CNS Drug News

Issue No. 178 17th January 2008

R&D Highlights Can AD symptoms be reversed

Study offers new clue to cause of PD within minutes?
Page 3 The beginning of 2008 has seen a potentially groundbreaking
development in Alzheimer's disease (AD) research - a study has
Baylor study suggests new treatments for HD documented marked improvement in AD within minutes of the
administration of a therapeutic molecule.
Page 5
The study, which was published in the 9th January online edition of
Addex’ ADX10059 fails to reduce acute anxiety in Phase the Journal of Neuroinflammation (10.1186/1742-2094-5-2), highlights
IIa study the importance of cytokines in AD and focused on TNF alpha in
particular. Normally, TNF alpha finely regulates the transmission of
Page 7 neural impulses in the brain, but in AD, the study authors hypothesised
that elevated levels of TNF alpha interfere with this regulation. To
Progress reported with new treatment mechanisms for reduce these elevated levels, patients received an injection of Enbrel
schizophrenia (etanercept), which was discovered by Immunex (Amgen) and jointly
developed with Wyeth.
Page 9
This therapeutic, which binds and inactivates excess TNF alpha, is
PRODUCT Highlights FDA approved to treat a number of immune-mediated disorders and
was used off-label in the new research. In the study, a dramatic and
unprecedented therapeutic effect in an AD patient was observed:
Forest/Merz file lawsuits for Namenda patent improvement within minutes following delivery of perispinal
infringement etanercept. While the article discusses one patient, many other
Page 4 subjects with mild-to-severe AD received the treatment, and all have
shown sustained and marked improvement.
Breckenridge/Taro settle litigation with Novartis over According to Dr Sue Griffin, of the University of Arkansas for Medical
generic Trileptal Sciences: “It is unprecedented that we can see cognitive and
Page 13 behavioural improvement in a patient with established dementia
within minutes of therapeutic intervention.” She believes that it is
imperative that the medical and scientific communities immediately
AGREEMENT Highlights undertake to further investigate and characterise the physiologic
mechanisms involved, adding that: ”Even though this report
Pfizer/Taisho finalise agreement for novel schizophrenia predominantly discusses a single patient, it is of significant scientific
drug candidate interest because of the potential insight it may give into the processes
involved in the brain dysfunction of Alzheimer's.”
Page 10
Despite the positive results and their potential impact on sales of
Janssen enters supply agreement for ER tramadol; Enbrel, Amgen has remained cautious in its response. In a statement
expands Fentanyl TAIFUN deal on the company's website, Amgen has commented: ''It is important
to note that the study published was a case study involving a single
Page 12 patient. This study was not supported nor endorsed by Amgen. While
Amgen and others have long recognized the potential for tumor
Sepracor enters deal for Bial’s anti-epileptic compound necrosis factor (TNF) inhibitors to have an effect on neurological
conditions, we have carefully examined this study and believe that
Page 14 at this time there is insufficient scientific data to support the use of a
TNF inhibitor as a means of treating Alzheimer's disease. Amgen will
EDITOR continue to review data on the use of Enbrel (etanercept) and other
Lucy Vann anti-inflammatory agents for the treatment of Alzheimer’s disease.''
CONTRIBUTING EDITORS As stated in Espicom's 4D Pharma, Enbrel has benefited from
Ros Smallman, Fiona Cowie, continuous development, leading to a number of new launches and
Matthew Dennis, Johanna Shiu, Andrew Way approvals in recent years. The product's sales growth has profited
PUBLISHER from its competitive profile and significant increases in the usage of
biologics in both rheumatology and dermatology settings. In 2006,
Eric Wigart Enbrel sales reached US$2,879 million and Espicom recently anticipated
Conditions of Sale that sales would increase to US$4,409 million by 2011. However, if these
• CNS Drug News must not be reproduced, abstracted, stored in a retrieval system or results are replicated and lead to an approval for AD, Amgen could see
Enbrel sales rocket.
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
Can AD symptoms be reversed within minutes?..................................................................1
NEURODEGENERATIVE DISORDERS.......................3
Parkinson's Disease - R&D Update........................................................3
Study offers new clue to cause of PD.....................................................................................3
Alnylam and collaborators receive MJFF grant to develop RNAi therapeutic for PD..........3
Product News........................................................................................3
Sun amends ANDA for generic Stalevo Tablets.....................................................................3
Alzheimer's Disease - R&D Update........................................................3
CoMentis reports positive Phase I data with beta-secretase inhibitor................................3
Prana completes Phase IIa trial of PBT2 in early AD..............................................................4
Pipex initiates Phase II trial of Coprexa for AD.......................................................................4
Product News........................................................................................4
Forest/Merz file lawsuits for Namenda patent infringement..............................................4
Eisai introduces new Aricept dose formulations for severe AD in Japan.............................4
Multiple Sclerosis - Product News.....................................................4
Biogen Idec/Elan provide update on Tysabri's utilisation, safety and exposure.................4
Other Neurodegenerative Disorders - R&D Update...........................5
Baylor study suggests new treatments for HD.....................................................................5
Amarin to commence Phase IIa trial with AMR-101 in AAMI...............................................5
Agreement News...................................................................................5
Yissum licenses small molecule for neurodegenerative diseases to Eucalyptus................5
Cerebrovascular Disorders...........................6
R&D Update.............................................................................................6
ReNeuron provides update on IND application for SC therapy trials...................................6
UCLA discovery offers promise for SCI patients.....................................................................6
Alseres concludes enrolment in Phase I/IIa trial of Cethrin for acute SCI.............................6
Study identifies new gene for CVT.........................................................................................6
Agreement News...................................................................................7
BrainStorm/Rutgers expand collaboration for spinal cord injury cure................................7
Anxiolytics/Sleep Disorders...........................7
R&D Update.............................................................................................7
Addex' ADX10059 fails to reduce acute anxiety in Phase IIa study......................................7
Ambien CR improves chronic insomnia in patients with co-morbid GAD...........................7
Somaxon plans Silenor NDA submission following mouse carcinogenicity study.............8
Product News........................................................................................8
Hemispherx addresses FDA questions on Ampligen NDA....................................................8
Antidepressants..............................................8
R&D Update.............................................................................................8
Rexahn raises funds for compound development................................................................8
Psychotic Disorders........................................9
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CNS Drug News
R&D Update.............................................................................................9
Progress reported with new treatment mechanisms for schizophrenia.............................9
Chromosome abnormality may increase autism risk; UCLA study identifies new
genetic link..............................................................................................................................9
Product News........................................................................................10
AstraZeneca submits sNDAs for Seroquel XR in bipolar mania and depression..................10
FDA approves additional dosage strengths of Shire's Vyvanse............................................10
Agreement News...................................................................................10
Addex/Merck forge deal over schizophrenia drug candidate..............................................10
Pfizer/Taisho finalise agreement for novel schizophrenia drug candidate.........................10
Analgesics/Anaesthetics................................11
R&D Update.............................................................................................11
Dosing commences in US Phase II trial of Innocoll's bupivacaine implant..........................11
Arcion raises funds to continue development of ARC-4558..................................................11
Zogenix raises funds for pain compound development.......................................................11
Product News........................................................................................11
Sugammadex NDA assigned FDA priority review status......................................................11
FDA accepts BEMA Fentanyl NDA for filing............................................................................12
Agreement News...................................................................................12
Janssen enters supply agreement for ER tramadol; expands Fentanyl TAIFUN deal..........12
Therapies to Treat Substance Dependence....12
R&D Update.............................................................................................12
Evotec successfully completes Phase I study with EVT 302..................................................12
Agreement News...................................................................................13
Alkermes enters agreement with Cilag for Vivitrol in Russia/CIS.........................................13
Anti-Epileptics................................................13
R&D Update.............................................................................................13
FDA grants ODD to Ovation's clobazam for LGS and Jazz' JZP-8 for recurrent ARS.............13
Amarin reports completion of preclinical nasal lorazepam study.......................................13
Product News........................................................................................13
Breckenridge/Taro settle litigation with Novartis over generic Trileptal............................13
Agreement News...................................................................................14
Sepracor enters deal for Bial's anti-epileptic compound......................................................14
Eating Disorders.............................................14
R&D Update.............................................................................................14
Neurogen opts not to advance NGD-4715 to Phase II testing..............................................14
Stimulation of brain CPT-1 decreases food intake and body weight...................................14
Orexigen reports 48-week results of Phase IIb Empatic trial...............................................14
Brain-imaging study offers new clues to overeating...........................................................15
Drugs used in Nausea & Vertigo.....................16
Product News........................................................................................16
Generic Kytril approved following patent expiry..................................................................16
Aloxi Capsules sNDA accepted for review by FDA..................................................................16
General Development News...........................16
R&D Update.............................................................................................16
XenoPort provides clinical trial update..................................................................................16
Lundbeck moves compound into clinical development but discontinues other................17
Researchers elucidate mechanisms behind fragile X syndrome..........................................17
Agreement News...................................................................................17
£4 million consortium investment to accelerate research into mental illness....................17
Medistem modifies licence agreement with ICM.................................................................17
COMPANY INDEX.................................................18
COMPOUND INDEX..............................................19
17th January 2008
CNS Drug News
NEURODEGENERATIVE DISORDERS
Parkinson's Disease - R&D Update
Study offers new clue to cause of PD
A glitch in the mechanism by which cells recycle damaged
components may trigger Parkinson's disease (PD), according to a study
by scientists at the Albert Einstein College of Medicine of Yeshiva
University.
Senior author, Dr Ana Maria Cuervo, previously showed that mutant
forms of alpha-synuclein (found in the 5 to 10 per cent of patients who
have familial PD) are poorly digested via autophagy and block the
breakdown of other substances. While these mutations are rare, other
modifications of alpha-synuclein (eg, phosphorylated and oxidised
forms) can be found in the brains of all PD patients.
In this study, which was published in the 2nd January online edition
of the Journal of Clinical Investigation (10.1172/JCI32806), Cuervo
and her colleagues looked at how several different modified forms
of alpha-synuclein affected autophagy in vitro and in tissue culture.
One particular modification of alpha-synuclein was found to interfere
with autophagy: the compound created by the interaction of alpha-
synuclein with dopamine (DA).
Alpha-synuclein molecules modified by DA bound tightly to the
lysosomal membrane, but got stuck there and were not effectively
transported into the lysosome. As a result, the alpha-synuclein
molecules altered by DA were poorly degraded and the presence of
these molecules on the lysosomal membranes also interfered with the
autophagic digestion of other compounds.
The researchers propose that inhibition of autophagy caused by DA's
alteration of alpha-synuclein could explain the selective death of DA-
producing nerve cells in PD. Indeed, interference with autophagy
has also been implicated in other neurodegenerative disorders,
including Alzheimer's disease. It is thought that by devising strategies
for boosting autophagy in nerve cells or suppressing the chemical
reactions that interfere with the process, for example by lowering
alpha-synuclein expression, researchers may be able to treat patients
who have these conditions.
Alnylam and collaborators receive MJFF grant to
develop RNAi therapeutic for PD
Alnylam Pharmaceuticals is part of a research team that has
been awarded a new US$3.8 million grant from the Michael J Fox
Foundation (MJFF) to further develop an RNA interference (RNAi)
therapeutic for the treatment of Parkinson's disease (PD). The four-
year grant, which is part of the Foundation's LEAPS (Linked Efforts to
Accelerate Parkinson's Solutions) initiative, was awarded to Alnylam,
Mayo Clinic, and the Parkinson's Institute and Clinical Center of
Sunnyvale, CA.
The LEAPS award will fund research focused on the further
development of an RNAi therapeutic targeting alpha-synuclein.
Continued research will look at whether reducing levels of alpha-
synuclein in the brain can slow or halt the progression of PD. Alnylam
and collaborators have designed and synthesised small interfering
RNAs (siRNAs) that are specific to the alpha-synuclein gene. Previously-
reported in vivo data show that siRNAs administered into the brain
17th January 2008 ©
Espicom Business Intelligence
NEURODEGENERATIVE DISORDERS
were effective in reducing alpha-synuclein levels, thus suggesting
the applicability of RNAi therapeutics as a possible disease-modifying
therapy for PD.
Product News
Sun amends ANDA for generic Stalevo Tablets
Orion has been informed that Sun Pharmaceutical Industries has
amended its ANDA with the FDA seeking authorisation to produce
and market generic versions of Stalevo Tablets (carbidopa+levodo
pa+entacapone) 25/100/200 and 37.5/150/200mg in the US. Sun's
amendment to its ANDA involves a Paragraph IV challenge to Orion's
US Patent No. 5,446,194.
Stalevo is an enhanced levodopa treatment originated by Orion
and marketed in the US by its exclusive licensee, Novartis, for the
