targeted. Tau aggregates are confined inside brain
cells, making it especially difficult to develop a therapy to target and
clear them from the cell.
The therapeutic approach is based on using fragments of abnormal
tau protein as a vaccine. These fragments are studded with phosphate
groups, which are thought to promote the aggregation of tau. The
Abs generated by the vaccine are therefore likely to bind to abnormal
tau and promote its breakdown. Meanwhile, normal tau, which has
important biological functions, would be far less affected.
The transgenic mice in the study were predisposed to forming
tau tangles early in life. Although a decline in motor abilities had
progressed by eight months, the mice still remained healthy enough
to walk, feed and attempt simple behavioural tasks. However, the
mice did not undergo thorough cognitive testing, which requires
intact mobility to navigate various mazes.
The battery of behavioural tests at five and eight months of age
showed that immunised mice performed better. These mice were
also found to have less tau protein tangles in the brain. An object-
recognition test showed that immunised mice and their controls
remained cognitively normal, although mental deficits were
expected to appear after the maximum eight-month period allowed
in the study. The mice in the study also had tau aggregates in the
hippocampus. The vaccine cleared tangles in this region, suggesting
that the immunotherapy could improve cognition.
The Abs raised by the vaccine must reach the brain by traversing
the blood-brain barrier. In this animal model (and also in AD), there
is a breakdown of this barrier. In addition, it is well established that
neurons have receptors that can bind to and promote the uptake
of Abs, and the team's studies indicate that ''sick'' neurons that
are accumulating tau aggregates take up more Abs than healthy
neurons. The Abs then end up at the site where they can interact with
pathological tau protein in the neuron and promote its clearance.
Neurochem reports negative results from North
American Alzhemed trial
Neurochem has reported top-line results from the North American
Phase III trial that was designed to assess the safety, efficacy and
disease-modification effect of Alzhemed (tramiprosate) for the
treatment of Alzheimer's disease (AD).
Following a recent meeting with the FDA and subsequent statistical
analyses, this trial, despite the descriptive data showing numerical
differences, did not demonstrate a statistically significant difference
in favour of tramiprosate with respect to the primary endpoints over
18 months of treatment. However, a substantial difference observed in
hippocampal volume did approach statistical significance.
Due to significant interference from high between-site variations
that complicated the statistical analyses beyond expectations, the
company believes that it is not possible to draw definitive conclusions
with respect to the treatment effect of tramiprosate.
6th September 2007
CNS Drug News NEURODEGENERATIVE DISORDERS

This was a multi-centre, double-blind, placebo-controlled, three-arm,

Obesity
parallel-designed, 18-month trial that included 1,052 patients with
mild-to-moderate AD, who were recruited across 67 sites in Canada
and the US, and randomised to receive either placebo or tramiprosate
100 or 150mg twice daily. All patients were required to be treated with

Drug
conventional symptomatic AD therapies during the trial and to be on
a stable dose of such therapies for at least four months prior to the
initial screening visit of the study.

DiscOveries:
In the trial, tramiprosate was generally safe and well tolerated. The
incidence of serious adverse events reported in patients treated with
tramiprosate was comparable to that for patients in the placebo
group. The most common adverse events (>10 per cent) reported
more frequently for tramiprosate than placebo were nausea, falling,
diarrhoea, dizziness, body weight decrease and vomiting. What the future hOlDs
Tramiprosate has received fast track designation from the FDA for the
treatment of mild-to-moderate AD and is a small, orally-administered
Now
amyloid beta (Abeta) antagonist, which crosses the blood-brain available with online
barrier, binds to soluble Abeta peptide and interferes with the amyloid news tracker service!
cascade that is associated with amyloid deposition and the toxic
effects of Abeta peptide in the brain.
While only recently identified as a major
At the recent FDA meeting, Neurochem sought feedback on health concern, obesity levels have been
appropriate next steps, especially with respect to the statistical models growing steadily and the condition
and detailed analysis of potential confounding factors. The Agency
recognised the difficult issues surrounding a trial of this magnitude, threatens to rank among the biggest
with its significant site effect and the large number of covariates causes of premature death in both the
identified during the modelling process, but advised that neither the
proposed adjusted models nor any further adjustments could be used
industrialised and emerging economies.
for this trial to provide results in support of a claim of clinical efficacy. The rewards are high for those who can bring
However, the Agency recognised that it might be possible to utilise
the findings of the North American study to potentially revise the
effective treatments to market, but questions
statistical analysis plan and/or modify the study design of the ongoing remain...
European Phase III trial of tramiprosate for the treatment of AD.
• What are the strengths and weaknesses for
In the European trial, to date, 966 mild-to-moderate AD patients are current therapy approaches?
enrolled at 69 clinical centres in ten countries. The European Data • Which research approach is likely to achieve
Safety Monitoring Board has met three times and recommended on best clinical and commercial results and
each occasion that the study should continue. In August, Neurochem when are the resulting drugs likely to reach
stopped patient screening activities as it had met its recruitment target
and the company is presently considering potential modifications to
the market?
the European study to take best advantage of the experience gained • What are the development and regulatory
from the recently-completed North American trial. challenges companies must overcome?
Neurochem will continue to evaluate the treatment effect of The answers to these and many other
tramiprosate with post hoc evaluations to facilitate its understanding questions can be found in this new
of the data and assess any treatment effect from the North American
trial. The company has established a Special Advisory Board to assist it 120+ page strategic management report
over the coming months in reviewing and analysing the data from this Obesity Drug DiscOveries: What the future hOlDs
trial. The Board's mandate will also be to provide advice to Neurochem
as it considers its options for the future direction of the tramiprosate (published August 2007)
programme.
This report is available in paper,
Baxter/ADCS to pursue Phase III study of Gammagard pdf by email and online
Liquid for AD

Baxter International and the Alzheimer's Disease Cooperative Study In addition, for those needing to monitor
(ADCS) group have decided to pursue a multi-centre, US Phase III this developing area there is the Obesity
study evaluating the role of Gammagard Liquid, an intravenous Tracker, an online news service available
immunoglobulin (IVIg) preparation, for the treatment of patients with
mild-to-moderate Alzheimer's disease (AD).
for customers opting to buy the web
edition of this report
IVIg has been used for almost three decades to treat primary
immunodeficiency. The rationale for testing it as a possible treatment
for AD is based on the presence of natural antibodies that are
www.espicom.com/obesity
6th September 2007 ©
Espicom Business Intelligence Page 
NEURODEGENERATIVE DISORDERS
directed against several forms of amyloid beta (Abeta). Treatment
with naturally-occurring antibodies against Abeta contained in IVIg
may result in the clearance of Abeta from the brain, as well as the
dissolution of plaques.
The decision to pursue the study is based on the results of two
completed open-label clinical studies, plus the preliminary analysis of
interim data from a double-blind, placebo-controlled, Phase II study
by a team at Weill Cornell Medical College. In this study, 24 patients
with mild-to-moderate AD were randomly assigned to receive
Gammagard Liquid (n=8), Gammagard S/D (n=8) or placebo (n=8)
for six months. Cognitive, behavioural and functional measures were
collected at baseline, and at three and six months of treatment. The
primary endpoints of the trial were cognitive function (as measured
by ADAS-Cog score) and global function (as assessed by ADCS-CGIC
rating). The prespecified criterion for going forward with Phase III was
a favourable outcome in IVIg-treated patients relative to those given
placebo. Final results of the analysis of the study are expected later
this year.
This Phase II study follows earlier Phase I results in eight patients that
were reported at the International Conference on Alzheimer's Disease
in July 2006. Although these findings are promising, both studies were
small and results must therefore be confirmed in a larger, sufficiently-
powered study.
The study protocol will be submitted to the FDA for review in the
coming months, with the intention of initiating patient recruitment
early in 2008. The trial is jointly sponsored by the National Institutes of
Health and Baxter, and will include approximately 35 academic centres
in the US that are members of ADCS.
Phase I studies completed with ELND-005/AZD-103
Transition Therapeutics has reported the completion of Phase I studies
with the Alzheimer's disease (AD) drug candidate, ELND-005/AZD-103.
Transition and its development partner, Elan, have performed
multiple Phase I studies evaluating the safety, tolerability and
pharmacokinetic profile of ELND-005/AZD-103 in healthy volunteers.
Orally-administered ELND-005/AZD-103 may act through the unique
mechanism of preventing and reversing the fibrilisation of amyloid
beta.
Approximately 110 subjects have been exposed to ELND-005/AZD-103
in multiple Phase I studies, including single and multiple ascending
dosing, pharmacokinetic evaluation of levels in the brain, and
cerebrospinal fluid (CSF) and plasma studies. ELND-005/AZD-103 was
safe and well tolerated at all doses and dosing regimens examined,
with no severe or serious adverse events observed. The compound
was also shown to be orally bioavailable, cross the blood-brain barrier
and achieve levels in the human brain and CSF that were shown to be
effective in animal models of AD. The pharmacokinetic and safety data
obtained in the Phase I studies will be used to select the appropriate
doses for Phase II trials.
The next steps in the development of ELND-005/AZD-103 will be the
submission of data supporting Phase II studies to the FDA. Transition
and Elan anticipate starting Phase II by the end of 2007 or early 2008.
Study supports statin use for AD
Scientists have found evidence showing an association between statin
use and a lower risk of neuropathologic changes in the brain that are
associated with Alzheimer's disease (AD).
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CNS Drug News
In the study, which was published in the 28th August issue of
Neurology (2007;69:878-885), researchers at the University of
Washington, the Veterans Affairs Puget Sound Health Care System and
the Group Health Cooperative of Puget Sound reviewed autopsies on
110 patients aged 65 to 79 years, who had died in the course of a long-
term, community-based study on cognitive changes in the elderly.
After controlling for age and other factors, they found that the brains
of statin users showed significantly reduced risk of having the typical
signs of AD than non-users, including a more than two-fold reduction
in the risk of having neurofibrillary tangles.
Nymox Pharmaceutical holds US and global patent rights for the use
of statin drugs for the prevention and treatment of AD, including for
patients at risk of AD because of vascular-related risk factors or disease.
These findings demonstrate an association between antecedent statin
use and neurofibrillary tangle burden at autopsy, however, it has been
cautioned that additional study is needed to examine whether statin
use may be causally related to decreased development of AD-related
neuropathologic changes.
For details of a study suggesting the continued use of statins after a
stroke, see Cerebrovascular Disorders, R&D Update.
Product News
Aricept approved for severe AD in Japan
Aricept (donepezil) has been approved to treat severe Alzheimer's
disease (AD) in Japan, meaning it is now approved there to treat all
stages of the disease. An acetylcholinesterase inhibitor developed
by Eisai, Aricept is the only approved prescription medicine for the
treatment of AD in Japan and was approved for this new indication in
the US in October 2006, where it is co-promoted with Pfizer.
The approval was based on the results of clinical trials conducted
both in Japan and abroad. The trial in Japan, involving approximately
300 patients with severe AD, compared the efficacy of Aricept 5 and
10mg/day versus placebo. In this six-month, multi-centre, randomised,
double-blind, placebo-controlled study, the patients treated with
both doses of Aricept showed a statistically significant improvement
in cognitive function compared to those taking placebo. In addition,
those patients treated with 10mg/day showed a statistically significant
improvement in global function compared to the placebo group. No
statistically significant difference was observed between the 5mg/day
dose group and the placebo group in the rate of adverse events (AEs),
while in the 10mg/day dose group, patients experienced a statistically
higher incidence of AEs compared to the placebo group, with the
most commonly observed being gastrointestinal in nature and mild-
to-moderate in severity.
The recommended initial dose for adult patients is Aricept 3mg
administered orally once daily, increasing to 5mg once daily after one
to two weeks. For patients with severe AD, administration should be
started with Aricept 5mg once daily and the daily dose increased to
10mg after four weeks.
Ranbaxy receives tentative FDA approval for
galantamine tablets
On 28th August, Ranbaxy Laboratories received tentative FDA
approval to manufacture and market galantamine tablets 4, 8 and
12mg on an exclusive basis. Galantamine, which is marketed by
Janssen Pharmaceutica (Johnson & Johnson) as Razadyne, is indicated
6th September 2007
CNS Drug News NEURODEGENERATIVE DISORDERS

for the treatment of mild-to-moderate dementia of the Alzheimer's

disease type and Ranbaxy will benefit from the 180-day shared
exclusivity on the product. Final approval is anticipated on 14th
December 2008.
SMi present their 6th Annual Conference on…
Multiple Sclerosis - R&D Update Clinical Trials in CNS
th th
26 & 27 November 2007, Copthorne Tara Hotel,
Tysabri demonstrates significant HRQoL London
improvements for MS patients PLUS AN ASSOCIATED HALF-DAY POST-
CONFERENCE WORKSHOP
According to data published in the 14th August online edition of
the Annals of Neurology (10.1002/ana.21163), multiple sclerosis (MS) Combination compounds in CNS and efficacy
patients treated with Tysabri (natalizumab) showed a significant boosting
improvement in health-related quality-of-life (HRQoL) measures when
compared to those receiving placebo. These results are from the first 28th November 2007, Copthorne Tara Hotel,
Phase III MS studies to have demonstrated improvement on HRQoL London
measures in patients with relapsing forms of MS. In association with: PharmaNeuroBoost
Tysabri is a therapy approved for relapsing forms of MS in the US
and relapsing-remitting MS (RRMS) in the EU. Discovered by Elan
This year the SMi Group has set to explore the
and co-developed with Biogen Idec, the product is also approved in latest advancements in CNS clinical trials design
Switzerland, Canada, Australia and Israel. and conduction, and is offering the chance to gain
unique insights into the field.
The two-year, randomised, double-blind, placebo-controlled, multi-
centre trials, AFFIRM (Natalizumab Safety and Efficacy in Relapsing Building on the success of the previous events, the
Remitting Multiple Sclerosis) and SENTINEL (Safety and Efficacy of conference offers a packed and varied agenda
Natalizumab in Combination with Interferon Beta-1a in Patients
covering recent results, case study presentations
with Relapsing Remitting Multiple Sclerosis), were conducted
in 2,113 patients with relapsing forms of MS. In AFFIRM, patients and analysis methods. In addition, a networking
received natalizumab 300mg (n=627) or placebo (n=315), while in drinks reception has also been set at the end of the
SENTINEL, participants received Avonex (interferon [IFN] beta-1a) plus first day, enabling attendees to exchange thoughts
natalizumab 300mg (n=589), or IFN beta-1a plus placebo (n=582). The and ideas in a relaxed social setting.
SF-36 and a Subject Global Assessment Visual Analogue Scale (VAS)
were administered at baseline, as well as at weeks 24, 52 and 104. Odds To download a brochure visit our website at:
ratios for clinically-meaningful improvement or worsening on the www.smi-online.co.uk/2007cnstrials13.asp
SF-36 Physical Component Summary (PCS) and Mental Component
Summary (MCS) were also calculated. The excellent speaker line up includes:
In the AFFIRM trial, natalizumab-treated patients showed: a statistically - Dr Gail Farfel, Novartis
significant improvement in the SF-36 PCS beginning at week 24 and Vice President and CNS Therapeutic Area Head
all subsequent time points, compared with a decline in the placebo-
treated group; a statistically significant improvement in the SF-36 MCS
- Dr Menelas N Pangalos, Wyeth
at week 104, compared with a decline in the placebo-treated group; Vice President, Neuroscience Research,
and statistically significant benefits using the VAS when compared - Dr Tanya Ramey, Pfizer,
with placebo at weeks 52 and 104. Natalizumab-treated patients Clinical Lead, Neurosciences
showed sustained improvement from baseline QoL measures, not - Dr Stig Johan Wiklund, AstraZeneca,
just a slowing down of QoL deterioration, while HRQoL measures Director Statistical Science, Technical and Scientific
correlated with common measures of MS severity, including the EDSS, Development,
sustained disability progression, relapse number, MSFC and volume of
- Dr Michel Dib, Sanofi-Aventis,
T2-hyperintense and T1-hypointense lesions. Improvements on QoL
measures were also observed in the SENTINEL study. Medical Director, CNS
- Dr Paul Thompson, GlaxoSmithKline,
For details of Tysabri being recommended in the UK for use in highly- CPDM-Neurology Biomarker Group
active RRMS, see Product News. - Dr James V Cassella, Alexza Pharmaceuticals,
Senior Vice President, Research and Development
PDL to focus on Ab discovery and development

PDL BioPharma is to undertake a significant strategic change to focus TO REGISTER YOUR PLACE
on the discovery and development of novel antibodies (Abs) in select Go online at:
immunological diseases and oncology, following a months-long
www.smi-online.co.uk/2007cnstrials13.asp
business and portfolio review.
OR
PDL has revised its corporate strategy to take advantage of its clinical Contact Luke Pentney on tel: +44 (0)20 7827
and preclinical portfolio, and leverage its ability to innovate in the 6186/ email: lpentney@smi-online.co.uk
science and development of monoclonal Abs. PDL will focus its (Academic and Group discounts available)

6th September 2007 ©

Espicom Business Intelligence Page 
NEURODEGENERATIVE DISORDERS
research and development initiatives and strengthen its expertise in
two therapeutic areas, select immunological diseases and oncology.
The company's immunological programmes include daclizumab in
multiple sclerosis and other indications, Nuvion (visilizumab) in various
potential indications and several preclinical candidates. The company
is planning an R&D update in mid-November to detail the status of its
initiatives.
Recruitment completed for Sativex Phase III trial in
MS neuropathic pain
Patient recruitment has been completed in GW Pharmaceuticals'
double-blind, randomised, placebo-controlled, pivotal Phase III trial of
Sativex, a buccal spray composed primarily of tetrahydrocannabinol
and cannabidiol, in patients with central neuropathic pain due to
multiple sclerosis (MS), who have achieved inadequate pain relief with
existing therapies.
The study has recruited 339 patients in the UK, Canada, France, Spain
and the Czech Republic, and is GW's largest clinical trial, to date. The
duration of treatment in the trial is 14 weeks and the last patient will
exit the study at the end of 2007, with headline results expected in the
first half of 2008.
GW previously carried out a similar pivotal Phase III trial with positive
results. This study showed that Sativex was significantly superior to
placebo in reducing pain (p=0.005) and sleep disturbance (p=0.003).
This second pivotal Phase III study in MS neuropathic pain has two
potential roles in the regulatory strategy for Sativex, as follows:
• in Europe, this study may provide a clinical data package to
support a regulatory submission for Sativex in the indication of
MS neuropathic pain; and
• in Canada, this study is intended to meet the condition associated
with the approval of Sativex in order to obtain a full Notice of
Compliance.
Sativex is already approved in Canada, where it is exclusively marketed
by Bayer, as adjunctive treatment for the symptomatic relief of
neuropathic pain in MS and in cancer pain. Health Canada approved
Sativex under the Notice of Compliance with conditions policy.
Product News
Biopartners submits Biferonex in Europe
Biopartners Holdings, which was acquired by Bioton in March, has
submitted an MAA to the EMEA for Biferonex (interferon beta-1a [IFN
beta-1a]), a pH-neutral and human serum albumin-free formulation
of IFN beta for patients with relapsing-remitting multiple sclerosis
(RRMS).
IFN beta has been extensively studied in MS, exhibiting beneficial
effects in both the RR and progressive forms of the disease by
inhibiting inflammatory activity and thereby reducing nerve cell
damage. It is also thought to inhibit damage to the myelin sheath by
both preventing a T-cell-mediated autoimmune response to myelin
and reducing the effect of other naturally-occurring compounds that
can enhance the autoimmune response.
This formulation boasts a low incidence of neutralising antibodies and
is therefore expected to optimise drug treatment effectiveness, plus
the product's neutral pH minimises the risk of injection site reactions,
which is anticipated to enhance tolerability.
Page  ©
Espicom Business Intelligence
CNS Drug News
NICE recommends Tysabri for use in highly-active
RRMS
Final guidance by the UK's National Institute for Health and Clinical
Excellence (NICE) has recommended the NHS' use of Biogen Idec/
Elan's Tysabri (natalizumab) in people with highly-active relapsing-
remitting multiple sclerosis (RRMS).
Tysabri is the first treatment for MS to be recommended for use by
NICE and the first to be specifically licensed for highly-active RRMS.
Data indicate that over two years, treatment with the product for
highly-active RRMS, defined as those with two or more relapses and
MRI activity, leads to a 64 per cent reduction in the risk of disability
progression and an 81 per cent reduction in annualised relapse rate
compared with placebo.
For details of Tysabri demonstrating significant health-related quality-
of-life improvements for MS patients, see R&D Update.
New Rebif formulation approved in Europe
The EC has granted marketing authorisation for a new formulation
of Merck Serono's (Merck KGaA) Rebif (interferon beta-1a) for the
treatment of relapsing multiple sclerosis. The formulation has been
developed to increase treatment benefit by improving injection
tolerability, while targeting an improved immunogenicity profile.
The decision applies to all 27 countries in the EU, as well as Iceland,
Liechtenstein and Norway, with launches in the various EU countries
starting in September. The new formulation will be available in the
same strengths and pharmaceutical forms as currently registered, ie,
8.8, 22 and 44mcg, as a solution for injection in prefilled syringes.
Questcor approves new strategy for HP Acthar Gel
For details, see Anti-Epileptics, Product News.
Agreement News
Teva partners with Compugen for CGEN-54
Teva Pharmaceutical Industries has signed an agreement covering
Compugen's CGEN-54, a novel splice variant of monocyte
chemoattractant protein 1 (MCP1). The agreement covers both an
initial research collaboration and an option to Teva for a worldwide
exclusive development and commercialisation licence.
CGEN-54, a drug candidate for chronic inflammatory diseases, is one
of a large number of novel splice variants predicted in silico using a
Compugen discovery engine and then experimentally validated.
Under the terms agreed, Compugen will provide Teva with research
quantities of CGEN-54. Teva will then conduct further in vivo validation
experiments and has received from Compugen an option to enter
into an exclusive worldwide milestone and royalty-bearing licence
agreement for the development and commercialisation of any
resulting products.
CGEN-54 is an antagonistic variant of MCP1, which is induced in
response to various inflammatory stimuli. Binding of this protein to
its cognate receptor, CCR2, leads to the recruitment of specialised
immune cells into the site of inflammation, often leading to chronic
inflammation. CGEN-54 has been shown to inhibit MCP1-related
6th September 2007
CNS Drug News NEURODEGENERATIVE DISORDERS

activity. The inhibition of the MCP1-CCR2 pathway represents a

promising target to effectively modulate disease progression in a
A new market-leading strategic analysis from Espicom
number of chronic inflammatory diseases, such as multiple sclerosis.
EmErging OppOrtunitiEs
Other Neurodegenerative Disorders in inhalatiOn & nasal
- R&D Update spray gEnEric Drugs
McMaster study suggests kinase inhibitor use for HD From emerging specialist manufacturers to
According to research published in the 18th August online edition
established companies seeking new opportunities,
of Human Molecular Genetics (10.1093/hmg/ddm217), a team at alternative drug-delivery technologies are
McMaster University has made an insight into how Huntington's increasingly being seen as a route to a competitive
disease (HD) is triggered. edge in the generics industry.
Dr Ray Truant has been studying the biological role of the huntingtin This new report from Espicom provides a complete
protein and the sequences in the protein that tell it where to go within review of the emerging opportunities and operating
a brain cell. The researchers have discovered a small protein sequence environment for inhalation and nasal spray drugs.
in huntingtin that allows it to locate to the part of the cell that is critical
for protein quality control. Similar findings have been seen to be Providing…
important for other neurodegenerative diseases, such as Parkinson's
and Alzheimer's.
• Product forecasts by value 2006 to 2011
• Patent expiry opportunities to 2016
Huntingtin protein is essential for normal development in mammals • Generic market context
and is found in all cells, yet its function was unknown. Now, it appears • Competitive evaluation with 18 company
that huntingtin is crucial for a brain cell's response to stress and moves
from the endoplasmic reticulum into the nucleus. However, when reviews
mutant huntingtin is expressed, it enters the nucleus as it should in THERAPY AREAS AND PRODUCTS ASSESSED
response to stress, but cannot exit properly, piling up in the nucleus
and leading to brain cell death in HD. The researchers also found that
Asthma & COPD
huntingtin can be sent to the nucleus by kinases and determined the • Flixotide/Flovent (fluticasone propionate)
3D shape of this sequence. The team's work indicates that if mutant • Serevent (salmeterol xinafoate)
huntingtin is prevented from entering the nucleus, it cannot kill a • Seretide/Advair (salmeterol
brain cell, which suggests that a kinase inhibitor drug may be effective xinafoate+fluticasone propionate)
for HD.
• Pulmicort (budesonide)
Protox acquires HUMxin research programme from • Combivent (ipratropium bromide+salbutamol)
Medicenna • Xopenex (levalbuterol)