treatment of Parkinson's disease. Sun previously filed Paragraph IV
certifications against Orion's US Patent Nos. 6,500,867 and 6,797,732,
and Orion subsequently sued Sun (November 2007) in the US for
patent infringement. Of the six Orion patents listed in the FDA's
Orange Book, three have not received Paragraph IV certifications from
Sun (US Patent Nos. 4,963,590, 5,112,861 and 5,135,950), and the latest
of these expires on 31st October 2010. Together with Novartis, Orion is
currently evaluating its legal options to protect its rights.
Alzheimer's Disease - R&D Update
CoMentis reports positive Phase I data with
beta-secretase inhibitor
CoMentis has completed a Phase I study of its proprietary, orally-
bioavailable, small-molecule beta-secretase inhibitor, CTS-21166,
which is being developed as a disease-modifying treatment for
Alzheimer's disease (AD).
This was designed as a dose-escalation study to assess the safety,
tolerability, pharmacokinetics (PKs) and pharmacodynamics of CTS-
21166 in healthy volunteers following intravenous administration.
Forty-eight subjects received one of six different doses or placebo,
and the study measured levels of CTS-21166 and levels of amyloid beta
(Abeta) in the plasma.
The results indicate that CTS-21166 is safe and well tolerated.
Pharmacodynamic proof of activity was achieved as subjects
displayed a robust, sustained and dose-related reduction in plasma
Abeta in both area-under-curve (AUC) reduction and peak reduction,
with effects lasting over 72 hours. Single-dose administration of CTS-
21166 produced a >60 per cent reduction of plasma Abeta measured
either by AUC over 24 hours or as a maximal reduction relative to pre-
dose levels. The highest doses of CTS-21166 further demonstrated a
sustained reduction in AUC that was >40 per cent over 72 hours.
CTS-21166 demonstrated good PK properties, including dose-
proportional exposure and very low inter-subject PK variability. In
addition, the PK profile is consistent with once-daily dosing and will
support a commercial product. Inhibition of beta-secretase reduces
Abeta production and could slow the progression of AD. CTS-21166
is the first of several highly-selective, potent and orally-active beta-
Page 
NEURODEGENERATIVE DISORDERS
secretase inhibitors being developed by CoMentis that show positive
efficacy in preclinical models of AD. CoMentis anticipates launching
a Phase II study of oral CTS-21166 in AD patients during 2008, plus in
an effort to accelerate the development of this platform, the company
is in advanced partnership negotiations with multiple parties and
expects to complete a transaction during the first quarter of the year.
Prana completes Phase IIa trial of PBT2 in early AD
Prana Biotechnology has completed its Phase IIa trial of PBT2 in
patients with early Alzheimer's disease (AD). This double-blind,
placebo-controlled study exploring the safety and tolerability of PBT2,
also measured the drug's effects on the mechanism and progression
of the disease, by investigating biomarkers of AD, as well as
measures of cognition. All patients have completed their final clinical
assessment. The data are being analysed and results are expected in
the first quarter of 2008.
Pipex initiates Phase II trial of Coprexa for AD
Pipex Pharmaceuticals has initiated a Phase II trial of its lead
anticopper drug candidate, Coprexa (oral tetrathiomolybdate), for the
treatment of Alzheimer's disease (AD). The study is being led by the
clinical research group that first discovered and has most extensively
studied and published findings of elevated toxic free copper levels in
the serum of AD patients. The trial is also being partially supported by
a grant from the Italian Ministry of Health, which is expected to fund
approximately 30 per cent of the cost.
Coprexa is an oral, small-molecule agent that is highly specific for the
reduction of free copper in serum, the most toxic form of copper in
the body, and is thus ideally suited for the treatment of CNS diseases in
which abnormal serum and CNS copper homeostasis are implicated.
The double-blind, placebo-controlled, Phase II trial is intended to
enrol 150 mild-to-moderate AD patients who have elevated levels
of free copper. Patients will be randomised on a 1:1 basis to receive
either Coprexa plus an acetylcholineserase inhibitor or placebo plus
an acetylcholineserase inhibitor during the course of the study. The
primary endpoint is to evaluate cognition at 24 and 52 weeks utilising
the ADAS-Cog, while secondary endpoints will evaluate changes in
hippocampal volume measured by MRI, as well as other advanced
neuroimaging markers of AD progression. The study is being
conducted at four sites throughout Italy.
Product News
Forest/Merz file lawsuits for Namenda patent
infringement
Forest Laboratories and Merz have filed lawsuits in the US District
Court for the District of Delaware against several companies for
infringement of US Patent No. 5,061,703 (the '703 patent), which
relates to Forest's Namenda (memantine), an NMDA receptor
antagonist indicated for the treatment of moderate-to-severe
dementia of the Alzheimer's disease type. The defendants named in
the lawsuits include Barr Laboratories, Cobalt Laboratories (Cobalt
Pharmaceuticals), Lupin, Orchid Chemicals & Pharmaceuticals, Teva
Pharmaceuticals USA (Teva Pharmaceutical Industries), Upsher-Smith
Laboratories, Wockhardt, and related companies and subsidiaries
thereof.
The '703 patent expires in April 2010, however, Forest has applied for
patent term extension, which if granted, would extend this patent
until September 2013. As previously reported, Forest had received
Page  ©
Espicom Business Intelligence
CNS Drug News
notification from several companies that they had filed ANDAs with
Paragraph IV certifications to obtain approval to market generic
versions of Namenda (see CNS 177).
Editor's note: Forest markets memantine as Namenda in the US, whilst
Lundbeck markets the product as Ebixa, both under licence from Merz,
which markets it as Axura/Akatinol in a number of markets worldwide.
Eisai introduces new Aricept dose formulations for
severe AD in Japan
Eisai has introduced new dose formulations of Aricept (donepezil),
Aricept Tablet 10mg and Aricept D Tablet 10mg, for the treatment of
severe Alzheimer's disease (AD), in Japan.
On 23rd August 2007, Eisai obtained approval of additional efficacy
and dosage for Aricept in the treatment of severe AD, as well as
marketing authorisation for the new 10mg dose formulations, in
Japan. These new formulations were added to the National Health
Insurance drug price list as of 21st December.
Aricept, an acetylcholinesterase inhibitor developed by Eisai, is the
only approved prescription medicine for the treatment AD in Japan. In
the US, where it is co-promoted with Pfizer, Aricept received approval
for the treatment of severe AD in October 2006. Since then, this
indication has been approved in India, the Philippines, New Zealand,
Canada, Australia and Thailand.
Multiple Sclerosis - Product News
Biogen Idec/Elan provide update on Tysabri's
utilisation, safety and exposure
Biogen Idec and Elan have reported new data on the global utilisation,
safety and overall patient exposure of Tysabri (natalizumab). As of late
December, more than 21,000 patients were on commercial and clinical
therapy worldwide. To date, the safety data continue to support a
favourable benefit-risk profile for the drug.
According to data available to the companies as of late December:
• in the US, approximately 12,900 patients were on Tysabri
therapy commercially and approximately 2,500 physicians have
•
prescribed the therapy;
internationally, approximately 7,500 patients were on Tysabri
therapy commercially;
• in global clinical trials, approximately 700 patients were on
Tysabri therapy; and
• there have been no cases of progressive multifocal
leukoencephalopathy since re-launch in the US and launch
internationally in July 2006.
In addition, as of mid-December:
• cumulatively, in the combined clinical trial and post-marketing
settings, up to 30,900 patients have been treated with Tysabri;
and
• of those patients, up to 6,300 have received at least one year of
therapy with the drug.
Tysabri, which was discovered by Elan and co-developed with Biogen
Idec, is approved for relapsing forms of multiple sclerosis (MS) in
the US and relapsing-remitting MS in the EU. It is available in the US
through the TOUCH Prescribing Program; all US prescribers, infusion
17th January 2008
CNS Drug News
sites and patients receiving the drug are required to enrol in TOUCH.
Safety information is also collected through ongoing clinical trials and
registries, including TYGRIS (Tysabri Global ObseRvation Program In
Safety) and the pregnancy registry, making this the largest long-term
patient follow-up effort undertaken for any MS therapy. In addition to
the US and EU, Tysabri is also approved for MS in Switzerland, Canada,
Australia, New Zealand and Israel.
Other Neurodegenerative Disorders
- R&D Update
Baylor study suggests new treatments for HD
Working with fruit flies, researchers at the Baylor College of Medicine
have discovered a new mechanism by which the abnormal protein in
Huntington's disease (HD) causes neurodegeneration. They have also
manipulated the flies to successfully suppress that neurodegeneration,
which suggests potential treatments to delay the onset and
progression of the disease in humans.
HD is caused by a mutation in the gene for the huntingtin (htt)
protein that causes an abnormally long number of glutamine repeats
at one end of the protein. Previous studies had concentrated on the
toxicity that the abnormal protein produces by forming cell-clogging
aggregates in the nuclei of neurons, however, most studies in animals
had not involved introducing the gene for full-length htt; instead, they
involved only a fragment.
In experiments reported in the 10th January issue of Neuron
(2008;57:27-40), the researchers introduced the gene for full-length
abnormal human htt into the fruit fly, Drosophila, and studied its
early effects on neural function. They found that before the abnormal
protein produced any toxic effects in the nuclei of neurons, it caused
abnormally high transmission of neurotransmitters among neurons.
Besides abnormal synaptic transmission, mutant htt also caused
neurodegeneration and degeneration in the flies' motor ability. The
researchers found that they could suppress these abnormalities by
introducing other mutations into the fly genome that either reduced
neurotransmission or reduced the activity of calcium channels in the
membranes of neurons.
These findings unveil a mechanism of pathogenesis for expanded
htt that does not require its nuclear accumulation in detectable
amounts. Instead, it is thought that the increased neurotransmission
likely represents a mechanism of pathogenesis taking place at early
stages of disease progression. Furthermore, the results point to
increased synaptic transmission as a therapeutic target with the
potential of delaying HD onset and thus likely impacting disease
progression. According to the researchers, the ability to genetically
suppress the abnormal neurotransmission and neurodegeneration
further defines specific therapeutic targets and supports the idea
that calcium channel antagonists, and perhaps other inhibitors of
neurotransmission, offer an attractive therapeutic option due to their
specificity and wide usage.
Amarin to commence Phase IIa trial with AMR-101 in
AAMI
Amarin has received the necessary regulatory and ethical approvals
to commence a Phase IIa trial in age-associated memory impairment
(AAMI) with AMR-101 (ultra-pure ethyl-eicosapentanoic acid). The
company previously reported positive results from a preclinical
programme in memory and cognition using AMR-101.
17th January 2008 ©
Espicom Business Intelligence
NEURODEGENERATIVE DISORDERS
This double-blind, placebo-controlled study will enrol 96 patients
with AAMI, who will be randomised to receive AMR-101 1, 2 or 4g, or
placebo twice daily over a six-week period. Efficacy will be assessed
by a computerised battery of cognition tests designed by Cognitive
Drug Research. The study is being conducted in the UK and patient
recruitment is expected to commence shortly, with initial results
anticipated in the second half of 2008.
Agreement News
Yissum licenses small molecule for
neurodegenerative diseases to Eucalyptus
Yissum, the technology transfer company of the Hebrew University of
Jerusalem, has licensed an orally-available small molecule for several
biological indications to Eucalyptus. The molecule, N-acetylcysteine
amide (AD4), is an antioxidant in development for the prevention and
treatment of Parkinson's disease (PD), Alzheimer's disease, multiple
sclerosis (MS) and other neurodegenerative diseases that are linked
to oxidative stress, plus has broader applications in biology. AD4 is
administered orally and able to cross the blood-brain barrier.
Under the terms agreed, Eucalyptus has acquired exclusive worldwide
rights to develop and commercialise the molecule. Yissum, together
with Ramot, the technology transfer company of Tel Aviv University,
and Mor Research Applications, the technology transfer company of
Clalit Health Services, will receive up-front and milestone payments
in accordance with development progress, plus royalties from sales of
final products.
Preclinical data showed the ability of AD4 to protect cells in culture
from oxidative damage. Furthermore, the molecule was shown to
protect neuronal cells from damage in rodent models of both PD
and MS. It is anticipated that the low toxicity of AD4, as evidenced in
the laboratory, together with its neuroprotective function and high
bioavailability, will make it highly suitable for the treatment of CNS
disorders.
Obesity
Drug DiscOveries:
What the future hOlDs
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While only recently identified as a
major health concern, obesity levels
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CEREBROVASCULAR DISORDERS
Cerebrovascular Disorders
R&D Update
ReNeuron provides update on IND application for SC
therapy trials
ReNeuron has provided an update on progress with its IND application
to the FDA to commence initial clinical trials in the US with its ReN001
stem cell (SC) therapy for stroke.
On 3rd December, the company revealed that it had submitted its
responses to the requests made by the FDA in respect of the original
IND application. ReNeuron has subsequently been notified that the
IND currently remains on clinical hold. While most of the substantive
issues raised by the Agency in the original IND hold letter have
been satisfactorily addressed in the amended IND package, there
is a small number of further hold issues that remain to be resolved.
The company intends to meet with the FDA shortly to discuss and
agree an approach to resolving these remaining issues in a timely
fashion. Indeed, based on the proof-of-concept, safety and product
manufacturing data package that it has and is continuing to build for
ReN001, ReNeuron remains confident that this therapy can be taken
into the clinic during 2008.
In the meantime, ReNeuron is continuing its preparations for the
clinical phase of development with its ReN001 therapy. These
preparations include continuing dialogue with regulatory authorities
in other key territories such as the UK, with a view to further clinical
trial applications in these territories in due course.
UCLA discovery offers promise for SCI patients
A University of California, Los Angeles (UCLA) study has shown that
the CNS can re-organise itself and follow new pathways to restore
the cellular communication required for movement. Published in the
January issue of Nature Medicine (2008;14:69-74), the discovery could
lead to new therapies for people with traumatic spinal cord injuries
(SCIs).
Using a mouse model, the researchers blocked half of the long
nerve fibres in different places and at different times on each side of
the spinal cord. They left untouched the spinal cord's centre, which
contains a connected series of shorter nerve pathways. The latter
convey information over short distances up and down the spinal cord.
Suprisingly, most of the mice regained the ability to control their legs
within eight weeks; they walked more slowly and less confidently than
before their injury, but still recovered mobility.
When the researchers blocked the short nerve pathways in the centre
of the spinal cord, the regained function disappeared, returning the
animals' paralysis. This step confirmed that the nervous system had
re-routed messages from the brain to the spinal cord via the shorter
pathways and that these nerve cells were critical to the animals'
recovery.
This study has identified cells that researchers can target in their
attempts to restore communication between the brain and spinal
cord. The UCLA team's next step will be to learn how to entice nerve
cells in the spinal cord to grow and form new pathways that connect
across or around the injury site, enabling the brain to direct these cells.
If the researchers succeed, the findings could lead to the development
of new strategies for restoring mobility following SCI.
Page  ©
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CNS Drug News