Protox Therapeutics has entered into an asset purchase agreement for

Allergic rhinitis
the acquisition of Medicenna Ventures' HUMxin Program, a research • Flixonase (fluticasone propionate)
programme to develop fully-humanised fusion proteins based upon • Rhinocort (budesonide)
the Bcl-2 family, which are key components of apoptosis. HUMxin • Nasonex (mometasone furoate)
represents a third technology platform for the company and may have • Nasacort (triamcinolone acetonide)
application for the treatment of neurodegenerative diseases.
Influenza
Prior to joining Protox as President and Chief Executive Officer, Dr
Fahar Merchant founded Medicenna and had worked with the
• Relenza (zanamivir)
National Institutes of Health (NIH) to develop the HUMxin Program.
Medicenna entered into a CRADA with the NIH related to the HUMxin
Migraine
Program. Pursuant to the terms agreed, Medicenna has transferred • Imigran (sumatriptan)
the HUMxin CRADA and all its rights and interests to Protox, and the • Zomig (zolmitriptan)
company has agreed to pay Medicenna C$209,680 for its audited out-
of-pocket HUMxin CRADA and related expenses incurred, to date. Half Osteoporosis
of this amount will be paid to Medicenna in cash and the other half • Miacalcin (calcitonin-salmon)
in the form of 127,854 common shares of the company, which will be
subject to a four-month hold period. • Fortical (calcitonin-salmon [rDNA origin])

Study suggests cancer drugs may have use for HD Anaesthesia

• Ultane (sevoflurane)
Scientists at the University of Leeds have made what is thought to be • Suprane (desflurane)
a major breakthrough in the understanding and potential treatment
of Huntington's disease (HD). They have discovered that one of the
body's naturally-occurring proteins is preventing 57 genes from
www.espicom.com/ins
6th September 2007 ©
Espicom Business Intelligence Page 
NEURODEGENERATIVE DISORDERS
operating normally in the brains of patients with HD. In addition, the
destructive nature of this protein could potentially be halted using
drugs that are already being used to help cancer patients.
According to Dr Lezanne Ooi, the research could lead to radical
changes in treatment for HD patients and the fact that these cancer
drugs have already been through the clinical trials process should
accelerate the time it takes for this research to impact directly on
patients.
Ooi's research, which was carried out in collaboration with the
University of Milan and King's College, London, and published in
the 27th June issue of the Journal of Neuroscience (2007;27:6972-
6983), has identified the effects of one of the body's proteins on the
neurons of HD patients. Neurons are usually protected by brain-
derived neurotrophic factor (BDNF), whose many functions also
include encouraging the growth and differentiation of new neurons
and synapses. However, in HD patients, the repressor protein known
as repressor element 1-silencing transcription factor (REST), which is
usually found only in certain regions of the brain, enters the nucleus of
the neuron and decreases the expression of BDNF.
Ooi has also been studying some of the enzymes that assist the
function of this protein. It is these enzymes that provide the
mechanism for the protein to cause disruption in the brains of HD
patients and that are already being targeted by certain cancer drugs.
Allergan/ExonHit compound to begin clinical trials
Clinical testing is to be initiated with the first new chemical entity
(NCE) to emerge from Allergan and ExonHit Therapeutics' strategic
collaboration to identify, develop and commercialise drugs
targeted at the treatment of neurodegenerative diseases, pain and
ophthalmology. The NCE, designated EHT/AGN001, has a novel
mechanism of action and will enter a Phase I study later in 2007.
Under terms previously agreed, Allergan will assume responsibility
for the ongoing clinical development and commercialisation of
EHT/AGN001, while contingent upon progress, ExonHit will receive
milestone payments and royalties upon commercialisation.
FSMA/Tikvah establish collaboration to develop
TIK-201 for SMA
Families of Spinal Muscular Atrophy (FSMA) and Tikvah Therapeutics
have established a collaboration to help advance and accelerate the
clinical development of TIK-201, the latter's new formulation of sodium
phenylbutyrate, for the treatment of spinal muscular atrophy (SMA).
This collaboration is focused on utilising the existing Project Cure SMA
clinical network and protocols to clinically test Tikvah's non-viscous,
concentrated solution formulation.
SMA results from the loss of both copies of the survival motor
neuron (SMN1) gene. Early ex vivo and other clinical results suggest
that sodium phenylbutyrate, amongst other histone deacetylase
inhibitors, may be effective in the treatment of SMA by increasing
production of the remaining SMN2 protein. However, such trials have
been complicated by difficulties in administering currently-available
tablet and powder preparations of sodium phenylbutyrate due to its
unpleasant taste and smell, plus other properties. Tikvah's proprietary
formulation overcomes these limitations and is optimised for the
delivery of drugs to infants, toddlers and others with swallowing
difficulties by conventional routes of administration. Specific details
on the trial design and dates will be available later this year, with the
goal of beginning enrolment in the first half of 2008.
Page 10 ©
Espicom Business Intelligence
CNS Drug News
Ketasyn improves memory in AAMI study
Data from a Phase II study in age-associated memory impairment
(AAMI) have shown that Accera's lead compound, Ketasyn (AC-1202),
has a positive and clinically-meaningful effect on memory in older
adults.
The randomised, double-blind, placebo-controlled, parallel trial was
conducted at six centres in the US. A total of 159 subjects (mean age,
65 years) diagnosed with AAMI received either Ketasyn or placebo
for 90 days, followed by a two-week washout period. Subjects
underwent genomic testing for variations in the coding regions of
genes that are known to influence memory and cognition, including
the apolipoprotein E gene (APOE), a known genetic risk factor for
Alzheimer's disease (AD). On days zero, 30, 60, 90 and 104, subjects
were evaluated through a battery of neuropsychometric tests that
measure various aspects of memory and cognition.
Ketasyn showed significant efficacy in tests of memory. On average,
subjects taking the compound performed significantly better on
the First-Last Name Association test (FLN) than those taking placebo
(p=0.042). In another memory test, known as Name-Face Recognition
(NFA), Ketasyn-treated subjects under the age of 59 years improved
significantly more than placebo subjects at day 90 (p=0.0217).
Consistent with the findings of Accera's Phase IIa and IIb AD studies,
subjects who did not have the APOE4 genotype (E4[-]) responded
particularly well to treatment: E4(-) subjects showed a further
significant treatment effect of Ketasyn in the FLN at day 90 (p=0.012).
In contrast, and consistent with the AD trial results, APOE4(+) subjects
showed no difference between Ketasyn and placebo for FLN scores at
day 90 (p=0.4639).
The safety profile of Ketasyn was positive, as shown in the previous AD
trials. The incidence of adverse events was low and similar between
Ketasyn and placebo groups.
AAMI symptoms may be related to declines in glucose metabolism
in the brain that are also associated with ageing. Ketasyn is an orally-
available compound that is metabolised into ketone bodies, which
the brain can use for energy even when its ability to process glucose
is impaired.
Accera recently completed a Phase IIb trial in AD patients that
confirmed Ketasyn's safety and efficacy, as measured by improvement
in ADAS-Cog scores, and the company plans to initiate a pivotal, multi-
centre, Phase III trial in early 2008 in mild-to-moderate AD patients.
This study will focus on several measures of efficacy, including the
ADAS-Cog, safety and the role of insulin regulation in AD.
Study suggests new targets for neurodegenerative
diseases
Researchers have provided new information about how
communication among neurons may be prevented from deteriorating
in conditions such as Alzheimer's disease (AD). The results, which were
published in the August issue of Molecular & Cellular Proteomics
(2007;6:1318-1330), may lead to new therapies for the treatment of not
only AD, but also motor neuron and prion diseases.
Most current research efforts to find a treatment for AD and similar
conditions focus on what happens to the main part of a neuron,
but recent studies have examined how neuronal communication is
impaired in human diseases such as AD. The deterioration of synapses
and axons can be delayed via a protein created by the slow Wallerian
6th September 2007
CNS Drug News
degeneration (Wlds) gene, although how this protein works is still a
mystery. In the study, researchers from the University of Edinburgh
and colleagues identified 16 proteins that are affected by the Wlds
gene.
Although details are still missing, Wlds probably prevents these
proteins from deteriorating synapses and axons. The team found
that some of the proteins had previously been shown to deteriorate
synapses and axons, but, unexpectedly, eight proteins regulated the
function of mitochondria. These results reveal for the first time that
mitochondria are involved in the protection of neurons provided
by the Wlds gene and suggest that targeting some of the proteins
identified in this study may lead to novel therapies for the treatment
of AD, as well as motor neuron and prion diseases.
Neuralstem forms collaboration to advance SCs into
ALS patients
Neuralstem has entered into a collaborative agreement with the ALS
Clinic at University of Michigan Health System, the goal of which is to
provide further proof-of-principle data to move the company's spinal
cord stem cells (SCs) into patients with amyotrophic lateral sclerosis
(ALS; Lou Gehrig's disease).
Neuralstem's patent-protected technology enables, for the first time,
the ability to produce neural SCs of the human brain and spinal cord
in commercial quantities, and the ability to control the differentiation
of these cells into mature, physiologically-relevant human neurons
Cerebrovascular Disorders
R&D Update
Data confirm NXY-059's inefficacy for AIS
Data published in the 9th August issue of the NEJM (2007;357:562-571)
have confirmed that NXY-059 is ineffective for the treatment of acute
ischaemic stroke (AIS) within six hours after the onset of symptoms.
NXY-059, a free radical–trapping agent, showed promise as a
neuroprotectant in the SAINT I (Stroke–Acute Ischemic NXY Treatment
I) trial, reducing disability when given to patients who had AIS,
therefore confirmation of efficacy was sought in a second, larger trial,
named SAINT II.
A total of 3,306 patients with AIS were enrolled in the randomised,
double-blind trial to receive a 72-hour infusion of intravenous NXY-
059 or placebo within six hours after the onset of stroke symptoms.
The primary endpoint was the distribution of disability scores on the
modified Rankin Scale (mRS) at 90 days, with scores on neurologic and
activities of daily living scales examined as secondary endpoints. The
researchers also tested the hypothesis that NXY-059 would reduce
alteplase-related intracranial haemorrhages.
The efficacy analysis was based on 3,195 patients. The results indicate
that prognostic factors were well balanced between the treatment
groups, plus mortality was equal in the two groups and adverse event
rates were similar. However, the distribution of scores on the mRS
did not differ between the NXY-059-treated group (n=1,588) and the
placebo group (n=1,607; p=0.33 by the Cochran–Mantel–Haenszel
test; odds ratio for limiting disability, 0.94; 95% CI, 0.83 to 1.06).
6th September 2007 ©
Espicom Business Intelligence
CEREBROVASCULAR DISORDERS
and glia. The company expects that its first IND application will be for
the treatment of ischaemic paraplegia, and hopes to submit its initial
application to the FDA and begin its first clinical trial during 2007.
Agreement News
Option to IPL455,903 not exercised by Inflazyme
Inflazyme Pharmaceuticals has confirmed that it will not exercise
its option to IPL455,903, a PDE-IV inhibitor discovered and patented
by the company. Under the limited licence granted to Helicon
Therapeutics in January 2003, Inflazyme had 90 days to exercise its
option after receiving certain information that included the results of
the first Phase IIa study.
Helicon recently completed a Phase IIa study with IPL455,903 in
elderly subjects with age-associated memory impairment. Inflazyme
commented on the results of this study in June and stated that the
data may support further clinical studies with the compound, as well
as the development of the company's other PDE-IV inhibitors (see
CNS 165). However, Inflazyme has insufficient cash to exercise the
option, which is estimated to be in the range of C$3 million to C$4
million based on limited information provided by Helicon. By not
proceeding with the option, Inflazyme will receive certain royalties
on any product commercialised. Helicon only has rights in the field of
learning and memory disorders, while Inflazyme has retained rights to
this compound for all other uses.
Furthermore, analysis of categorised scores on the mRS confirmed the
lack of benefit: the odds ratio for trichotomisation into mRS scores of 0
to 1 versus 2 to 3 versus 4 to 6 was 0.92 (95% CI, 0.80 to 1.06). There was
no evidence of efficacy for any of the secondary endpoints and among
patients treated with alteplase, there was no difference between the
NXY-059 and placebo groups in the frequency of symptomatic or
asymptomatic haemorrhage.
These data confirm the SAINT II results that were reported in October
2006, which indicated that NXY-059 had shown no efficacy in
AIS. At that time, AstraZeneca revealed that it planned no further
development of NXY-059 in AIS, but would analyse the pooled data
from the SAINT I and II trials in close co-operation with the SAINT
Steering Committee and Renovis, to ensure that learnings for further
stroke research were identified and communicated.
Sinobiomed completes evaluation of preclinical
studies on first rhK
Sinobiomed has provided an update on preclinical trial progress for
the recombinant human kallikrein (rhK1) being developed by its 82
per cent-owned subsidiary, Shanghai Wanxing Bio-pharmaceuticals.
Shanghai Wanxing researchers are developing rhK1, the world's first
rhK, with purity levels as high as 98 per cent and low production costs,
to treat stroke and peripheral vascular disorders, plus to prevent blood
clots and thrombosis.
The preliminary results of the preclinical research show that dogs can
be safely injected with 400-times the normal human dose. Trial results
in dogs and rabbits further demonstrated that rhK1 could significantly
reduce the nerve function barrier caused by ischaemic brain infarction,
decrease the infarction scope and attenuate cerebral oedema. The
Page 11
CEREBROVASCULAR DISORDERS
animal study also showed that the efficacy of rhK1 is better than
that of the kallikrein treatments extracted from human fluids and
organs. Once the preclinical study data have undergone final analysis,
Shanghai Wanxing intends to apply for approval to undertake clinical
research. The clinical study of rhK1 is expected to begin with ischaemic
brain infarction and extend to other conditions.
Shanghai Wanxing has applied for a Chinese patent for rhK1 and is
applying to the Patent Control Treaty for an international patent.
Study suggests continued use of statins after stroke
The results of a study published in the 28th August issue of Neurology
(2007;69:904-910) have suggested that people who stopped taking
their statins while hospitalised after a stroke were 4.7-times more
likely to have died or be dependent on others for their care three
months after the stroke than people who kept taking the drugs.
According to study author, Dr José Castillo, of the University of
Santiago de Compostela in Spain, the results strongly support the
recommendation to physicians to continue statin drugs during the
acute phase of an ischaemic stroke.
The study involved 89 people who were already taking the cholesterol-
lowering drugs at the time when they had a stroke. For the first three
days after being admitted to the hospital, 46 of the patients received
no statin drugs, while 43 received the drugs. After three months, 27
people (60 per cent) in the group that received no statins had either
died or were disabled to the point that they could not complete their
daily activities independently, compared to 16 people (39 per cent) in
the group that kept taking statins.
For details of a further study demonstrating the positive effects of
statin use, see Neurodegenerative Disorders, Alzheimer's Disease -
R&D Update.
CanCer Drug
DisCoveries:
what the future holDs
This market analysis provides a unique examination
of five key oncology therapy areas: breast cancer,
non-small cell lung cancer, colorectal cancer, prostate
cancer and renal cancer.
Understand the prospects for this US$47.2 billion market
• Breast cancer: Focusing on the changes in the gold
standard, the impact of novel therapies on treatment
and the new drugs in development.
• Non-small cell lung cancer: Focusing on the launch
of novel therapies into the arena; are they dramatically
changing the way NSCLC is treated?
• Colorectal cancer: Focusing on the evolution of
new treatment regimens, the development of new
formulations and advances in cancer vaccines.
• Prostate cancer: Focusing on current hormonal
therapies, the treatment of hormone refractory prostate
cancer and improvements in screening.
• Renal cancer: With up to 9 new launches by 2012, renal
cancer is in an exciting stage of development.
www.espicom.com/canrep
Page 12 ©
Espicom Business Intelligence
CNS Drug News
ReGen provides results of small-scale zolpidem study
ReGen Therapeutics has reported the results of a small-scale study that
is part of its clinical programme designed to explore the antidormancy
effect of zolpidem.
This was a double-blind, Phase IIa study in 20 conscious, fully-
perceptive ambulant patients having various debilities as a
consequence of brain damage. It was performed in collaboration
with ReGen's subsidiary, Guildford Clinical Pharmacology Unit, and
investigators at the Walko Medical Centre in Springs, South Africa,
where the antidormancy effect of zolpidem was first discovered.
The study compared various single doses of a novel sublingual spray
formulation (2.5, 5 and 10mg) with an existing tablet formulation
(10mg) in terms of the onset and degree of sedation. It also looked for
preliminary signs of efficacy, although the study was small and only
single doses of drug were given. The results indicate that:
• the 2.5mg spray regimen was no more sedative than placebo;
• the 5 and 10mg spray regimen induced sedation in a dose-
responsive manner;
• the spray showed a faster onset of action (sedative effect) than
the tablet; and
• the 5mg spray induced the same peak level of sedation as the
10mg tablet (15 vs 90 minutes, respectively).
According to ReGen, the fact that a spray is absorbed faster and more
completely than tablets will enable patients to control the effect more
accurately. Furthermore, as a dose of 2.5mg caused no more sedation
than placebo, it may be possible that repeated 2.5mg spray doses will
show efficacy without undue sedation.
Based on these results, the company now has the confidence to
continue the development of novel zolpidem formulations for the
treatment of brain dormancy and is reviewing options to achieve this.
ImaRx proceeds with Phase I/II trial of SonoLysis+tPA
therapy in AIS
ImaRx Therapeutics has received approval from a Data and Safety
Monitoring Board (DSMB) to proceed with the second dose cohort
in its TUCSON (Transcranial Ultrasound in Clinical SONoLysis) study
evaluating SonoLysis plus tissue plasminogen activator (tPA) therapy
in patients with acute ischaemic stroke (AIS).
ImaRx' SonoLysis programme is focused on the development of
product candidates that involve the administration of its proprietary
MRX-801 microbubbles and ultrasound to break up blood clots and
restore blood flow to oxygen-deprived tissues with or without a
thrombolytic drug.
Initiated in January, the dose-escalation, Phase I/II trial is expected to
enrol a total of 72 patients in four successive cohorts, each receiving
an increasing dose of MRX-801 microbubbles, ultrasound and the
standard dose of tPA. The DSMB reviews the data from each cohort
before granting approval to enrol patients in the next successive
cohort utilising a higher dose of MRX-801 microbubbles. ImaRx
expects to complete enrolment in this trial in the first half of 2008.
For details of ImaRx receiving a grant to study changes in the
permeability of the blood-brain barrier with targeted microbubbles
and ultrasound, see General Development News, R&D Update.
6th September 2007
CNS Drug News
Anxiolytics/Sleep Disorders
Product News
FDA sets PDUFA action date for indiplon capsules
The FDA has accepted Neurocrine Biosciences' resubmission of its
NDA for indiplon 5 and 10mg capsules for the treatment of insomnia
and has set a PDUFA action date of 12th December.
Editor's note: in June, Neurocrine resubmitted its NDA for indiplon
5 and 10mg capsules for the treatment of insomnia in both adult
and elderly patients to the FDA (see CNS 164). Indiplon, which was
licensed from DOV Pharmaceutical in 1998, is a non-narcotic, non-
benzodiazapine agent that acts on a specific site of the GABA-A
receptor and potentiates the action of GABA. While other drugs also
act on this receptor, indiplon's mechanism is unique in that it has
been shown to bind more selectively to the specific subtype of GABA-
A receptors within the brain that are believed to be responsible for
promoting sleep.
Agreement News
Tikvah signs licensing deal with P2D for LY156735
Tikvah Therapeutics has signed a licensing agreement with Phase
2 Discovery (P2D), a drug-development company affiliated with
researchers at the University of Cincinnati School of Medicine,
Department of Psychiatry, for worldwide rights to develop and
Antidepressants
R&D Update
TCA discovery may lead to more effective drugs
Researchers at Oregon Health & Science University (OHSU) have
identified a new mechanism by which tricyclic antidepressants (TCAs)
inhibit neurotransmitter transporters. Reported in the 23rd August
issue of Nature (2007;448:952-956), the discovery may improve the
design of new antidepressants that are more effective than currently-
marketed TCAs, which have been prescribed for decades, but have
been largely supplanted by selective serotonin reuptake inhibitors
because of their lack of specificity.
The researchers began their studies with the goal of understanding
how TCAs interact with their clinical target, sodium-coupled
neurotransmitter transporters. Disorders such as depression, epilepsy,
autism or obsessive-compulsive disorder can result from impaired
function of sodium-coupled neurotransmitter transporters, therefore
these molecules are the target of a variety of drugs, including TCAs.
However, it has been difficult to understand precisely how these
molecules function and interact with drugs, as the transporters
found in humans are not amenable to study. Instead, the researchers
focused on a sturdier transporter in bacteria that functions similarly.
That molecule, called LeuT, is used by the bacterium, Aquifex aeolicus,
which thrives in superheated deep-sea vents. LeuT transports leucine
across the bacterial membrane.
6th September 2007 ©
Espicom Business Intelligence
ANXIOLYTICS/SLEEP DISORDERS / ANTIDEPRESSANTS
commercialise LY156735 for the treatment of circadian rhythm,
sleep disorders and depression. Tikvah will also explore additional
indications for LY156735 through its own research and development
efforts in special subpopulations, and other general conditions of
sleep deprivation and/or insomnia, among others.
P2D acquired LY156735 from Eli Lilly in 2001. Under its own IND
application, P2D has generated substantial Phase II data demonstrating
statistically significant improvement in both objective and subjective
sleep measures. Pilot clinical studies, which were conducted by
P2D in response to the unique receptor binding profile of LY156735,
suggest that improved efficacy in standard measures of sleep may be
possible compared to another melatonin agonist. Further, in patients
with severe insomnia, LY156735 significantly decreased latency to
persistent sleep compared to placebo. Efficacious results were also
obtained in pilot clinical studies where jet lag was induced by a time
shift in an aerospace temporal isolation clinical laboratory unit.
In receptor binding studies, LY156735 has equal or better affinity
for 5-HT2c receptors as agomelatine, a molecule that acts as an
antidepressant, in part, through interaction with melatonin receptors
and 5-HT2 receptors. The potential antidepressant actions of LY156735
have been shown in a preclinical rodent model of antidepressant
activity.
P2D will be transferring its open IND application for LY156735 to
Tikvah, which will then assume responsibility for the further clinical
development and commercialisation of the compound, which will be
known as TIK-301.
The team explored how the TCA, clomipramine, which had been
found to be a potent inhibitor of LeuT, attached to the bacterial
transporter. X-ray crystallography was used to develop a detailed
structure of clomipramine attached to LeuT. Furthermore, how two
other TCAs, desipramine and imipramine, attached to LeuT was also
analysed.
One plausible way for a drug to interfere with a transporter's function
is by physically blocking the part of the molecule that binds to
the molecule to be transported. The steady-state kinetic data and
crystallographic studies revealed, however, that clomipramine and the
other TCAs do not attach to the same site on the transporter as leucine.
Rather, they plug into a cleft in a different part of the transporter and
lock it into a conformation that traps leucine, preventing it both from
passing through and being released. This cleft is on the region of the
transporter that juts outside the cell. Similar findings were reported
in an article published in the 9th August online edition of Science
(10.1126/science.1147614) by researchers at New York University (NYU).
They found that desipramine binds LeuT in the same cleft, but the two
groups diverge in their conclusions about the relevance of the TCA
site in LeuT to the antidepressant site in the human neurotransmitter
transporters. The NYU team argues that it is identical, whereas the
OHSU researchers are more cautious, suggesting that the TCA site is
different and probably located 'deeper' in the human transporter,
close to or overlapping the substrate site. Nevertheless, the concept
Page 13
PSYCHOTIC DISORDERS
that a molecule binding to an allosteric site may inhibit a transporter
by stabilising an occluded or locked state is one that has not previously
been described.
The OHSU team hypothesised that the TCA molecules slowed the
release of leucine from the transporter. Indeed, it was found that the
transporter released leucine approximately 700-times slower when
clomipramine was attached. This study is thought to define a new
principle for the inhibition of this class of sodium-coupled transporters
and the discovery of the new mechanism may spur the development
Psychotic Disorders
R&D Update
Lilly's LY2140023 shows antipsychotic activity in
humans
The results of an investigational, Phase II study have demonstrated
that Eli Lilly's LY2140023, a selective agonist for metabotropic
glutamate 2/3 (mGlu2/3) receptors, has antipsychotic activity.
In this double-blind, placebo-controlled, proof-of-concept trial,
which was published in the 2nd September online edition of Nature
Medicine (10.1038/nm1632), a total of 196 patients with schizophrenia
were randomly assigned to four weeks of treatment with either
LY2140023 (40mg twice daily), Zyprexa (olanzapine; 15mg daily) as
an active control, or placebo. All participants were hospitalised to
ensure patient safety and tapered off from any pretrial antipsychotic
medications (no therapeutically-stable patients were included in the
trial). In all, 118 patients completed four weeks of the planned study
treatment.
It was found that treatment with LY2140023 or olanzapine resulted in
a statistically significant improvement in PANSS total score (primary
outcome) compared to placebo (-20.8, p<0.001; -26.7, p<0.001;
respectively). Both groups showed a rapid response, within one
week. After four weeks of treatment, both the LY2140023 (32 per cent,
p<0.001) and olanzapine (41.2 per cent, p<0.001) groups demonstrated
significantly greater response rates compared to the placebo group
(3.2 per cent). Additionally, a mean 0.51kg weight reduction from
baseline was observed in the LY2140023 group. A moderate, but
statistically significant weight gain was observed in the olanzapine
group (0.74kg, p=0.017) relative to the placebo group.
Results showed that the placebo arm experienced the highest rate of
study discontinuation due to lack of efficacy, however, discontinuation
due to adverse events (AEs) was not significantly different across the
three treatment groups (p=0.66).
Overall, LY2140023 40mg twice daily was found to be safe and well
tolerated, with most AEs being mild-to-moderate in severity and not
treatment limiting. The most common treatment-emergent AEs in
the LY2140023 group were insomnia, affect lability (p=0.038), nausea,
headache, somnolence and blood creatine phosphokinase increase.
The AE profile of LY2140023 did not include prolactin increase or
worsening of extrapyramidal symptoms. Although mood lability
seems to represent the most important potential AE, this outcome
was observed primarily at one clinical site. In the olanzapine group,
treatment-emergent AEs included elevation in blood triglyceride
levels (p=0.005), insomnia, weight gain (p=0.034), somnolence,
akathisia, agitation and periodontitis (p=0.03).
Page 14 ©
Espicom Business Intelligence
CNS Drug News
of improved inhibitors. In future studies, the OHSU researchers will seek
to isolate and crystallise the delicate human transporter for structural
studies to establish if the basic same inhibitory mechanism is at work.
Agreement News
Tikvah signs licensing deal with P2D for LY156735
For details, see Anxiolytics/Sleep Disorders, Agreement News.
LY2140023 is an investigational compound that is being developed
as a new treatment option for schizophrenia. It is an oral prodrug
that once administered, is metabolised to provide the active
mGlu2/3 receptor agonist called LY404039. Most currently-approved
antipsychotic medications work by affecting dopamine or serotonin,
but for LY2140023, the active substance, LY404039, is thought to work
by reducing the presynaptic release of glutamate in brain regions
where mGlu2/3 receptors are expressed.
According to Lilly, these data provide compelling new evidence
that mGlu2/3 receptor agonists have antipsychotic properties and
may provide a completely new therapeutic approach for treating
schizophrenia and, perhaps, other neuropsychiatric disorders. Further
studies are either planned or ongoing to learn more about the safety
and effectiveness, including determining an optimal therapeutic dose
for LY2140023.
Duke study uncovers clues about possible OCD
mechanism
Duke University Medical Center investigators have discovered that
mice with a genetic mutation that prevents their brain cells from
producing one key protein exhibited obsessive-compulsive disorder
(OCD)-like behaviour and when given a replacement dose of the
protein in a specific region of the brain or drugs used to treat humans
with the disorder, many of these mice seemed to get better. This
research, which was published in the 23rd August issue of Nature
(2007;448:894-900), may have uncovered important clues about a
possible mechanism for OCD.
In their experiments, the researchers focused on the striatum, an
area that controls the planning and execution of movement, as well
as other cognitive functions. In normal brains, a protein known as
SAPAP3 is crucial for nerve signals to travel from one nerve cell to
another across the synapse. This protein is produced at high levels
in the cells that make up the striatum. When the researchers looked
closely at the brain cells of the mutant mice, they found that there
were defects in the synapses. When they returned the protein into
the striatum of the mutant mice, the synaptic defects were repaired
and their OCD-like behaviours subsided. This is thought to be the first
direct evidence that a synaptic defect in the striatum caused these
OCD-like behaviours.
The researchers also found that selective serotonin reuptake inhibitors
(SSRIs) reduced anxiety levels and suppressed the over-grooming
in the mutant mice, further suggesting that what they observed
in mice may also be analogous to human OCD. While SSRIs are the
most commonly-prescribed drug for humans with OCD, they are
only effective for approximately half of the patients, suggesting that
many pathways involving different neurotransmitters are likely to be
6th September 2007
CNS Drug News PSYCHOTIC DISORDERS