Alseres concludes enrolment in Phase I/IIa trial of
Cethrin for acute SCI
Alseres Pharmaceuticals has concluded enrolment in a Phase I/IIa trial
of Cethrin for acute spinal cord injury (SCI). A total of 48 subjects have
been enrolled at nine sites in the US and Canada. Interim reported
data from the trial have demonstrated encouraging safety and efficacy
results over a 30-fold dose range. The company expects to release
periodic updates of the data in 2008, following protocol-specified
patient evaluations, and plans to begin a placebo-controlled, Phase IIb
trial in acute SCI at sites in the US, Canada, Europe and other countries
in the first half of the year.
Cethrin, which has been granted orphan drug status in the US,
contains a proprietary protein that inactivates the action of Rho, a key
enzyme that prevents axon regeneration and recovery after an SCI.
In February 2005, enrolment began in the open-label, non-placebo-
controlled, dose-escalating, Phase I/IIa trial in subjects with acute SCI
at sites in the US and Canada. The study assessed five dose levels of
Cethrin from 0.3 to 9mg in both thoracic and cervical injuries.
The trial design includes a number of post-treatment evaluations of
the subjects for safety and efficacy, for up to one year after treatment.
The efficacy measurements assess changes in subjects' sensory
and motor functions, as well as overall recovery, as measured by the
American Spinal Injury Association (ASIA) Impairment Scale. Subjects
in the trial suffered a complete thoracic or cervical SCI and were
thus classified as an A on the ASIA Impairment Scale at the time of
enrolment into the study.
The six-month interim data on 37 of these subjects treated with doses
of up to 6mg indicate that 27 per cent of the Cethrin-treated subjects
improved from ASIA A to ASIA B or better. When subjects with cervical
injuries who were treated with Cethrin were analysed separately,
approximately 46 per cent exhibited a conversion rate from ASIA A
to ASIA B or better. Moreover, approximately 18 per cent of subjects
overall and 38 per cent of subjects with cervical injuries improved to
ASIA C or better over the six months, the hallmark of which is recovery
of some motor function. In subjects with cervical injuries, the interim
efficacy data also suggest that the response rate observed is dose-
dependent at doses up to 6mg.
To date, the safety and tolerability data for dose levels up to 6mg
indicate that Cethrin appears to be safe and well tolerated. There have
been no serious adverse events related to Cethrin as determined by
the investigators and the independent Data Safety Monitoring Board
(DSMB). There were two deaths of subjects enrolled in the trial, which
the DSMB and clinical investigators attributed to causes related to the
subjects' initial SCI, other injuries or pre-existing conditions, and not
related to Cethrin.
Study identifies new gene for CVT
Researchers have identified a new gene linked to cerebral venous
thrombosis (CVT). The study, which was published in the 8th January
issue of Neurology (2008;70:129-132), compared 78 people with CVT
in Germany to 201 healthy people. It was found that a variant of the
gene known as Factor XII C46T is more common in people with this
condition than in healthy people. A total of 16.7 per cent of those with
CVT had the gene variant, compared to 5.5 per cent of those without
the condition. The results were the same after adjusting for factors
that could affect blood clotting, such as age, gender, smoking and
use of oral contraceptives. Study author, Dr Christoph Lichy, of the
17th January 2008
CNS Drug News
University of Heidelberg, believes that although these results need
to be confirmed, it appears that people with CVT should be tested for
this gene and be considered for use of blood-thinning medication to
prevent future blood clots.
Agreement News
BrainStorm/Rutgers expand collaboration for spinal
cord injury cure
BrainStorm Cell Therapeutics has expanded its collaboration with
Rutgers, The State University of New Jersey in an effort to cure spinal
cord injuries through the company's adult stem cell (SC) research.
Anxiolytics/Sleep Disorders
R&D Update
Addex' ADX10059 fails to reduce acute anxiety in
Phase IIa study
Addex Pharmaceuticals has revealed that ADX10059 did not reduce
acute anticipatory anxiety in a small Phase IIa study in patients
with dental anxiety, however, some signs of anxiolytic activity were
observed. The development of ADX10059 for migraine and gastro-
oesophageal reflux disease (GORD) is continuing as planned.
This double-blind, placebo-controlled trial was conducted at
specialist UK dental centres. It included 50 patients with moderately-
severe dental anxiety who underwent a routine dental procedure.
Patients received a single dose of ADX10059 250mg or placebo
60 minutes prior to a dental procedure. Anxiety was measured at
specific time points before, during and after the procedure using the
Visual Analogue Scale of anxiety (VAS anxiety). Skin conductance, an
objective measure of the physiological response to stress and patient
ratings of study medication effectiveness were also collected.
The primary endpoint, VAS anxiety at 60 minutes after dosing
(immediately prior to the start of the dental procedure), did not show
a statistical difference between ADX10059 and placebo (mean VAS
4.81 vs 4.67cm, respectively). However, signs of anxiolytic activity were
observed in the trial. Although the differences were not statistically
significant, patients in the ADX10059 group had lower increases in skin
conductance at all time points from 30 minutes post-dose, suggesting
a lower level of stress. In addition, patients rated ADX10059 as more
effective, with 56 per cent rating it as good or excellent, compared
to 30 per cent of those who received placebo. Also, 15 per cent of
patients receiving ADX10059 rated it as poor, compared to 39 per cent
of patients receiving placebo; statistical analyses of the patient ratings
are ongoing. ADX10059 was generally well tolerated in the study and
there were no serious adverse events.
ADX10059 is a negative allosteric modulator of metabotropic
glutamate receptor 5. Fenobam, a product with a similar mechanism
of action, demonstrated efficacy in patients with generalised anxiety
disorder after repeated administration in studies conducted in the
1980s. Although ADX10059 did not demonstrate efficacy in this
clinical model of acute anticipatory anxiety, Addex believes that the
compound has potential for other types of human anxiety, especially
where therapeutic administration of a longer duration is necessary.
Addex will complete analysis of the data from this study before
17th January 2008 ©
Espicom Business Intelligence
ANXIOLYTICS/SLEEP DISORDERS
BrainStorm is developing adult SC therapeutic products, derived
from autologous bone marrow (BM) cells, for the treatment of
neurodegenerative diseases. The NurOwn patent-pending technology
allows for the differentiation of BM-derived SCs into functional
neurons and astrocytes, as demonstrated in animal models.
This study, combined with BrainStorm's unique differentiation process,
uses SCs derived from human BM that are expanded and induced to
secrete neurotrophic factors.
Preliminary evidence has indicated that transplantation of
differentiated human BM-derived SCs improved the motor behaviour
of subjects used in animal studies, as measured by motor and walking
analysis.
announcing further plans for ADX10059 in the anxiety indication.
The company noted that although VAS anxiety is a well-recognised
way to measure response to anxiolytics, it is a subjective measure and
consequently, can make interpretation of drug activity challenging,
particularly in smaller studies.
Addex intends to start Phase IIb testing of ADX10059 in both migraine
and GORD in mid-2008, as planned. In preparation for the Phase IIb
programme, ADX10059 formulation work is nearing completion and
the first galenic formulation of the product is expected to enter a
confirmatory Phase I programme around the end of the first quarter
of the year. An unformulated version of ADX10059 (ie, the active
pharmaceutical ingredient in capsule) met primary endpoints in
separate proof-of-concept, Phase IIa studies in migraine and GORD in
2007.
Ambien CR improves chronic insomnia in patients
with co-morbid GAD
Results from a new study have shown that sanofi-aventis' Ambien CR
(zolpidem extended-release [ER]) tablets CIV provided improvement in
sleep onset, sleep maintenance and total sleep time (TST) for patients
with co-morbid chronic insomnia and generalised anxiety disorder
(GAD) compared to placebo. Zolpidem ER also improved sleep-related
next-day functioning measures.
This was a multi-centre, double-blind, parallel-group, randomised,
placebo-controlled trial in 381 adults aged 21 to 64 years with co-
morbid chronic insomnia and GAD. The study evaluated the overall
improvement of insomnia, as measured by TST, in patients treated with
zolpidem ER and the antidepressant, Lexapro/Cipralex (escitalopram),
compared to treatment with placebo and escitalopram. Patients
received zolpidem ER 12.5mg (n=191) or placebo (n=190) each night,
followed by escitalopram 10mg each day during the eight-week study,
followed by a one-week period of escitalopram only.
Researchers assessed treatment efficacy during clinic visits at weeks
one, two, four, six and eight, and through daily patient-reported
Morning Sleep Questionnaires (MSQ). The MSQ measured the primary
efficacy outcome of TST, in addition to measurements of sleep onset
latency, wake time after sleep onset, number of awakenings, quality of
sleep and sleep-related next-day functioning.
TST was increased in the zolpidem ER group throughout the study.
At week eight, such patients reported sleeping an average of 106
minutes more than baseline, while placebo-treated patients reported
Page 
ANTIDEPRESSANTS
sleeping an average of 68 minutes more (p<0.0001). On average,
zolpidem ER-treated patients reported falling asleep sooner and
exhibited improved sleep maintenance, based upon fewer night-time
awakenings and decreased wake time after sleep onset compared to
placebo-treated patients (p<0.0001). At week eight, the number of
night-time awakenings decreased in the zolpidem ER+escitalopram
group (-1.33+/-1.26) compared to the placebo+escitalopram group
(-0.76+/-1.02), and time to sleep onset was reduced by 55.1 (+/-67.3)
minutes with zolpidem ER, compared to a reduction of 26.8 (+/-58.7)
minutes with placebo (p<0.0001). In addition, patients reported
improvements in secondary measures relating to daytime functioning,
including morning energy, morning concentration and sleep impact
on daily activities.
Treatment was well tolerated during the study and adverse events
(AEs) were similar between treatment groups. AEs occurred in 76 per
cent of patients treated with zolpidem ER+escitalopram and 71 per
cent of the patients treated with placebo+escitalopram. The most
frequent AEs experienced by both treatment groups were nausea,
dizziness and fatigue. These AEs have been reported in previous
studies of both zolpidem ER and escitalopram, and are known to
be part of the safety profile of both treatments. One patient in each
treatment group experienced different serious AEs.
Somaxon plans Silenor NDA submission following
mouse carcinogenicity study
Somaxon Pharmaceuticals has completed a 26-week, transgenic
mouse carcinogenicity study of Silenor (doxepin). Based on the
results of this study and a review of such results with its consultant
toxicologists, Somaxon intends to proceed with the submission of an
NDA for Silenor, which is now estimated to occur by mid-February.
Somaxon has completed four successful Phase III trials of Silenor
for the treatment of insomnia. As previously disclosed, based
on a request from the FDA in May 2006, the company initiated a
Antidepressants
R&D Update
Rexahn raises funds for compound development
Rexahn Pharmaceuticals has raised net proceeds of US$6.8 million in
a private placement of its common stock and three-year warrants to
purchase its common stock for a group of accredited investors in Korea.
The company expects to raise an additional US$1.8 million in a second
tranche, which is scheduled to close on 29th February. The proceeds
will be used for general corporate purposes, including the company's
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preclinical programme for Silenor consisting of standard genotoxicity,
reproductive toxicology and carcinogenicity studies. The results of
the transgenic mouse carcinogenicity study will be included in the
company's planned NDA submission, which will also include the
results of reproductive toxicology studies that were completed in
June. In August, Somaxon initiated a two-year rat carcinogenicity
study and the company plans to submit the results of that study as a
post-approval commitment.
Product News
Hemispherx addresses FDA questions on Ampligen
NDA
Hemispherx Biopharma has formally submitted to the FDA detailed
responses to all of the 14 questions posed by the Agency concerning
the company's NDA for Ampligen (Poly I. Poly C12U) to treat chronic
fatigue syndrome (CFS). Hemispherx received the questions from the
FDA on 5th December, at which point the application was deemed by
the Agency as ''not sufficiently complete'' to permit substantive review
under 21 CFR 314.101(R). Consequently, the FDA's consideration of the
NDA was postponed, pending receipt of the company's answers to the
questions (see CNS 176).
With the exception of a topical product for skin cancer, no Toll-
like receptor-type compounds have yet received full regulatory
clearance; Ampligen is the first in this class of RNA molecules
now seeking commercialisation. A recent independent study
enumerated three primary causes of early death in CFS populations
at large (without administration of Ampligen) that may be
attributable to the disease: 1) cardiovascular events; 2) suicide; and
3) untreatable life-threatening malignancies/tumours. In response
to the FDA's questions, as well as within the body of its NDA,
Hemispherx has discussed how Ampligen may address these and
other high-risk aspects of CFS.
ongoing research and development programmes relating to a number of
compounds, such as Serdaxin. Rexahn intends to initiate Phase II trials for
Serdaxin, a compound for the treatment of depression, in 2008.
Serdaxin acts on the neurotransmission systems of serotonin and
dopamine, which are key controlling mechanisms of anxiety and
mood disorders. In animal models, the compound increased levels
of serotonin and dopamine in the brain, exhibited potent anxiolytic
activities, and induced significant active imaging changes in the rat
brain. Furthermore, Serdaxin did not disrupt learning and memory
functions unlike current anxiolytic drugs.
17th January 2008
CNS Drug News
Psychotic Disorders
R&D Update
Progress reported with new treatment mechanisms
for schizophrenia
All treatments for schizophrenia approved by the FDA have had
a single treatment mechanism at their core, the blockade of the
dopamine D2 receptor. However, the introduction of clozapine in
the 1980s suggested that other brain targets might complement the
blockade of dopamine D2 receptors to treat symptoms that failed to
respond to the typical antipsychotics. Indeed, new research related to
three new treatment approaches has been reported in the 1st January
issue of Biological Psychiatry.
In the first study (2008;63:86-91), a Georgetown University-led
research team tested a novel drug that inhibits the breakdown of
the transmitter, N-acetylaspartylglutamate (NAAG), which activates a
receptor that reduces schizophrenia-like behaviours in some animal
models. The findings indicate that this drug is effective in an animal
model of schizophrenia and support the conclusion that NAAG
peptidase inhibitors represent a breakthrough in the discovery of a
completely novel means of adjunct therapy for schizophrenia that is
analogous to the use of selective serotonin reuptake inhibitors for the
treatment of depression.
In the second article (2008;63:92-97), Chiba University researchers
and colleagues demonstrated that repeated administration of the
N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine
(PCP), decreased the density of alpha7 nicotinic receptors (alpha7
nAChRs) in the mouse brain, and that the novel alpha7 nAChR
agonist, SSR180711, could ameliorate PCP-induced cognitive deficits
in mice. These findings suggest that alpha7 nAChR agonists, including
SSR180711, could be potential therapeutic drugs for cognitive deficits
in schizophrenic patients.
Finally, in the third investigation (2008;63:98-105), University of
California researchers and colleagues found that the recently-
discovered 5-HT7 receptor might be of importance for understanding
certain aspects of schizophrenia. Their study focused on sensory input
processing, which is often impaired in schizophrenia, and found that
blockade of this particular serotonin receptor in mice alleviates this
impairment. The results indicate that atypical antipsychotics may
promiscuously exert some of their beneficial effects through the 5-
HT7 receptor, and suggest that further exploration of this receptor as a
treatment target may lead to more specific and better medications for