involved. Duke researchers are currently looking for additional gene

variations that may affect how nerve signals cross synapses, as well as Market An expanding
beginning studies to determine if the gene mutant they discovered in forecasts and market, a

BiOequivalent generiC drugs in Brazil

mice plays a role in humans with OCD. trend analysis! growing
Corcept raises funds to advance Corlux population,
Corcept Therapeutics has reported a US$10.1 million private equity
a regulatory
financing, the proceeds from which are to be used to conduct the regime supportive of the
next Phase III trial evaluating Corlux (mifepristone) for the treatment of
the psychotic features of psychotic depression. The funds will also be generics sector, robust
used to conduct studies to extend and confirm the results of its recent domestic production and
study of Corlux for the prevention of antipsychotic-induced weight
gain, to continue development of its new chemical entities and for many untapped opportunities.
general corporate purposes, including working capital. Is Brazil the place for generic
AstraZeneca initiates Phase IIb trial of AZD3480 for companies to be?
cognitive deficits in schizophrenia
The world’s major emerging
AstraZeneca has initiated a Phase IIb trial of AZD3480 (TC-1734) for economies are attracting much
cognitive deficits in schizophrenia, for which there is no product investment and interest. Brazil is not
currently approved. The company entered into an exclusive global
licence and research collaboration agreement for this Targacept
least among them, and it is easy to see
compound in December 2005. why with a population of 189 million
and a GDP of US$978 billion in 2007.
In the double-blind, placebo-controlled study, which is being
conducted in the US and Canada, approximately 400 patients taking
atypical antipsychotics will be randomly assigned to one of three dose Key areas addressed:
groups of AZD3480 or placebo over a 12-week period. The primary • 5-year market forecast to 2012
outcome measure is the MATRICS cognitive test battery, which • The generics market in context
includes assessments of cognitive functions across nine different
domains; secondary measures include life functioning, such as
• Review of the product registration
performance in day-to-day tasks and social skills. The trial is expected procedure
to complete by the end of 2008. • Pricing issues and reimbursement
• Political, legal and economic
AZD3480 was designed to target select neuronal nicotinic receptors
and has been evaluated in 12 clinical trials, to date, in approximately assessment
540 subjects. In a previous Phase IIb trial conducted by Targacept in • Insightful review of 20 major
OppOrtunities and Challenges fOr

age-associated memory impairment, AZD3480 achieved statistically domestic and foreign players in
significant results on all of the primary endpoints, reflecting improved
cognitive performance by memory-impaired older adults. A Phase IIb
the market
trial in Alzheimer's disease is also ongoing. • Detailed product registration data
• Who produces what?
Product News
AstraZeneca's Seroquel XR approved in the All this and more can be found in
Netherlands this new 200-page management
report, published in April 2007
The Netherlands' regulatory authority, MEB (Medicines Evaluation
Board), has approved AstraZeneca's Seroquel XR (quetiapine)
Extended-Release Tablets, a once-daily medicine for the treatment
of schizophrenia in adult patients. With Seroquel XR, which was Includes A weAlth
approved for the treatment of schizophrenia in the US in May (see
CNS 163), patients can achieve a dose within the recommended range of InformAtIon
from the second day of treatment, plus the MEB approval also includes
relapse prevention in the long-term treatment of schizophrenia. not AvAIlABle In
AstraZeneca will proceed with the mutual recognition procedure,
seeking similar approvals across Europe.
englIsh elsewhere!
The approval was based on clinical trials evaluating effectiveness
and safety at doses of 400, 600, and 800mg/day, in acute treatment,
relapse prevention, and in a non-inferiority study of acute efficacy
and safety when switching from the original formulation to Seroquel www.espicom.com/brazilgen
6th September 2007 ©
Espicom Business Intelligence Page 15
ANALGESICS/ANAESTHETICS
XR. In the studies, Seroquel XR showed its potential as a once-daily
treatment for both acute and clinically-stable schizophrenia patients,
with the effective dose range reached within two days of starting
treatment; the data demonstrated that this range is between 400 and
800mg/day.
Beyond schizophrenia, ongoing clinical studies of Seroquel XR cover
bipolar disorder, major depressive disorder and generalised anxiety
disorder.
Risperdal receives FDA approvals in children and
adolescents
On 22nd August, the FDA approved Risperdal (risperidone) for the
treatment of schizophrenia in adolescents aged 13 to 17 years, as well
as for the short-term treatment of manic or mixed episodes of bipolar I
disorder in children and adolescents aged ten to 17 years.
This is the first FDA approval of an atypical antipsychotic drug to
treat either disorder in these age groups. Until now, there has been
no approved drug for the treatment of schizophrenia available for
paediatric use and only lithium has been approved for the treatment
of bipolar disorder in adolescents aged 12 years and over. The FDA
first approved Risperdal in 1993, for the treatment of schizophrenia
Analgesics/Anaesthetics
R&D Update
Cymbalta reduces pain in fibromyalgia patients; sNDA
submitted to FDA
New data presented at MYOPAIN 2007, the Seventh World Congress
On Myofascial Pain Syndrome and Fibromyalgia Syndrome, held from
19th to 23rd August, in Washington DC, suggest that patients with
fibromyalgia treated with Eli Lilly's Cymbalta (duloxetine) 60 or 120mg
experienced a greater reduction in pain severity beginning one week
after starting duloxetine than those taking placebo, as measured by
the Brief Pain Inventory Average Pain Score (BPI). Furthermore, Lilly
has submitted an sNDA to the FDA for Cymbalta, for the management
of fibromyalgia. The submission is based on data from approximately
1,400 patients in five clinical trials.
The study, which included patients with and without depression, also
showed greater improvements in patients taking duloxetine than in
those taking placebo in scores on the PGI-I. At three months, patients
treated with duloxetine 60 or 120mg/day showed a significantly
greater reduction in pain and improvement in PGI-I scores compared
with those taking placebo. At three months, more patients treated
with either duloxetine 60 or 120mg showed a significantly greater
reduction in pain, as measured by a 30 per cent improvement in
baseline BPI scores (50.7 and 52.1 per cent, respectively) compared
with patients taking placebo (36 per cent).
At six months, patients taking duloxetine 60 or 120mg maintained
reduced BPI scores and patients taking 120mg had improved PGI-I scores
compared with those taking placebo. Furthermore, at the end of the
six-month trial, more patients treated with duloxetine 60 or 120mg
showed a response to treatment, defined as a 50 per cent reduction
of baseline BPI scores (32.6 and 35.9 per cent of patients, respectively),
compared with patients taking placebo (21.6 per cent).
Page 16 ©
Espicom Business Intelligence
CNS Drug News
in adults. The drug was later approved for the short-term treatment
of acute manic or mixed episodes associated with bipolar I disorder
in adults, and the treatment of irritability associated with autistic
disorder in children and adolescents aged five to 16 years. Risperdal
is marketed in the US by Janssen Pharmaceutica and promoted by
McNeil Pediatrics (both Johnson & Johnson).
The efficacy of Risperdal in the treatment of schizophrenia in
adolescents was demonstrated in two short-term (six to eight weeks),
double-blind, controlled trials involving more than 430 adolescents. All
patients were experiencing an acute episode of schizophrenia at the
time of enrolment. Treated patients generally had fewer symptoms,
including a decrease in hallucinations, delusional thinking and other
symptoms of their illness.
The efficacy of Risperdal in the treatment of manic or mixed episodes
in children or adolescents with bipolar I disorder was demonstrated
in a three-week, randomised, double-blind, placebo-controlled,
multi-centre trial involving 160 children and adolescents who were
experiencing a manic or mixed episode. Treated patients generally
had fewer symptoms, including a decrease in their elevated mood and
hyperactivity, and other symptoms of their illness. Drowsiness, fatigue,
increase in appetite, anxiety, nausea, dizziness, dry mouth, tremor and
rash were among the most common side effects reported.
Discontinuation rates over six months were similar among the groups
(45.3 and 46.3 per cent for duloxetine 60 and 120mg vs 50 per cent for
placebo). Adverse event (AE)-related discontinuation was significantly
higher in patients taking 120mg (26.5 per cent), but not in the 60mg
(15.3 per cent) group, as compared with placebo (13.2 per cent).
Discontinuations due to lack of efficacy were not statistically different
among treatment groups.
AEs were similar to those seen in prior duloxetine studies. In this study,
the most common AEs (occurred at a rate of >=5 per cent and at least
twice the rate of placebo) included nausea, dry mouth, constipation,
somnolence, fatigue, insomnia, decreased appetite, hyperhydrosis,
cough, tremor, rash and weight increase.
Acura secures funds for Phase III trial of OxyADF
Tablets
Acura Pharmaceuticals has entered into a securities purchase
agreement with an investor group that is expected to raise net cash
proceeds to the company, after expenses relating to closing the
transaction, of approximately US$14.5 million.
The company plans to utilise a portion of the net proceeds to fund
Study 105, a pivotal Phase III trial of OxyADF (oxycodone+niacin)
Tablets, its lead product candidate utilising Aversion Technology.
This is a randomised, double-blind, placebo-controlled, multi-centre,
repeat-dose study of the safety and efficacy of OxyADF Tablets for the
treatment of acute, moderate-to-severe postoperative pain following
bunionectomy surgery in adult patients.
It is a three-arm trial comparing two dose levels of OxyADF Tablets
to placebo, with study medication administered to patients every six
hours for 48 hours following the onset of moderate-to-severe pain
following bunionectomy surgery. Study 105 is targeted to enrol 135
patients per arm (approximately 405 patients in total).
6th September 2007
CNS Drug News ANALGESICS/ANAESTHETICS

M onoclonal
As previously reported, Acura has executed a clinical trial development
agreement with a contract research organisation and commenced
preliminary Study 105 start-up activities. Now that new funding has

a ntibodies :
been secured, the company intends to proceed with enrolment in the
study. Acura believes that the completion of Study 105 is critical to a
505(b)(2) NDA submission for OxyADF Tablets.

Meda completes acquisition of MedPointe what the future ANTICANCER PRODUCTS

Meda AB has completed its acquisition of MedPointe for a final holds • Abegrin
MedImmune
purchase price of SKr 5,229 million, with consolidation of the company • ACA 125
starting immediately (see CNS 167). New shareholders in Meda include After years of anticipation Cell Control Biomedical
the Carlyle Group, the Cypress Group and other US investors, which and encouraging responses • adecatumumab
will have a combined shareholding in Meda of approximately 7 per Micromet/Merck KGaA
to pathfinder products, • Antibody 3F8
cent. With the acquisition, Meda will have full marketing coverage in monoclonal antibodies are MSKCC
both the US and Europe, with revenues of approximately SKr 9 billion.
now set to realise their true • BB-10901
Neuromed raises funds to accelerate development of
clinical and commercial ImmunoGen

pain treatments
potential. But what are the •Virexx BrevaRex
prospects for the products • catumaxomab
Neuromed Pharmaceuticals has completed a series E financing of
that will lead the market? Fresius Biotech/TRION Pharma
• CNT0328
US$53.3 million, which will allow the company to accelerate the Centocor
development of its drugs to treat pain, including NMED-1077 (OROS HUGE POTENTIAL • Cotara
Hydromorphone), a product for chronic pain that is in Phase III While large pharma companies Peregrine Pharma
development. predictably take aim at the largest • daclizumab
treatable populations (breast cancer, PDL BioPharma/Roche
Neuromed recently acquired the US marketing rights to NMED- colorectal disease, NHL, leukaemia), • epratuzumab
there is an abundance of niches Immunomedics
1077, an extended-release formulation of hydromorphone, from • ertumaxomab
ALZA (Johnson & Johnson). Current formulations of hydromorphone for monoclonal antibody therapy
Fresius Biotech/TRION Pharma
marketed in the US are immediate release, requiring dosing several applications and a staggering • galiximab
times per day. NMED-1077 employs the OROS PUSH-PULL osmotic number of potential disease targets. Biogen Idec
delivery system to release hydromorphone at a controlled rate over an Smaller developer companies • HA20/IMMV-106
extended period. are likely to become more visible Immunomedics
as their products move closer to • HuMax-EGFr
regulatory approval. Genmab
Neuromed is also evaluating two pathways for the development of • ipilimumab
new classes of oral pain drugs. In collaboration with Merck & Co, the Bristol-Myers Squibb
That is why this new management • KW-2871
company is researching compounds that are designed to block the
report, published in April 2007 is Kyowa Pharmaceutical
N-type calcium channel, a target linked to pain signal transmission.
essential for everyone working in • matuzumab
Separately, Neuromed is also developing T-type calcium channel
the field. The report covers over EMD Pharma/Merck/Takeda
blockers for the treatment of acute and chronic pain, as well as other
30 leading compounds originating • MDX-060
potential disorders such as epilepsy and hypertension. Medarex
from the largest blue-chip
multinationals to smaller developer • ofatumumab
Cannasat to commence Phase I study of CAT 310 companies. Genmab
• oregovomab
Unither
Health Canada has approved Cannasat Therapeutics' clinical trial KEY EVALUATION FOR EACH • Rencarex
application for a Phase I study of CAT 310, its cannabinoid-based Wilex Centocor
PRODUCT
product that is designed to help manage neuropathic pain and other • SGN-30
It is vital that new compounds can
disorders. Seattle Genetics
be seen in the wider competitive/ • ticilimumab
development landscape. For that Pfizer/Amgen
This is a randomised, single-dose, crossover study comparing two reason we have established a • volociximab
different formulations of the drug in normal healthy male volunteers. unique competitor analysis based PDL BioPharma
The primary objectives of the trial are to evaluate the safety, tolerability on each of the following criteria: • zanolimumab
and pharmacokinetics of the CAT 310 prototypes, with enrolment in Genmab/Merck KGaA
Canada expected to begin in early October. • Novelty/rationale for mechanism
of action RHEUMATOLOGY
Icagen raises funds via Pfizer investment • Proof of concept/clinical data PRODUCTS
• Management/clinical expertise • belimumab
• Competition within the Human Genome Sciences/GSK
Icagen has completed the previously-reported sale of 2,688,172 shares • certolizumab pegol
marketplace
of common stock to Pfizer at a price of US$1.86 per share, resulting in UCB
• Risks associated with developing a
gross proceeds to the former of approximately US$5 million. Icagen • golimumab
drug within a therapeutic class Centocor/Schering Plough
has an option to sell up to an additional US$10 million of common
stock to Pfizer at the time of exercise, subject to certain terms and • HuMax CD-20
conditions, at any time during the 18 months following the execution
Order your copy today Genmab
• tocilizumab
of the purchase agreement. www.espicom.com/mab Chugai/Roche