disorders such as schizophrenia.
Chromosome abnormality may increase autism risk;
UCLA study identifies new genetic link
A multi-institutional study involving Massachusetts General Hospital
researchers has identified a chromosomal abnormality that appears
to increase susceptibility to autism. The investigators, whose work
was published in the 9th January online edition of the NEJM (10.1056/
NEJMoa075974), found that a segment of chromosome 16 is either
missing or duplicated in approximately 1 per cent of individuals with
autism or related disorders, a frequency that is comparable to other
genetic syndromes associated with the disorder. Population studies
indicate that up to 90 per cent of cases of autism and autism spectrum
disorders (ASDs) have some genetic component, but only 10 per cent
can be attributed to known genetic and chromosomal syndromes.
17th January 2008 ©
Espicom Business Intelligence
PSYCHOTIC DISORDERS
Since several of those conditions involve deletions or duplications of
chromosomal segments, including an inherited deletion of a region
of chromosome 15, the investigators conducted a complete genome
scan of samples from the Autism Genetic Resource Exchange, which
contains DNA from families in which at least one child has autism or a
related disorder.
The scan of more than 1,400 affected individuals and a similar
number of their unaffected parents revealed that an identical region
of chromosome 16 was deleted in five individuals with an ASD, but
not in any of the parents, implying that the deletion had occurred
spontaneously and was not inherited. To confirm this observation,
clinical testing data from almost 1,000 patients from the Children's
Hospital Boston, approximately half of whom had been diagnosed
with autism or a related developmental delay, were evaluated.
Among those with a developmental disorder, five children had the
same deletion and in another four, the chromosome segment was
duplicated. Again, no abnormalities were seen in the DNA of children
without autism or developmental delay.
Confirmatory data were also obtained by colleagues from deCODE
genetics, who found the same deletion in three out of almost 300
individuals with an ASD, as well as in a few with other psychiatric or
language disorders. Among almost 20,000 members of the deCODE
database who had not been evaluated for language or psychiatric
disorders, the deletion was seen in only two individuals. Results from
the deCODE scan indicate that, while this chromosomal deletion
occurs in only 0.01 per cent of the general population, it is 100-times
more prevalent in those with ASDs.
These large, non-inherited chromosomal deletions are extremely rare,
so finding precisely the same deletion in such a significant proportion
of patients suggests that it is a very strong risk factor for autism.
The researchers are now pursuing more detailed genetic studies to
determine which genes in this region are responsible for this effect in
order to gain a better understanding of the underlying biology and
potential clues to therapeutic approaches.
In addition...
University of California, Los Angeles (UCLA) scientists have used
language onset as a tool for identifying a new gene linked to autism.
The research team also discovered that the gene is most active in brain
regions involved with language and thought. Interestingly, evidence
for the genetic link came from the DNA of families with autistic boys
rather than those with autistic girls.
The findings were published in the January issue of the American
Journal of Human Genetics (2008;82:150-159), which also featured
two studies from research teams at Yale University and Johns Hopkins
University that used different methods to pinpoint the same gene
(2008;82:160-164 & 165-173). The coincidences suggest that the gene,
called contactin-associated protein-like 2 (CNTNAP2), likely plays a key
role in the development of autism. According to Dr Daniel Geschwind,
the study's principal investigator, this gene may not only predispose
children to autism, but may also influence the development of brain
structures involved in language, providing a tangible link between
genes, the brain and behaviour.
Late language onset is a symptom shared by most children with
autism. In an earlier study, the UCLA investigators studied the DNA
of 291 families nationwide who had donated blood samples to the
Page 
PSYCHOTIC DISORDERS
Autism Genetic Resource Exchange. Each family had at least one
autistic child; youngsters who had never spoken were excluded. The
findings connected a specific region of chromosome 7 known as 7q35
to autism.
In the current study, the researchers scrutinised every gene in the
7q35 region using DNA samples from 172 families. They identified four
promising genes; one of the candidates was CNTNAP2. To verify their
findings, the scientists conducted a second test on a new group of 304
families. The CNTNAP2 gene showed up consistently, confirming its
implication in language development.
In a second approach, the researchers examined CNTNAP2's presence
in early brain tissue and discovered that the gene was most active in
developing brain structures involved in language and thought. In an
unexpected third finding, the scientists found that statistical evidence
for the gene was strongest in families with autistic boys.
Less of an association appeared in families with autistic boys and girls,
or in families with autistic girls only. Autism strikes boys three-times
as often as girls and it is thought that this finding may partly explain
why. The researchers' next step will be to identify more traits, such
as seizures or other symptoms, that will help them to track down
additional genes linked to the disorder.
Product News
AstraZeneca submits sNDAs for Seroquel XR in
bipolar mania and depression
AstraZeneca has submitted two separate sNDAs to the FDA for
once-daily Seroquel XR (quetiapine) Extended-Release Tablets to
seek approval for the treatment of manic and depressive episodes
associated with bipolar disorder.
Seroquel XR is currently approved in eight countries, including the
US, Canada and the Netherlands, for the acute and maintenance
treatment of schizophrenia in adults. The bipolar mania submission
is based on a clinical study of once-daily treatment with Seroquel XR
compared to placebo, with a primary endpoint of change in YMRS
total score (week three), in 316 patients with bipolar mania. Meanwhile,
the bipolar depression submission is supported by a clinical study of
once-daily treatment with Seroquel XR compared to placebo, with a
primary endpoint of change from baseline in MADRS total score after
eight weeks of treatment, in 280 patients diagnosed with bipolar
depression.
Doses of Seroquel XR administered in both the bipolar mania (400
to 800mg/day) and bipolar depression (300mg/day) studies were
comparable to the FDA-approved recommended doses for Seroquel
immediate-release tablets in those indications. Both studies met their
primary endpoint and it is expected that they will be presented at
major scientific congresses in 2008.
FDA approves additional dosage strengths of Shire's
Vyvanse
On 10th December, Shire received FDA approval for three additional
dosage strengths of the attention deficit hyperactivity disorder
(ADHD) treatment, Vyvanse (lisdexamfetamine dimesylate). Shire
expects the additional dosage strengths of 20, 40 and 60mg to
be available in retail pharmacies in the second quarter of 2008, to
supplement the existing 30, 50 and 70mg dosage strengths currently
available in pharmacies throughout the US.
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CNS Drug News
Vyvanse is currently approved in the US for the treatment of ADHD in
children aged six to 12 years. An sNDA for the drug, for the treatment
of ADHD in adults, is currently under review by the FDA.
Agreement News
Addex/Merck forge deal over schizophrenia drug
candidate
Addex Pharmaceuticals has entered into an exclusive worldwide
licence agreement with Merck & Co to develop ADX63365, an orally-
available drug candidate for the potential treatment of schizophrenia
and other undisclosed indications. Currently in preclinical
development, ADX63365 is a positive allosteric modulator (PAM) that
targets the metabotropic glutamate receptor 5 (mGluR5), which is
believed to be important as a target for the treatment of schizophrenia
and other conditions. The deal also includes mGluR5 PAM back-up
compounds discovered by Addex.
Under the terms agreed, Addex will receive US$22 million up-front
and is eligible for up to US$455 million in research, development,
regulatory and sales milestones for the first product developed for
two indications, plus up to US$225 million in additional development,
regulatory and sales milestones for a second product developed in
two indications.
Addex is eligible to receive royalties on the sales of any products
resulting from this collaboration. In addition, the company has an
option to co-promote in certain EU countries and will participate in
the joint oversight committee for further development that will be led
by Merck.
Preclinical research has shown that the activation of mGluR5 using
PAMs can act as an antipsychotic and reverse cognitive dysfunction
of schizophrenia. As a result, a product like ADX63365 could become
a first-line antipsychotic therapy that also improves cognitive
dysfunction, thereby offering advantages over other therapies on
the market or in development. On 3rd December, Addex announced
a separate collaboration with an affiliate of Merck (Merck Sharp &
Dohme Research) to discover and develop PAMs targeting mGluR4 for
the treatment of Parkinson's disease and other undisclosed indications
(see CNS 176).
Pfizer/Taisho finalise agreement for novel
schizophrenia drug candidate
Pfizer and Taisho Pharmaceutical have signed a definitive agreement,
which replaces the letter of intent previously signed between the
companies, for a worldwide (excluding Japan) collaboration to
research, develop and commercialise TS-032, a new schizophrenia
drug candidate discovered by Taisho that is currently in preclinical
development (see CNS 174).
TS-032 is a novel metabotropic glutamate receptor (mGluR) agonist
that may offer a new treatment option for CNS disorders. Although the
characteristics of mGluR are still only partly understood, this receptor
is believed to play a role in the transmission of glutamate and other
substances in the brain.
Abnormalities in the neurotransmission through mGluR may be one
cause for symptoms related to schizophrenia, as well as other CNS
disorders, and data show that mGluR agonists, such as TS-032, offer
potential as new treatments for schizophrenia.
17th January 2008
CNS Drug News
Through the definitive licence agreement, Taisho will grant exclusive
development and commercialisation rights outside of Japan for TS-
032 to Pfizer. Taisho will receive from Pfizer an initial payment of US$22
Analgesics/Anaesthetics
R&D Update
Dosing commences in US Phase II trial of Innocoll's
bupivacaine implant
The first in a series of planned Phase II trials to investigate Innocoll's
CollaRx bupivacaine surgical implant for the management of
postoperative pain has commenced dosing.
The implant is a biodegradable and fully-bioresorbable matrix of
purified fibrillar collagen impregnated with the local anaesthetic,
bupivacaine, which has been specifically developed and formulated
using Innocoll's proprietary CollaRx sponge technology. It is
under development in the US and Europe for the management
of postoperative pain following moderate/major abdominal,
gynaecological, abdominal, thoracic and orthopaedic surgeries. The
implant is intended to provide pain control directly at the surgical site
and thus reduce the level of additional analgesia required following
surgery. The collagen matrix naturally biodegrades over a few days
and the bupivacaine is released to provide local analgesia for up to 96
hours postoperatively.
Innocoll recently completed a Phase II trial in patients undergoing
hysterectomy surgery in the absence of gynaecological cancers
at Wexham Park Hospital in Slough, the UK. The results of this
trial provided evidence of sustained, postoperative analgesia for
approximately 96 hours, as measured by Visual Analogue Scale scores
and reduced dependence on systemic morphine administered by
patient-controlled analgesia.
This extended action was achieved despite a low total bupivacaine
dose (150mg as the hydrochloride salt), which is well below the
allowable daily dose and equivalent to that used by some practitioners
for a once-off wound infiltration with bupivacaine solution prior to
wound closure.
For the planned series of multi-centre, controlled, Phase II trials to
be performed in the US, Innocoll has appointed Premier Research
Group to co-ordinate up to five trials in a variety of soft and hard
tissue procedures, including hysterectomy, herniorrhaphy, open
gastrointestinal surgery and orthopaedic surgery. The first of these
trials that has commenced dosing will compare the analgesic effect of
the bupivacaine surgical implant versus a placebo implant and current
standard-of-care in patients undergoing abdominal hysterectomy
at eight different US sites. The other Phase II soft tissue trials in
herniorrhaphy and open gastrointestinal surgeries are expected to
commence in early 2008.
Arcion raises funds to continue development of
ARC-4558
Arcion Therapeutics has raised US$8.8 million in a series A round of
financing, which will help the company to continue its work with ARC-
4558 (topical clonidine gel), a treatment for alleviating moderate and
severe pain associated with diabetic neuropathy. ARC-4558 offers an
17th January 2008 ©
Espicom Business Intelligence
ANALGESICS/ANAESTHETICS
million, plus milestone payments tied to the progress of development,
as well as royalties and milestone payments tied to sales if TS-032 is
approved by regulatory authorities and launched.
alternative to current systemic treatments for neuropathic pain, which
often induce serious side effects. Arcion is expected to conduct a late-
stage clinical trial to demonstrate safety and efficacy. The company is
also evaluating other topical treatments in addition to ARC-4558, to
further its goal of providing pain relief with a favourable risk to benefit
ratio.
Zogenix raises funds for pain compound
development
Zogenix has raised US$18 million in a private placement of preferred
stock. Proceeds from the financing will be used to support the
commercialisation of sumatriptan DosePro (previously known as
Intraject), for which the company submitted an NDA with the FDA in
December. Proceeds will also be used to fund the development of the
company's late-stage, controlled-release (CR) opioid product that was
recently in-licensed from Elan (see CNS 176).
Zogenix' sumatriptan DosePro is a needlefree, single-use, easy-to-use,
subcutaneous delivery system for sumatriptan that will compete in the
triptan segment of the migraine market, while the CR opioid product
utilising the Elan SODAS technology will compete in the strong opioid
market for chronic pain.
Product News
Sugammadex NDA assigned FDA priority review
status
The FDA has assigned priority review status to Schering-Plough's
NDA for sugammadex. The product, which Schering-Plough acquired
through its combination with Organon BioSciences in November (see
CNS 175), was designed to reverse the effects of rocuronium bromide
(Zemuron/Esmeron/Eslax) or vecuronium bromide, muscle relaxants
commonly used during surgeries that require profound muscle
relaxation. If approved, sugammadex will be the first in a new selective
relaxant binding agent class of drugs, which work in an entirely new
and unique way to encapsulate the muscle relaxant molecule and
render it inactive.
According to Schering-Plough, sugammadex has the potential to
change the way that doctors practice anaesthesia as it will allow
anaesthesiologists to rapidly and safely reverse both shallow and
profound levels of muscle relaxation, which is not possible with
current reversal agents. In clinical trials, to date, sugammadex has
demonstrated the ability to rapidly reverse shallow and profound
depths of rocuronium-induced neuromuscular blockade (NMB),
thereby enabling control of the onset and offset of skeletal muscle
relaxation through the use of both drugs.
Sugammadex has also demonstrated the ability to reverse the effects
of NMB induced by vecuronium bromide. In a Phase III trial, the most
frequently-reported adverse events associated with sugammadex
regardless of relationship to the study drug were procedural pain and
nausea.
Page 11
THERAPIES TO TREAT SUBSTANCE DEPENDENCE
FDA accepts BEMA Fentanyl NDA for filing
The FDA has accepted for filing BioDelivery Sciences International's
(BDSI) NDA for BEMA Fentanyl, which was submitted on 31st October,
for the management of breakthrough cancer pain in opioid-tolerant
patients (see CNS 174). A final decision by the Agency is expected in
August.
BEMA Fentanyl consists of a small, dissolvable, polymer disc,
formulated with the opioid narcotic, fentanyl, for application to
the buccal membranes. The efficacy results from a pivotal Phase
III efficacy trial in patients with breakthrough pain associated with
cancer demonstrated that subjects treated with BEMA Fentanyl