6th September 2007 ©

Espicom Business Intelligence Page 17
ANALGESICS/ANAESTHETICS
The purchase agreement was completed in conjunction with the
formation of a collaboration between Icagen and Pfizer for pain and
related disorders. After deducting transaction expenses payable by
the company, Icagen intends to use the net proceeds from this private
placement to fund its research and development programmes and
otherwise for general corporate purposes.
TorreyPines initiates multiple-dose tezampanel trial
TorreyPines Therapeutics has initiated a multiple-dose, Phase I trial to
evaluate the safety, tolerability and pharmacokinetics of tezampanel.
Tezampanel, an AMPA/kainate (AK) receptor antagonist that
selectively binds to certain AK receptors to potentially block the
transmission of pain signals, has been administered in single doses
to more than 300 patients and healthy adults. Data from this trial will
support the continued development of tezampanel for the treatment
of migraine, as well as allow TorreyPines to consider expanding the
compound's development into additional chronic pain conditions.
The double-blind, placebo-controlled trial will be conducted at
one centre in the US. Approximately 30 healthy male and female
volunteers, between the ages of 21 and 55 years, will be enrolled
in sequential, dose-escalating cohorts and receive once-daily
subcutaneous (sc) doses of placebo or tezampanel 40, 70 or 100mg for
four consecutive days.
These same dose strengths, given as a single-dose sc injection,
are currently being evaluated by TorreyPines in a Phase IIb trial of
tezampanel for acute migraine that has completed enrolment; the
company is on track to report top-line results in the fourth quarter of
this year.
In five placebo-controlled, Phase IIa trials, tezampanel demonstrated
proof-of-concept in multiple pain models. In a placebo- and active-
controlled trial in patients with acute migraine, the compound,
administered intravenously, achieved statistical significance on all
primary and secondary endpoints traditionally required for regulatory
approval. These endpoints included pain relief at two hours, pain-free
at two hours, and relief of nausea, photophobia and phonophobia.
Zolmitriptan nasal spray effective for cluster
headache
The results of a study published in the 28th August issue of Neurology
(2007;69:821-826) have indicated that zolmitriptan nasal spray is safe
and effective at rapidly treating cluster headaches.
The double-blind trial involved 52 people with cluster headache
who used zolmitriptan nasal spray 5 or 10mg, or placebo to treat 151
separate cluster headache attacks. It was found that 63 per cent of
people treated with the drug at the higher dose reported headache
relief at 30 minutes, compared to 50 per cent of those taking the lower
dose of zolmitriptan nasal spray and 30 per cent in the placebo group.
Furthermore, the 10mg dose worked as quickly as ten minutes in
some patients. Side effects were mild and no serious adverse events
were reported during the study.
Zolmitriptan is currently marketed as Zomig by AstraZeneca,
which sponsored this research. According to study author, Dr Alan
M Rapoport, from the David Geffen School of Medicine at the
University of California, Los Angeles, while the FDA has not approved
zolmitriptan nasal spray for use in cluster headaches, it may someday
be considered a first-line therapy.
Page 18 ©
Espicom Business Intelligence
CNS Drug News
Anesiva completes enrolment for Phase III Zingo trial
in adults
Anesiva has completed enrolment in a Phase III study of Zingo
(lidocaine) powder intradermal injection system to reduce the pain
associated with peripheral venous access procedures in adults.
The study has enrolled 699 patients undergoing intravenous
cannulation or venipuncture procedures at multiple centres in the US.
Patients have been randomised to receive treatment with either Zingo
or placebo approximately one to three minutes prior to the peripheral
venous access procedure.
Zingo, a fast-acting topical, needlefree system for local analgesia, was
approved by the FDA on 16th August, to reduce the pain associated
with venous access procedures, such as intravenous insertions or
blood draws, in children aged three to 18 years (see CNS 168). Anesiva
expects to report results from the adult trial in October, with the goal
of utilising the data to file an sNDA for the use of Zingo in adults.
Cadence completes enrolment in Phase III trial of iv
acetaminophen
Cadence Pharmaceuticals has completed patient enrolment in a
pivotal Phase III trial to evaluate its investigational product candidate,
intravenous (iv) acetaminophen, for the treatment of acute pain
following gynaecologic surgery.
Referred to as the IV APAP 301 Study, this randomised, double-blind,
placebo-controlled trial has enrolled a total of 331 subjects at 27 sites
throughout the US. Patients were treated with either iv acetaminophen
or placebo in the 48-hour period following gynaecologic surgery.
The primary endpoint of the trial is analgesic efficacy, measured
by reduction in pain intensity, compared to placebo. According to
Cadence, with enrolment completed two months ahead of schedule,
the company is on track to report top-line results of this study in early
2008.
Furthermore, Cadence has provided an update on its clinical
development programme for iv acetaminophen, which consists
of three pivotal Phase III efficacy trials, two safety studies and two
pharmacokinetic (PK) studies, as follows:
Pivotal Phase III efficacy trials Enrolment status
Treatment of pain following gynaecologic Completed
surgery (IV APAP 301 Study)
Treatment of fever in adults Ongoing
Treatment of fever in adults comparing iv and Ongoing
oral administration
Other trials Enrolment status
Adult PKs Completed
Adult safety Initiation in fourth quarter of 2007
Paediatric PKs Ongoing
Paediatric safety Initiation in fourth quarter of 2007
The company anticipates completing enrolment in the two remaining
planned Phase III efficacy trials of iv acetaminophen by the end of
2007. Additionally, Cadence's licensor for iv acetaminophen, Bristol-
Myers Squibb, is conducting a randomised trial of the product for
marketing purposes in Europe in patients undergoing total hip
replacement surgery. Cadence expects that data from this trial may
6th September 2007
CNS Drug News
be available in 2008, however, it does not plan to rely on this trial as
a pivotal efficacy study for its NDA submission. Assuming successful
completion of the planned clinical trials, Cadence expects to submit
a 505(b)(2) NDA to the FDA in the second half of 2008, requesting
marketing approval of iv acetaminophen for acute pain and fever in
adults and children.
Recruitment completed for Sativex Phase III trial in
MS neuropathic pain
For details, see Neurodegenerative Disorders, Multiple Sclerosis - R&D
Update.
Allergan/ExonHit compound to begin clinical trials
For details, see Neurodegenerative Disorders, Other Neurodegenerative
Disorders - R&D Update.
Product News
Daiichi Sankyo obtains additional indication for
fentanyl injection in Japan
As of 23rd August, Daiichi Sankyo Propharma has obtained approval
in Japan for an additional paediatric indication for fentanyl injection
0.1 and 0.25mg.
Fentanyl injection is used in analgesia and sedation, as well as
in anaesthesia and as an anaesthetic adjunct, but its use was
contraindicated in Japan for paediatric patients aged two years and
under because its safety in this group had not been established.
However, because of the urgent clinical needs in this area, a physician-
led Phase III trial was conducted in paediatric patients. On the basis of
the results, the additional indication in paediatric patients, including
infants aged two years and under, was filed for approval in September
2006.
FDA approves Watson and Actavis' generic Duragesic
products
On 20th August, Watson Pharmaceuticals received final FDA approval
of its ANDA for fentanyl transdermal system in 25, 50, 75 and 100mcg/
hour strengths. The system is a generic equivalent to ALZA's (Johnson
Anti-Epileptics
R&D Update
Study provides clues to origin of Lafora disease
For a century, scientists have known that Lafora disease is a progressive
and deadly form of epilepsy caused by a build-up of carbohydrates
in the brain. Although this type of epilepsy has been well described
in patients, researchers have been at a loss to explain precisely why,
on a molecular level, neurons begin to accumulate toxic amounts of
carbohydrate.
However, research published in the 30th July issue of the Journal of
Cellular Biology (2007;178:477-488) has offered a hint about the nature
of this malfunction. A team at the University of California, San Diego
6th September 2007 ©
Espicom Business Intelligence
ANTI-EPILEPTICS
& Johnson) Duragesic, which is indicated for the management of
persistent, moderate-to-severe chronic pain that requires continuous,
around-the-clock opioid administration for an extended period of
time and cannot be managed by other means such as non-steroidal
analgesics, opioid combination products or immediate-release
opioids. Watson's product was launched immediately.
Actavis (via its acquisition of Abrika Pharmaceuticals) also received
US clearance for its therapeutic equivalents of Duragesic in these
strengths on the same date, with Lavipharm Group and Mylan
Technologies having previously received approval of their versions.
Mylan and ALZA are currently the only companies listed for an
approved 12.5mcg/hour product. Actavis began distribution
immediately.
Agreement News
Cephalon acquires rights to Amrix
Cephalon has signed an agreement to acquire North American rights
to Amrix (cyclobenzaprine hydrochloride extended-release capsules)
from ECR Pharmaceuticals.
Under the terms agreed, Cephalon will acquire the rights to Amrix for
US$100 million cash and could also make future cash payments to ECR
upon the achievement of certain cumulative net sales milestones. The
transaction is expected to be accretive in 2008 and thereafter. Amrix
was developed by Eurand for ECR using its proprietary Diffucaps
technology. Eurand, as the licensor and exclusive manufacturer
of the product, will now work with Cephalon to support the
commercialisation of the product in the US. Eurand will receive royalty
payments from Cephalon on Amrix sales.
Amrix is a once-daily, extended-release version of cyclobenzaprine,
the active ingredient in Johnson & Johnson's Flexeril. Two dosage
strengths of Amrix (15 and 30mg) were approved by the FDA in
February, for short-term use as an adjunct to rest and physical
therapy for relief of muscle spasm associated with acute, painful
musculoskeletal conditions. Amrix provides relief from muscle spasm
comparable to that with cyclobenzaprine taken three-times daily and
currently has market exclusivity until the first quarter of 2010. There
is also a pending US patent application that contains claims directed
to the formulation of the product. Cephalon expects to launch the
product early in the fourth quarter.
has shown that humans, plants and protozoa all seem to rely on the
same basic cellular machinery to solve the problem of carbohydrate
build-up. The paper outlines the common mechanism that humans
and other organisms use to purge excess carbohydrates, as well as
how this information could help to develop a treatment for Lafora
disease.
Product News
Questcor approves new strategy for HP Acthar Gel
Questcor Pharmaceuticals' Board of Directors has approved a new
strategy and business model for HP Acthar Gel, a natural form
of adrenocorticotropic hormone, which may affect its use in the
Page 19
EATING DISORDERS / GENERAL DEVELOPMENT NEWS
treatment of certain diseases, including infantile spasms (IS) and
multiple sclerosis (MS). Specifically, Questcor will initiate a new pricing
model, create an expanded safety net for patients using Acthar and
provide a group of medical science liaisons to work with healthcare
providers who are administering the product.
Acthar is currently approved in the US for the treatment of MS
exacerbations and other conditions. No drug is approved in the US
for the treatment of IS, however, pursuant to guidelines published
by the American Academy of Neurology and the Child Neurology
Society, many child neurologists use Acthar to treat infants afflicted
with this condition. In June 2006, Questcor submitted an sNDA to the
FDA and is currently pursuing formal Agency approval for Acthar in
Eating Disorders
R&D Update
Data support Histalean's use in obese women under
50 years of age
Obecure has reported the preliminary results of a Phase II trial
designed to evaluate the efficacy and safety of Histalean (betahistine;
formerly OBE101) for the treatment of obesity. According to the
company, the results suggest a strong gender and age effect, and
support the potential of the drug as a breakthrough anti-obesity
agent in women aged 50 years or younger.
Histalean is comprised of betahistine, an H1 receptor agonist and
partial H3 receptor antagonist that is approved and marketed
worldwide, except in the US, for the treatment of vertigo. Obecure is
repurposing betahistine for the treatment of obese individuals and for
other weight management indications. The double-blind, placebo-
controlled study included 281 patients (males and females aged 18
to 65 years) with a body mass index ranging from 30 to 40, and was
conducted at 19 sites across the US. Subjects were randomised into
one of four groups comparing the safety and efficacy of Histalean 16,
32 or 48mg/day versus placebo, over the 12-week treatment period.
Top-line results show that although there was weight loss in many
of the patients, there were no statistically significant differences
among any of the treatment arms versus placebo. However, a post
hoc segmentation analysis revealed an important finding regarding
the effect of age and gender on drug response. Analysis of the
subpopulation consisting of females, aged 50 years or less, in the per-
protocol cohort demonstrated a substantial difference between the
General Development News
R&D Update
Memory commences Phase I programme for R4996/
MEM 63908
Memory Pharmaceuticals has dosed the first subject in the single
ascending-dose study of its Phase I programme for R4996/MEM
63908, a partial agonist of the nicotinic alpha-7 receptor. Compounds
acting on this receptor could be beneficial in the treatment of
Alzheimer's disease and schizophrenia, as well as other psychiatric
Page 20 ©
Espicom Business Intelligence
CNS Drug News
the treatment of IS. Previously, the FDA granted orphan designation
to HP Acthar Gel for this indication, therefore if Questcor is successful
in obtaining FDA approval for the IS indication, the company will also
qualify for a seven-year exclusivity period.
Questcor's new strategy is intended to create an economic model
that will allow it to support ongoing efforts to manufacture and
distribute Acthar, to conduct any FDA-required studies, to continue
the development of QSC-001, a unique, orally-disintegrating tablet
formulation of hydrocodone and acetaminophen for the treatment of
moderate-to-moderately severe pain, and to develop or acquire other
drugs or drug candidates for neurological disorders or rare diseases.
mean weight loss in the high-dose arm (48mg/day) versus the placebo
arm; the result showed a trend towards statistical significance (p=0.06
at eight weeks and p=0.146 at 12 weeks). The effect was even more
pronounced when the analysis was limited to non-hispanic women,
aged 50 years or younger. At the end of week 12, the 25 women on
Histalean 48mg had lost an average of 2.61kg (2.91 per cent) of their
weight, versus 23 women on placebo, who lost 0.4kg (0.43 per cent) of
their weight; this result was statistically significant (p=0.003).
However, the effect of ethnicity on drug responsiveness in the current
analysis is still inconclusive, since the number of hispanic women
in each study group was very small (four to five). Nevertheless, the
trajectory of weight loss in this high-dose group continued over the
entire study duration, up to and including the week 12 visit.
There were no drug-related serious adverse events (AEs) observed and
the incidence of AEs in the treatment arms was comparable to that
for patients in the placebo group. The only AE more common in the
treatment group was headache (<10 per cent).
Product News
FDA approves Caraco's generic Adipex-P
On 21st August, the FDA approved Caraco Pharmaceutical
Laboratories' ANDA for phentermine tablets 37.5mg, a bioequivalent
to Teva Pharmaceutical Industries' Adipex-P. Phentermine is
indicated only as short-term monotherapy for the management of
exogenous obesity. Caraco plans to market its product to the generic
pharmaceutical market immediately.
and neurological disorders. The randomised, double-blind,
placebo-controlled study will evaluate the safety, tolerability and
pharmacokinetics of ascending doses of R4996/MEM 63908 in healthy
adult male volunteers. The study will be conducted in Montréal,
Canada, under a clinical trial application that Memory filed with Health
Canada, and the company expects to complete it in the first quarter of
2008.
Furthermore, as part of the Phase I programme for R4996/MEM
63908, Memory is also planning to conduct a food interaction study in
healthy adult male volunteers, plus a randomised, placebo-controlled,
6th September 2007
CNS Drug News CONFERENCE LISTINGS

single-dose study in elderly male and female volunteers. R4996/
MEM 63908 is being developed as part of Memory's nicotinic alpha-7
receptor collaboration with Roche. Under the terms of the companies'
agreement, the initiation of this Phase I trial triggers a US$2 million
milestone payment from Roche.
ImaRx receives grant to study BBB permeability
ImaRx Therapeutics has received an approximately US$950,000 Phase
I STTR grant from the National Institute of Neurological Disorders and
Stroke to study changes in the permeability of the blood-brain barrier
(BBB) with targeted microbubbles and ultrasound over a two-year
period. Although vital for normal brain function, BBB impermeability
presents a problem when treating degenerative and malignant
disorders of the CNS.
Under the terms of this grant, ImaRx will evaluate whether
microbubbles and transcranial ultrasound can safely enhance drug
delivery across this barrier. ImaRx, in collaboration with Dr Thomas
Porter at the University of Nebraska Medical Center, will begin work
on the grant in the autumn.
For an update on ImaRx' TUCSON study, see Cerebrovascular
Disorders, R&D Update.