had a significantly greater reduction in pain as early as 15 minutes
(study primary endpoint) compared to those treated with placebo.
A subsequent safety study demonstrated a good tolerability profile,
including a lack of oral irritation or ulceration related to product
administration and use.
If BEMA Fentanyl is approved by the FDA, BDSI is expected to receive
milestone payments from its commercial partner, Meda AB, totalling
US$30 million and could begin receiving royalty revenues from the
product as early as the fourth quarter of 2008. In September, BDSI
reported a licensing agreement with Meda for the distribution rights
in the US, Canada and Mexico for BEMA Fentanyl (see CNS 170). This
followed Meda securing from BDSI the rights to distribute the product
in Europe; plans for submitting a regulatory application in Europe are
under way.
Agreement News
Janssen enters supply agreement for ER tramadol;
expands Fentanyl TAIFUN deal
Janssen Pharmaceutica (Johnson & Johnson) has entered into an
exclusive supply agreement for the marketing and distribution of
Biovail's once-daily, extended-release (ER) formulation of tramadol
Therapies to Treat Substance Dependence
R&D Update
Evotec successfully completes Phase I study with
EVT 302
Evotec has successfully completed a Phase I safety and tolerability
study of EVT 302, with the preliminary results confirming the
compound's good tolerability profile.
EVT 302, an orally-active, potent, highly-selective and reversible
inhibitor of MAO-B that is in development for smoking cessation, was
investigated in this ascending-dose study with repeated daily dosing,
in a total of 84 healthy young and elderly subjects. Healthy young male
subjects were treated with EVT 302 2.5, 5 or 15mg, or placebo for two
weeks, while healthy elderly male and female subjects were treated
with EVT 302 2.5 or 10mg, or placebo for four weeks. Each treatment
was received by 12 young and/or elderly subjects as appropriate.
The highest dose levels exceed the expected maximum therapeutic
dose planned to be used in further clinical trials. For the treatment
period and part of the subsequent washout phase, the subjects were
confined to the clinical research unit.
Page 12 ©
Espicom Business Intelligence
CNS Drug News
in 86 countries in two regions, Central and Eastern Europe, and the
Middle-East and Latin America. Under the terms of the ten-year
agreement, Biovail Laboratories International will manufacture and
supply to Janssen once-daily ER tramadol tablets in dosage strengths
of 100, 200 and 300mg at contractually-determined prices. Janssen
affiliates will be responsible for all related promotional costs, as well as
all regulatory filings and the management of the regulatory approvals
process.
In February 2007, Ortho-McNeil (J&J) launched Biovail's ER version of
tramadol for the treatment of moderate-to-moderately severe chronic
pain under the brandname, Ultram ER, in the US and Puerto Rico.
Ultram ER, which is available in 100, 200 and 300mg dosage strengths,
is the only once-daily tramadol formulation that has been approved
by the FDA. In November, Biovail Pharmaceuticals Canada, Biovail's
sales and marketing division, launched the product in Canada under
the brandname, Ralivia. Ralivia is indicated for the management of
moderate severity pain in patients who require continuous treatment
for several days or more. With respect to other regions, Biovail is
evaluating potential commercialisation options in Western Europe.
In addition...
Akela Pharma has extended the territory coverage of the initial licence
and development agreement it has with Janssen for Fentanyl TAIFUN,
to include Canada.
Fentanyl TAIFUN is a fast-acting fentanyl formulation delivered using
Akela's TAIFUN dry-powder inhaler for the treatment of breakthrough
cancer pain. The existing agreement already covers the EU, Eastern
Europe, Russia, the Middle-East and Africa. All the commercial and
contractual conditions remain in effect.
The product will be distributed by Janssen-Ortho (J&J) for the
Canadian market. Akela will receive a signing fee, development and
regulatory milestones, as well as commercial sales milestones that are
in line with current commercial expectations regarding the Canadian
market as compared with the EU market.
The study was aimed at investigating safety/tolerability,
pharmacokinetics and pharmacodynamics (inhibition of MAO-B in
platelets) during prolonged dosing with EVT 302 as compared to
placebo, and was conducted and successfully completed as planned
per protocol. The results are still blinded and will become available
as final evaluated data over the next two months, however the
preliminary data indicate that EVT 302 was well tolerated in young
and elderly subjects up to the highest dose levels tested in this study.
Adverse events (AEs) classified as possibly treatment-related were
transient and mostly of mild intensity; only very few moderate AEs
were reported. No severe or serious AEs occurred and no clinically-
relevant changes in laboratory values of haematology or clinical
chemistry were noted. In particular, there were no changes in liver
function tests in any subjects.
EVT 302's preclinical profile supports the potential for a superior
safety profile over marketed MAO-B inhibitors and better tolerability
compared to current treatments. In a single ascending-dose, Phase I
study by Roche (from whom the compound was in-licensed), EVT 302
was safe and well tolerated up to high dose levels and showed positive
pharmacokinetic properties with prolonged MAO-B inhibition, offering
the potential for once-weekly dosing at very low exposure levels.
17th January 2008
CNS Drug News
Two further Phase I studies with EVT 302 are currently ongoing. In
March 2007, Evotec initiated a PET study that is designed to assess
the occupancy of MAO-B in the brain after oral administration of
EVT 302 in patients, which helps to determine the therapeutic dose
range of EVT 302 for subsequent safety and efficacy trials; this study
is expected to be completed in early 2008. Furthermore, in November,
Evotec initiated a Phase I tyramine interaction study to confirm that
there was no cardiovascular liability with foods that contain high
amounts of tyramine. A first Phase II study to examine the effects of
EVT 302 on craving following smoking cessation is planned to start in
the first quarter of 2008.
Agreement News
Alkermes enters agreement with Cilag for Vivitrol in
Russia/CIS
Alkermes has entered into an exclusive agreement with Cilag (Johnson
& Johnson) to commercialise Vivitrol (naltrexone for extended release
injectable suspension) for the treatment of alcohol and opioid
Anti-Epileptics
R&D Update
FDA grants ODD to Ovation's clobazam for LGS and
Jazz' JZP-8 for recurrent ARS
Ovation Pharmaceuticals has been granted orphan drug designation
(ODD) by the FDA for clobazam as an adjunctive treatment for Lennox-
Gastaut syndrome (LGS), which is one of the most severe forms of
childhood epilepsy that frequently persists into adulthood.
Clobazam is a 1,5-benzodiazepene and has a distinctive chemical
structure compared to other currently-available benzodiazepines. It
was initially developed to reduce the adverse events (AEs) associated
with 1,4-benzodiazepines, while still maintaining efficacy. In animal
models, clobazam has been shown to work both by intensifying
GABA-mediated inhibitory effects and by increasing the activity
of glutamate transporters. In a Phase II trial, clobazam significantly
reduced drop seizures compared to baseline. The majority of AEs
observed in this trial were mild or moderate in severity and no serious
AEs resulted in premature discontinuation of drug treatment.
Clobazam is widely available, with approvals in more than 100
countries for various uses in both children and adults, including the
adjunctive treatment of epilepsy and anxiety. Though not currently
approved for any use in the US, Ovation plans to seek FDA approval
for clobazam as adjunctive treatment for patients with LGS. To support
this development programme, a global multi-centre, Phase III trial is
currently under way and enrolling patients.
In addition...
Jazz Pharmaceuticals has received ODD from the FDA for JZP-8, its
product candidate for the treatment of recurrent acute repetitive
seizures (ARS). JZP-8 is a novel drug-delivery formulation incorporating
clonazepam, a widely-prescribed benzodiazepine. The product
candidate is designed to be a fast-acting intranasal spray for the
treatment of recurrent ARS in patients with epilepsy. Jazz previously
completed development activities to select the active pharmaceutical
17th January 2008 ©
Espicom Business Intelligence
ANTI-EPILEPTICS
dependence in Russia and other countries in the Commonwealth of
Independent States (CIS). As part of the agreement, Cilag will pay up-
front and milestone payments up to US$39 million, as well as ongoing
royalties on commercial sales of Vivitrol in this territory, and the
product will be commercialised by Janssen-Cilag.
Alkermes will retain exclusive development and marketing rights
to Vivitrol in all markets outside of the US, Russia and other
countries in the CIS. In the US, Vivitrol is commercialised primarily
by Cephalon.
Under the terms agreed, Cilag will have primary responsibility for
filing the NDA for Vivitrol in Russia and other countries in the CIS.
Alkermes will be responsible for manufacturing Vivitrol, and will
receive from Cilag manufacturing revenues and a royalty based on
product sales.
Cilag will make an initial payment of US$5 million cash to Alkermes and
up to an additional US$34 million in cash payments upon regulatory
approvals for the product, certain agreed-upon events and levels of
Vivitrol sales. Additional terms were not disclosed.
ingredient for the product, to determine its formulation, and to assess
its safety and tolerability in early-stage studies. In December, the
company dosed the first patient in a Phase II trial of JZP-8.
Amarin reports completion of preclinical nasal
lorazepam study
Amarin has reported the successful completion of a preclinical proof-
of-concept study using a novel nasal formulation of lorazepam. The
study evaluated the extent of lorazepam's absorption after nasal
administration and the pharmacokinetics of the formulation.
This nasal lorazepam formulation utilises Elan's proprietary
NanoCrystal Technology and is in development for the out-patient
treatment of emergency seizures in epilepsy patients, specifically
status epilepticus and acute repetitive seizures. Amarin is now working
with a subsidiary of Elan to prepare the formulation for clinical
pharmacokinetic trials.
Product News
Breckenridge/Taro settle litigation with Novartis over
generic Trileptal
Breckenridge Pharmaceutical has settled a Paragraph IV litigation with
Novartis concerning Trileptal (oxcarbazepine), plus on 11th January,
the FDA approved the company's ANDA for oxcarbazepine 150, 300
and 600mg tablets in the US. Breckenridge enjoys a shared 180-day
exclusivity period and will immediately launch its oxcarbazepine
tablets, which are AB-rated to Novartis' Trileptal and used in treating
seizures.
In addition...
Taro Pharmaceutical Industries has settled a pending lawsuit with
Novartis and plans to launch oxcarbazepine 150, 300 and 600mg
tablets in the US.
Page 13
EATING DISORDERS
Taro recently settled litigation with Novartis regarding its Paragraph
IV certification challenging the latter's patent protection on Trileptal.
On 15th November, Taro received FDA approval of its ANDA for
oxcarbazepine tablets, but did not immediately launch the product at
that time, pending settlement of the litigation with Novartis.
These generic versions of Trileptal will no doubt further impact
Novartis' sales of the drug. As reported in Espicom's 4D Pharma, in
2006, Trileptal posted sales of US$721 million, an increase of 17.2 per
cent compared to 2005, whilst during 2007, the drug continued to
generate growth until the onset of generic competition in the latter
half of the year. Indeed, Espicom forecasts that Trileptal sales will
decrease to US$403 million by 2011.
Agreement News
Sepracor enters deal for Bial's anti-epileptic
compound
Sepracor has entered into an exclusive licensing agreement for
the development and commercialisation of Bial's anti-epileptic
compound, BIA 2-093 (eslicarbazepine acetate), in the US and Canada.
Under the terms agreed, Sepracor will be responsible for filing the
NDA and seeking marketing approval from the FDA, and contingent
on obtaining regulatory approval, commercialisation of the product in
Eating Disorders
R&D Update
Neurogen opts not to advance NGD-4715 to Phase II
testing
Neurogen has completed the follow-up component of a multiple
ascending-dose (MAD), Phase I study with NGD-4715, a melanin-
concentrating hormone-1 (MCH-1) receptor antagonist being
investigated for the treatment of obesity.
The initial phase of the study utilised three-times daily dosing for
14 days in healthy obese subjects exposed to a high caloric diet. As
previously reported, during this phase, moderate induction of the liver
enzyme, CYP3A4, occurred, increasing the probability of accelerating
the metabolism of other drugs administered concomitantly. In
addition, during the initial phase of the MAD study, lipid-lowering
effects were observed.
The follow-up study was designed to test the effect of twice-daily
(bid) dosing in healthy obese subjects on a restricted caloric diet
for 14 days. Using bid dosing, CYP3A4 induction was substantially
reduced, as measured by treatment with midazolam, a drug sensitive
to changes in CYP3A4 levels. With less frequent dosing and caloric
restriction in the current trial, no effect on lipids was observed. As in
the initial Phase I studies, no serious adverse events were observed,
however, vivid dreams and awakenings were reported by half of the
drug-treated subjects during the first week of dosing.
These results suggest that the effect of MCH-1 receptor antagonism
on caloric regulation and sleep architecture requires further study
in humans. Based on the results of the MAD studies, Neurogen has
Page 14 ©
Espicom Business Intelligence
CNS Drug News
the US. Sepracor anticipates that the NDA will be submitted to the FDA
in late 2008 or early 2009, with a potential product launch in late 2009
or early 2010, subject to FDA approval. In exchange, Bial is entitled
to receive an up-front payment of US$75 million and subsequent
payments upon the accomplishment of various development and
regulatory milestones, which could include up to an additional US$100
million if all milestones are met. Bial will also receive compensation
for providing finished product and milestone payments upon FDA
approval of additional indications, if any.
BIA 2-093 is a new chemical entity that has been designed to offer
patients with partial epilepsy additional control of their seizures and
improved quality of life. Bial is currently completing clinical evaluation
of BIA 2-093 for adjunctive use in partial seizures in adults with
epilepsy.
Eslicarbazepine acetate has been shown in clinical studies to be safe
and effective in the control of seizures as adjunctive therapy in adults.
Bial has tested the compound in three Phase III trials in 22 countries,
with over 1,000 patients randomised to an 18-week, acute double-
blind therapy and subsequently followed in a one-year, open-label
extension study. The potential for once-daily administration could be
an important clinical advantage for patients with epilepsy.
In addition, there may be benefits to patients such as reduced drug-
drug interactions, which may distinguish this drug from commonly-
used compounds such as carbamazepine.
determined that it will not advance the compound into Phase II testing
at this time, but will consider out-licensing its MCH programme for
potential development with a partner.
Stimulation of brain CPT-1 decreases food intake and
body weight
FASgen has reported new research results in the obesity field using
FAS89B, one of its proprietary compounds.
FASgen has conducted extensive research in the area of metabolic
disease disorders, specifically for the treatment of obesity and fatty
liver disease. The company has a long-standing co-operation with
the Johns Hopkins University and that joint research has produced
discoveries in the regulation of weight loss by the stimulation of
carnitinepalmitoyl-transferase-1 (CPT-1). FAS89B was characterised in
vitro as a selective inhibitor of brain CPT-1 and produced in vivo results
in mice of decreased feeding for three days and persistent weight loss
for six days, with no evidence of conditioned taste aversion.
This discovery, which was published in the 5th December online
edition of the American Journal of Physiology - Regulatory, Integrative
and Comparative Physiology (10.1152/ajpregu.00862.2006), adds
another tool for FASgen to use in its ongoing programme of research
into the field of treatment for obesity and fatty liver disease.
Orexigen reports 48-week results of Phase IIb
Empatic trial
Orexigen Therapeutics has reported 48-week results from a Phase
IIb trial of Empatic (bupropion+zonisamide; formerly Excalia), one of
its two obesity drug candidates. Weight loss through 48 weeks for
the highest Empatic dosage arm, in the intent-to-treat (ITT) double-
17th January 2008
CNS Drug News EATING DISORDERS

blind extension and completer groups, was 14 and 15.1 per cent,
respectively. This double-blind, placebo-controlled trial was the
company's first large, multi-centre trial of its novel sustained-release
(SR) formulation of zonisamide paired with bupropion SR. The primary
objective was to determine the optimal dose ratios of bupropion and
zonisamide. The trial randomised 623 obese patients, and included
only a minimal diet and exercise intervention.
The trial protocol permitted all patients who completed 24 weeks of
treatment to continue on their existing double-blind therapy for an
additional 24 weeks. Alternatively, patients who failed to achieve at
least a 5 per cent response 24 weeks after the start of treatment were
permitted to switch to the highest Empatic dose in a 24-week, open-
label extension. Most patients receiving Empatic therapy elected to
continue on their existing double-blind therapy for an additional 24
weeks and continued to lose weight in the time period from weeks 24
to 48. Analysis of their weight loss, as specified by the study protocol,
is referred to as the ITT - double-blind extension. Patients from this
group who completed treatment through week 48 are referred to
as completers - double-blind extension. Except with respect to the
placebo patients, only data for patients remaining on double-blind
treatment beyond week 24 were included in the analysis and data
from patients discontinuing blinded therapy through week 24 were
not imputed. The double-blind extension results are as follows:

Weight loss at 48 weeks (per cent)