Conference Listings
CNS CONFERENCES - DECEMBER 2007
DATE CONFERENCE TITLE CONTACT TEL/FAX/E-MAIL
3-6 Molecular Mechanisms of Dr Rhian Hayward Tel: 44 122 369 6000
Neurodegeneration, St Mary's Parish, Fax: 44 122 369 6001
Antigua & Barbuda E-mail: rhian.hayward@abcam.com
7-8 Advances in Clinical Neuroimmunology, Prof Dr Jacek Losy Tel: 48 618 691 583
Poznan, Poland Fax: 48 618 691 583
E-mail: jlosy@amp.edu.pl
9-13 17th International Congress on CPO Hanser Service, Paulsborner Strasse Tel: 49 30 300 6690
Parkinson's Disease and Related 44, 14193 Berlin, Germany E-mail: berlin@cpo-hanser.de
Disorders, Amsterdam, the Netherlands
9-13 2007 Annual Meeting of the American American College of Tel: 1 615 324 2360
College of Neuropsychopharmacology, Neuropsychopharmacology, 545 Fax: 1 615 324 2361
Boca Raton, FL, US Mainstream Drive, Suite 110, Nashville, TN E-mail: acnp@acnp.org
37228, US
24-31 6th Annual Pulmonary, Infectious Sandra Barnhart Tel: 1 800 422 0711
Disease and Sleep Disorders Conference, Fax: 1 727 527 3228
Honolulu, HI, US E-mail: sandra@continuingeducation.net

NB: While every effort has been made to ensure that the above information is correct, CNS Drug News cannot accept any responsibility for any
decision taken on the information, which may be subject to change.

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6th September 2007 ©

Espicom Business Intelligence Page 21
COMPANY INDEX
COMPANY INDEX
Abrika Pharmaceuticals..................................................................................................19
Accera.......................................................................................................................................10
Actavis......................................................................................................................................19
Acura Pharmaceuticals....................................................................................................16
Allergan............................................................................................................................10, 19
ALZA.................................................................................................................................. 17, 19
Alzheimer’s Disease Cooperative Study................................................................... 5
Anesiva....................................................................................................................................18
AstraZeneca............................................................................................................11, 15, 18
Baxter International............................................................................................................ 5
Bayer........................................................................................................................................... 8
Biogen Idec..........................................................................................................................7, 8
Biopartners.............................................................................................................................. 8
Bioton......................................................................................................................................... 8
Bristol-Myers Squibb........................................................................................................18
Cadence Pharmaceuticals..............................................................................................18
Cannasat Therapeutics....................................................................................................17
Caraco Pharmaceutical Laboratories.......................................................................20
Cephalon................................................................................................................................19
Compugen............................................................................................................................... 8
Corcept Therapeutics.......................................................................................................15
Daiichi Sankyo......................................................................................................................19
DOV Pharmaceutical.........................................................................................................13
Duke University...................................................................................................................14
ECR Pharmaceuticals........................................................................................................19
Eisai.............................................................................................................................................. 6
Elan..................................................................................................................................... 6, 7, 8
Eli Lilly....................................................................................................................1, 13, 14, 16
Eurand......................................................................................................................................19
ExonHit Therapeutics.......................................................................................................10
Families of Spinal Muscular Atrophy........................................................................10
Group Health Cooperative of Puget Sound........................................................... 6
Guildford Clinical Pharmacology...............................................................................12
GW Pharmaceuticals........................................................................................................... 8
Helicon Therapeutics.......................................................................................................11
Icagen................................................................................................................................ 17, 18
ImaRx Therapeutics...................................................................................................12, 21
Inflazyme Pharmaceuticals...........................................................................................11
Janssen Pharmaceutica..............................................................................................6, 16
Johnson & Johnson........................................................................................ 6, 16, 17, 19
King’s College.......................................................................................................................10
Lavipharm Group...............................................................................................................19
Mayo Clinic............................................................................................................................... 3
McMaster University........................................................................................................... 9
Meda AB..................................................................................................................................17
Medicenna Ventures........................................................................................................... 9
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Page 22 ©
Espicom Business Intelligence
CNS Drug News
MedPointe.............................................................................................................................17
Memory Pharmaceuticals..............................................................................................20
Merck & Co.............................................................................................................................17
Merck KGaA.........................................................................................................................3, 8
Merck Serono.....................................................................................................................3, 8
Mylan Technologies..........................................................................................................19
Neuralstem............................................................................................................................11
Neurochem.........................................................................................................................4, 5
Neurocrine Biosciences...................................................................................................13
Neuromed Pharmaceuticals.........................................................................................17
New York University.....................................................................................................4, 13
Newron Pharmaceuticals................................................................................................. 3
Nymox Pharmaceutical..................................................................................................... 6
Obecure..................................................................................................................................20
Oregon Health & Science University........................................................................13
PDL BioPharma...................................................................................................................... 7
Pfizer..............................................................................................................................6, 17, 18
Phase 2 Discovery..............................................................................................................13
Protox Therapeutics............................................................................................................ 9
Questcor Pharmaceuticals.............................................................................................19
Ranbaxy Laboratories........................................................................................................ 6
ReGen Therapeutics.........................................................................................................12
Renovis....................................................................................................................................11
Roche........................................................................................................................................21
Shanghai Wanxing Bio-pharmaceuticals...............................................................11
Sinobiomed...........................................................................................................................11
Targacept................................................................................................................................15
Teva Pharmaceutical Industries.............................................................................8, 20
Tikvah Therapeutics..................................................................................................10, 13
TorreyPines Therapeutics...............................................................................................18
Transition Therapeutics..................................................................................................... 6
University of California.............................................................................................18, 19
University of Cincinnati...................................................................................................13
University of Edinburgh..................................................................................................11
University of Leeds.............................................................................................................. 9
University of Michigan.....................................................................................................11
University of Milan.............................................................................................................10
University of Nebraska.....................................................................................................21
University of North Carolina........................................................................................... 1
University of Santiago de Compostela................................................................1, 12
University of Washington.............................................................................................1, 6
Veterans Affairs Puget Sound Health Care System............................................. 6
Walko Medical Centre......................................................................................................12
Watson Pharmaceuticals................................................................................................19
Weill Cornell Medical College........................................................................................ 6
6th September 2007
CNS Drug News
COMPOUND INDEX
AC-1202....................................................................................................................................10
acetaminophen.................................................................................................... 18, 19, 20
Adipex-P..................................................................................................................................20
Alzhemed................................................................................................................................. 4
Amrix........................................................................................................................................19
Aricept........................................................................................................................................ 6
AZD-103..................................................................................................................................... 6
AZD3480.................................................................................................................................15
betahistine.............................................................................................................................20
Biferonex................................................................................................................................... 8
cannabidiol.............................................................................................................................. 8
CAT 310....................................................................................................................................17
CGEN-54.................................................................................................................................... 8
clomipramine................................................................................................................13, 14
Corlux.......................................................................................................................................15
cyclobenzaprine.................................................................................................................19
Cymbalta.................................................................................................................................16
daclizumab.............................................................................................................................. 8
desipramine..........................................................................................................................13
donepezil.................................................................................................................................. 6
duloxetine..............................................................................................................................16
Duragesic................................................................................................................................19
EHT/AGN001..........................................................................................................................10
ELND-005................................................................................................................................. 6
fentanyl....................................................................................................................................19
galantamine............................................................................................................................ 6
Gammagard........................................................................................................................5, 6
Histalean.................................................................................................................................20
HP Acthar Gel...........................................................................................................8, 19, 20
hydrocodone........................................................................................................................20
hydromorphone.................................................................................................................17
imipramine............................................................................................................................13
indiplon...................................................................................................................................13
interferon beta-1a............................................................................................................7, 8
IPL455,903..............................................................................................................................11
Ketasyn....................................................................................................................................10
lidocaine..................................................................................................................................18
The £2.4 billion UK generics market
Challenges fOr generiC
is one of the world’s largest in terms of
both size and generic penetration. In
2005 over 59% of prescriptions were
OppOrtunities and
dispensed as generics, accounting for
drugs in the uK
26% of the market value. But fierce
competition and price pressure are
turning up the heat. How will the
market continue to grow?
The report answers key questions such as:
• What is the estimated value of the UK generic market now
and in 2012?
• What is the current pricing and reimbursement situation for
generic drugs and how might it change?
• The market is set to grow over the next 5 years – what will be
the drivers?
• Which companies have marketing authorisation for
amlodipine and how does the generic compare to the brand?
• Major companies in the UK generics industry are merging
– will consolidation mean greater price competition?
www.espicom.com/ukgen
6th September 2007 ©
Espicom Business Intelligence
COMPOUND INDEX
LY156735..........................................................................................................................13, 14
LY2140023......................................................................................................................... 1, 14
MEM 63908.................................................................................................................... 20, 21
mifepristone..........................................................................................................................15
natalizumab........................................................................................................................7, 8
niacin........................................................................................................................................16
NMED-1077............................................................................................................................17
Nuvion....................................................................................................................................... 8
NXY-059...................................................................................................................................11
OBE101.....................................................................................................................................20
OxyADF............................................................................................................................16, 17
oxycodone.............................................................................................................................16
phentermine.........................................................................................................................20
QSC-001...................................................................................................................................20
quetiapine..............................................................................................................................15
R4996................................................................................................................................ 20, 21
Razadyne.................................................................................................................................. 6
Rebif............................................................................................................................................ 8
recombinant human kallikrein....................................................................................11
Risperdal.................................................................................................................................16
risperidone............................................................................................................................16
safinamide............................................................................................................................... 3
Sativex.................................................................................................................................8, 19
Seroquel...........................................................................................................................15, 16
sodium phenylbutyrate..................................................................................................10
TC-1734.....................................................................................................................................15
tetrahydrocannabinol........................................................................................................ 8
tezampanel...........................................................................................................................18
TIK-201......................................................................................................................................10
TIK-301......................................................................................................................................13
tramiprosate.......................................................................................................................4, 5
Tysabri....................................................................................................................................7, 8
visilizumab............................................................................................................................... 8
Zingo.........................................................................................................................................18
zolmitriptan...........................................................................................................................18
zolpidem.................................................................................................................................12
Zomig.......................................................................................................................................18
Key areas addressed:
• 5-year market forecast to 2012
for value
• The generics market in context
of the whole pharmaceutical
industry
• Pricing issues and
reimbursement
• Political, legal and economic
assessment
• Insightful review of 18 major
domestic and foreign players in
the market
• Detailed listing of 18 leading
products including prescription
data, price comparisons and
marketing authorisations
• Focus on developing generic
markets for statins and proton
pump inhibitors
Page 23
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