zonisamide SR (mg) bupropion SR (mg) ITT - double-blind completers - double-
extension blind extension
Group 1 120 280 10.1 12.1
Group 2 120 360 12.1 11.8
Group 3 240 280 11.8 12.4
Group 4 240 360 12 12.5
Group 5 360 280 10.8 11
Group 6 360 360 14 15.1
Group 7* placebo placebo 1.1 1.2

* Represents placebo weight loss at 24 weeks. As the majority (approximately 88 per cent) of the placebo patients did not achieve a 5 per cent
clinical response at 24 weeks, most (approximately 79 per cent) who completed 24 weeks switched to the highest Empatic dose. This aspect of
the trial introduces selection bias for patients most likely to lose weight and enhances the results for all groups in the trial. However, the impact is
greatest in the placebo arm because of the significantly higher proportion of placebo patients who switched to the highest Empatic dose after 24
weeks. As such, data for the actual 48-week, double-blind, placebo treatment arm are not presented.

Results of this trial also indicate that Empatic was safe and
generally well tolerated. As previously reported, the overall rate of
discontinuation due to adverse events (AEs) for the Empatic treatment
arms through the primary endpoint at 24 weeks was not statistically
different to the rate seen with placebo. This was also true with the
highest Empatic dose as compared to placebo. Between 24 and 48
weeks, the overall rate of discontinuation due to AEs among the
double-blind extension group receiving Empatic was <2 per cent.
Moreover, the discontinuation rate due to AEs in the double-blind
group of patients receiving the highest Empatic dose between weeks
24 and 48 was 0 per cent. AEs were consistent with the existing
package labels for one or both of the Empatic constituents and most
commonly included headache, insomnia, nausea or dry mouth. There
were no serious AEs that were attributed by investigators to Empatic.
The researchers studied the brain metabolism of 18 individuals with
body mass indices (BMI) ranging from 20 to 29. Each study participant
swallowed a balloon, which was then filled with water, emptied and
refilled again at volumes that varied between 50 and 70 per cent.
During this process, the researchers used functional MRI to scan the
subjects' brains. Subjects were also asked throughout the study to
describe their feelings of fullness.
By simulating feelings of fullness with the expandable balloon, the
researchers saw the activation of different areas of the brain in normal
weight and overweight people. The overweight subjects had less
activation in parts of the brain that signal satiety in normal weight
subjects and were also less likely than normal weight subjects to report
satiety when their stomachs were moderately full.

Orexigen recently submitted to the FDA the results of this trial at 24
weeks, which was the primary endpoint of the study. In subsequent
correspondence, the FDA confirmed the design of the company's next
planned Phase IIb trial; Orexigen plans to initiate this trial in the second
quarter of 2008. This study will be designed to evaluate Empatic
against individual monotherapies and placebo. Based on the above
results of the completed Phase IIb trial, the company expects to take
the highest dose ratio of Empatic, and possibly one lower dose ratio,
into this upcoming study.
Brain-imaging study offers new clues to overeating
It is thought that these findings, which were published in the 22nd
November online edition of NeuroImage (10.1016/j.neuroimage.2007.1
1.008), provide new evidence for why some people will continue to eat
despite having eaten a moderate-size meal.
One notable region of the brain, the left posterior amygdala, was
activated less in the high BMI subjects, but activated more in their
thinner counterparts. This activation was turned "on" when study
subjects reported feeling full. Subjects who had the highest scores
on self-reports of hunger had the least activation in the left posterior
amygdala.

Researchers at the US Department of Energy's Brookhaven National
Laboratory have found new clues as to why some people overeat and
gain weight while others do not. Examining how the human brain
responds to satiety messages delivered when the stomach is in various
stages of fullness, the scientists have identified brain circuits that
motivate the desire to overeat; treatments that target these circuits
may prove useful in controlling chronic overeating.
This study is thought to provide the first evidence of the connection
of the left amygdala and feelings of hunger during stomach fullness,
demonstrating that activation of this brain region suppresses hunger.
The findings indicate a potential direction for treatment strategies
targeting this brain region. The scientists also looked at a range of
hormones that regulate the digestive system, to see whether they
played a role in responding to feelings of fullness. Ghrelin, a hormone

17th January 2008 ©

Espicom Business Intelligence Page 15
DRUGS USED IN NAUSEA & VERTIGO / GENERAL DEVELOPMENT NEWS CNS Drug News
known to stimulate the appetite and cause short-term satiety, showed also had greater activation of the left amygdala, which indicates that
the most relevance. It was found that individuals who had greater ghrelin may control the reaction of the amygdala to satiety signals
increases in ghrelin levels after their stomachs were moderately full sent by the stomach.

Drugs used in Nausea & Vertigo

As the first company to file an ANDA with a Paragraph IV patent
Product News certification for granisetron injection, Teva has been awarded 180 days
of marketing exclusivity for this product.
Generic Kytril approved following patent expiry
Aloxi Capsules sNDA accepted for review by FDA
Following the expiration of patent protection on 28th December,
numerous companies have received final FDA approval for generic The FDA has accepted for filing MGI Pharma/Helsinn Healthcare's
versions of Roche's Kytril (granisetron). The drug is indicated for the sNDA for the 5-HT3 receptor antagonist, Aloxi (palonosetron) Capsules
prevention of: nausea and vomiting associated with initial and repeat for oral administration. Aloxi Injection is approved by the FDA for
courses of emetogenic cancer therapy, including high-dose cisplatin; the prevention of acute nausea and vomiting associated with initial
and, nausea and vomiting associated with radiation, including total and repeat courses of moderately- and highly-emetogenic cancer
body irradiation and fractionated abdominal radiation. Companies chemotherapy (CT), and for the prevention of delayed nausea and
receiving approvals included: vomiting associated with initial and repeat courses of moderately-
emetogenic cancer CT. The submission, which was made in October,
has a PDUFA date of 22nd August 2008 and if approved, will provide a
Company Dosage and form Approval date
more convenient dosage of Aloxi (see CNS 174).
APP Pharmaceuticals 0.1mg base/mL injection 31st December
Apotex 0.1mg base/mL injection 31st December The sNDA includes results from a trial in which patients were stratified
Barr Laboratories 1mg tablet 28th December by gender and history of CT, and randomly assigned to receive one of
Baxter Healthcare 1mg base/mL injection 31st December three doses of oral Aloxi (0.25, 0.5 or 0.75mg) or a single intravenous
CorePharma 1mg tablet 31st December (iv) 0.25mg dose. The primary objective of the study was to determine
Roxane Laboratories an oral dose that was non-inferior to the iv 0.25mg dose. Overall,
(Boehringer 1mg tablet 31st December results of the study indicate that the oral 0.5mg dose of Aloxi was non-
Ingelheim) inferior to the iv 0.25mg dose at inducing a complete response (CR;
no emesis, no rescue therapy) during both the early (0-24 hours) and
Teva Pharmaceutical
1mg tablet 28th December delayed phases (0-48, 0-72 and 0-120 hours) following administration
Industries
of moderately-emetogenic cancer CT. Specifically, CR rates for the
Teva Pharmaceutical 0.5mg dose of oral Aloxi were 76.3 and 58.8 per cent for the 0-24
0.1mg base/mL injection 31st December
Industries and 0-120 hour time periods, versus 70.4 and 59.3 per cent for the iv
Watson Laboratories 0.1mg base/mL injection 31st December 0.25mg dose, respectively.

General Development News

R&D Update
XenoPort provides clinical trial update
XenoPort has initiated a Phase II trial of XP19986 in spinal cord injury
(SCI) patients with spasticity, as well as the first clinical trial of XP21279,
a drug candidate designed to treat Parkinson's disease.
neuralgia (PHN) and painful diabetic neuropathy, as well as a Phase
II trial in PHN patients who have not responded to treatment with
gabapentin, all in the first quarter of 2008. In addition, GSK expects
to initiate, after discussion with the FDA, two pivotal dose-ranging
efficacy studies and an open-label, long-term study of XP13512 for
migraine prophylaxis in the second half of this year.
XP19986 Phase II trial in SCI patients with spasticity

In addition, XenoPort has confirmed plans to release top-line data
from two Phase III trials of XP13512 in patients with restless legs
syndrome (RLS) in the first quarter of 2008. The company also stated
that GlaxoSmithKline, its partner for XP13512 in the US and other
countries worldwide, excluding certain Asian countries, plans to file
an NDA for the compound in RLS with the FDA in the third quarter
of 2008. GSK also intends to initiate two polysomnography studies of
XP13512 in RLS patients in the second half of 2008, in order to explore
XP13512's potential benefits in sleep.
XenoPort also reiterated GSK's plans to initiate additional clinical trials
of XP13512 in other CNS-related disorders. GSK intends to initiate
separate dose-ranging, Phase II trials of XP13512 in post-herpetic
XenoPort's multiple-dose, placebo-controlled, Phase II trial of
XP19986 is designed to evaluate the efficacy, safety and tolerability
of a sustained-release (SR) formulation (designated as SR1) of XP19986
in patients with spasticity due to SCI. XenoPort believes that the SR1
formulation of XP19986, which provides sustained drug exposure over
12 hours, could provide improved therapy when dosed twice daily
(bid) in spasticity patients.
The trial is being conducted at multiple study centres in the US. Three
doses of XP19986 are being assessed in a randomised, crossover
comparison versus placebo, with 12 subjects to be enrolled at each
dose level. Eligible subjects undergo a washout and baseline period,
followed by XP19986 (10, 20 or 30mg) or placebo, administered bid
in the first treatment segment. After a washout period, each subject

Page 16 ©
Espicom Business Intelligence 17th January 2008
CNS Drug News
receives the other treatment in the second treatment segment.
The primary outcome measure in this study is the Ashworth Scale
assessment of muscle tone.
XP21279 Phase I trial
XP21279 is a new chemical entity that is a transported prodrug
of levodopa. It is designed to engage natural nutrient transport
mechanisms located throughout the length of the gastrointestinal
(GI) tract and then be rapidly converted to levodopa by the body's
endogenous enzymes. In addition to levodopa, the metabolic
breakdown products of XP21279 are substances with favourable safety
characteristics. Because XP21279 is designed to be well absorbed from
the lower GI tract, XenoPort believes that it can be formulated for SR,
thus reducing fluctuations of levodopa levels in the bloodstream.
XenoPort's randomised, double-blind, placebo-controlled, single-dose,
Phase I trial is designed to assess the safety and pharmacokinetics (PK)
of a prototype SR formulation of XP21279 administered with carbidopa
and to compare its PK profile to that of Sinemet (levodopa+carbidopa).
Twelve healthy subjects will participate in a three-period study. Each
subject receives two 250mg tablets of XP21279 (216mg equivalent of
levodopa) or placebo under fasted and fed conditions during the first
two periods, followed by Sinemet (two levodopa 100mg+carbidopa
25mg tablets) administered in an open-label manner in the same
subjects in the third period. Subjects dosed with XP21279 receive two
Lodosyn (carbidopa) 25mg tablets every 12 hours on the day prior to,
and on the day of, each treatment (except on the morning of Sinemet
dosing). Blood and urine will be collected to determine the PK profile
of XP21279, levodopa, levodopa metabolites and carbidopa, with
preliminary PK results expected in the first quarter of 2008.
Lundbeck moves compound into clinical
development but discontinues other
Lundbeck has initiated Phase I studies with Lu AA37096 to investigate
the drug's safety, tolerability and pharmacokinetic profile. At the
same time, the company has decided to discontinue the further
development of Lu AA44608, which was in Phase I for the potential
treatment of mood disorders.
Lu AA37096 has been discovered based on findings with the unique
mechanism of action of Cipralex/Lexapro (escitalopram), but
incorporates effects on a number of additional targets in the brain.
Lu AA37096 has shown convincing effects in animal models of mood
disorders, as well as in pain models.
Researchers elucidate mechanisms behind fragile X
syndrome
Researchers at the University of Texas Southwestern Medical Center
(UT Southwestern) have reported progress in uncovering how brain
cells are affected in fragile X syndrome. Indeed, according to senior
author, Dr Kimberly Huber, the team may have discovered a core
mechanism underlying the syndrome.
Huber's research with mice focuses on how fragile X syndrome affects
communication between cells in the hippocampus. Her findings show
that two different chemical signals go awry in fragile X syndrome,
indicating that drugs that interact with these signals might be a
pathway to help treat the syndrome. Huber previously co-discovered
that mice genetically engineered to lack the Fmr1 gene have a
defective signalling system in the brain that controls learning in the
hippocampus. This system relies on glutamate, which under normal
circumstances, causes nerve cells to make proteins and change their
17th January 2008 ©
Espicom Business Intelligence
GENERAL DEVELOPMENT NEWS
electrical firing patterns in response to learning situations. Without
a properly-working Fmr1 gene, the glutamate signalling system
malfunctions. In 2007, she and colleagues at UT Southwestern
found that acetylcholine affects the same protein-making factory as
glutamate.
In the current study, which was published in the 9th January issue
of the Journal of Neuroscience (2008;28:543-547), Huber and post-
doctoral researcher, Dr Jennifer Ronesi, investigated a protein called
Homer, which serves as a kind of structural support for the glutamate
system. In fragile X syndrome, the Homer-glutamate support system
is disconnected. Huber's group discovered that this disconnection
results in an inability of brain cells to make the new proteins important
for learning and memory. These results show that Homer plays a vital
role making proteins and learning, which may also indicate where
drugs could be targeted.
Agreement News
£4 million consortium investment to accelerate
research into mental illness
P1vital has entered into a consortium agreement with AstraZeneca
Pharmaceuticals, GlaxoSmithKline, Lundbeck, Organon (Schering-
Plough) and Wyeth, under which the consortium partners will
fund a series of studies over a period of three years to establish the
sensitivity of healthy volunteer CNS experimental medicine models
and validate their ability to detect the efficacy of novel compounds.
The studies will be carried out by P1vital in collaboration with clinical
psychopharmacology groups in the UK, based at the University of
Bristol, Cardiff University, the Institute of Psychiatry, the University of
Manchester and the University of Oxford. The objective of the studies
is to validate existing healthy volunteer models and to develop novel
models in the areas of anxiety, cognitive disorders, depression and
schizophrenia.
The initial studies will validate new surrogate biomarkers for positive,
negative and cognitive deficits in schizophrenia. In depression, the
consortium will validate an "at risk" group (dysphoric volunteers)
using a recently-established emotional test battery as a surrogate
population. In cognitive disorders, studies will focus on two recently-
developed virtual reality models and examine their utility for the
early detection of cognitive deficits in mild cognitive impairment
and schizophrenia. Studies will also investigate the potential efficacy
of antidepressant drugs in treating anxiety disorders using an
experimental model of anxiety.
Medistem modifies licence agreement with ICM
Medistem Laboratories has modified its licence agreement with the
Institute for Cellular Medicine (ICM), with the effect of: (i) revising
the royalty rate from 85 per cent of ICM's pre-tax income to 20 per
cent of its gross revenues; (ii) extending the term of the agreement
from expiring in 2010 to perpetuity; and (iii) removing Medistem's
obligation to fund ICM pursuant to the agreement. According to
Medistem, these events will allow the company's management to
focus on its biotech endeavours, while retaining cash flows related to
the ICM licence.
In May 2006, Medistem executed a technology licensing and royalty
agreement that enables ICM to culture stem cells (SCs) and work with
physicians to develop and deliver Medistem's SC technologies and
therapies. Initially, Medistem planned to focus on the development
of SC-based therapeutics for a number of currently-incurable
neurological conditions, such as Parkinson's and Alzheimer's diseases.
Page 17
COMPANY INDEX
COMPANY INDEX
Addex Pharmaceuticals..............................................................................................7, 10
Akela Pharma........................................................................................................................12
Albert Einstein College of Medicine........................................................................... 3
Alkermes.................................................................................................................................13
Alnylam Pharmaceuticals................................................................................................. 3
Alseres Pharmaceuticals................................................................................................... 6
Amarin................................................................................................................................ 5, 13
Amgen....................................................................................................................................... 1
Arcion Therapeutics..........................................................................................................11
AstraZeneca...................................................................................................................10, 17
Barr Laboratories.................................................................................................................. 4
Baylor College of Medicine.............................................................................................. 5
Bial..............................................................................................................................................14
BioDelivery Sciences International............................................................................12
Biogen Idec.............................................................................................................................. 4
Biovail.......................................................................................................................................12
BrainStorm Cell Therapeutics......................................................................................... 7
Breckenridge Pharmaceutical......................................................................................13
Brookhaven National Laboratory..............................................................................15
Cephalon................................................................................................................................13
Chiba University.................................................................................................................... 9
Cilag...........................................................................................................................................13
Clalit Health Services.......................................................................................................... 5
Cobalt Pharmaceuticals.................................................................................................... 4
CoMentis...............................................................................................................................3, 4
deCODE genetics................................................................................................................. 9
Eisai.............................................................................................................................................. 4
Elan.................................................................................................................................4, 11, 13
Eucalyptus................................................................................................................................ 5
Evotec................................................................................................................................12, 13
FASgen.....................................................................................................................................14
Forest Laboratories.............................................................................................................. 4
Georgetown University..................................................................................................... 9
GlaxoSmithKline..........................................................................................................16, 17
Hebrew University of Jerusalem................................................................................... 5
Helsinn Healthcare............................................................................................................16
Hemispherx Biopharma.................................................................................................... 8
Immunex.................................................................................................................................. 1
Innocoll....................................................................................................................................11
Institute for Cellular Medicine......................................................................................17
Janssen Pharmaceutica...................................................................................................12
Jazz Pharmaceuticals........................................................................................................13
Johns Hopkins University.......................................................................................... 9, 14
Johnson & Johnson....................................................................................................12, 13
Lundbeck........................................................................................................................... 4, 17
Lupin........................................................................................................................................... 4
Massachusetts General Hospital.................................................................................. 9
Mayo Clinic............................................................................................................................... 3
Cost effective Multi-User
Have You solutions?
Considered... Contact Clare Mills for more information
Email: clare_mills@espicom.com
Tel: +44 (0)1243 756051
Fax: +44 (0)1243 756418
Page 18 ©
Espicom Business Intelligence
CNS Drug News
Meda AB..................................................................................................................................12
Medistem Laboratories...................................................................................................17
Merck & Co.............................................................................................................................10
Merz............................................................................................................................................. 4
MGI Pharma...........................................................................................................................16
Mor Research Applications.............................................................................................. 5
Neurogen...............................................................................................................................14
Novartis.......................................................................................................................3, 13, 14
Orchid Chemicals & Pharmaceuticals........................................................................ 4
Orexigen Therapeutics....................................................................................................14
Organon........................................................................................................................... 11, 17
Orion........................................................................................................................................... 3
Ortho-McNeil.......................................................................................................................12
Ovation Pharmaceuticals...............................................................................................13
P1vital.......................................................................................................................................17
Parkinson’s Institute and Clinical Center.................................................................. 3
Pfizer.............................................................................................................................4, 10, 11
Pipex Pharmaceuticals....................................................................................................... 4
Prana Biotechnology.......................................................................................................... 4
Ramot......................................................................................................................................... 5
ReNeuron................................................................................................................................. 6
Rexahn Pharmaceuticals.................................................................................................. 8
Roche.................................................................................................................................12, 16
Rutgers, The State University of New Jersey.......................................................... 7
sanofi-aventis......................................................................................................................... 7
Schering-Plough.......................................................................................................... 11, 17
Sepracor..................................................................................................................................14
Shire...........................................................................................................................................10
Somaxon Pharmaceuticals.............................................................................................. 8
Southwestern Medical Center.....................................................................................17
Sun Pharmaceutical............................................................................................................ 3
Taisho Pharmaceutical.....................................................................................................10
Taro Pharmaceutical Industries...................................................................................13
Tel Aviv University................................................................................................................ 5
Teva Pharmaceutical Industries.................................................................................... 4
University of Arkansas........................................................................................................ 1
University of California..................................................................................................6, 9
University of Heidelberg................................................................................................... 7
University of Texas.............................................................................................................17
Upsher-Smith Laboratories............................................................................................. 4
US Department of Energy..............................................................................................15
Wockhardt............................................................................................................................... 4
Wyeth...................................................................................................................................1, 17
XenoPort..........................................................................................................................16, 17
Yale University........................................................................................................................ 9
Yeshiva University................................................................................................................ 3
Yissum........................................................................................................................................ 5
Zogenix....................................................................................................................................11
17th January 2008
CNS Drug News COMPOUND INDEX

COMPOUND INDEX
ADX10059................................................................................................................................. 7
ADX63365...............................................................................................................................10
Akatinol..................................................................................................................................... 4
Aloxi...........................................................................................................................................16
Ambien...................................................................................................................................... 7
Ampligen.................................................................................................................................. 8
AMR-101.................................................................................................................................... 5
ARC-4558................................................................................................................................11
Aricept........................................................................................................................................ 4
Axura........................................................................................................................................... 4
BEMA Fentanyl.....................................................................................................................12
BIA 2-093.................................................................................................................................14
bupivacaine...........................................................................................................................11
bupropion.......................................................................................................................14, 15
carbidopa.......................................................................................................................... 3, 17
Cethrin....................................................................................................................................... 6
clobazam................................................................................................................................13
clonazepam...........................................................................................................................13
clonidine.................................................................................................................................11
Coprexa..................................................................................................................................... 4
CTS-21166.............................................................................................................................3, 4
donepezil.................................................................................................................................. 4
doxepin..................................................................................................................................... 8
Ebixa............................................................................................................................................ 4
Empatic.............................................................................................................................14, 15
Enbrel......................................................................................................................................... 1
entacapone............................................................................................................................. 3
eslicarbazepine acetate..................................................................................................14
etanercept................................................................................................................................ 1
ethyl-eicosapentanoic acid............................................................................................. 5
EVT 302.............................................................................................................................12, 13
FAS89B.....................................................................................................................................14
fentanyl....................................................................................................................................12
Fentanyl TAIFUN..................................................................................................................12
granisetron............................................................................................................................16
JZP-8..........................................................................................................................................13
Kytril..........................................................................................................................................16
levodopa............................................................................................................................ 3, 17
lisdexamfetamine dimesylate.....................................................................................10
lorazepam..............................................................................................................................13
Lu AA37096...........................................................................................................................17
Lu AA44608...........................................................................................................................17
memantine.............................................................................................................................. 4
N-acetylcysteine amide.................................................................................................... 5
naltrexone..............................................................................................................................13
Namenda.................................................................................................................................. 4
natalizumab............................................................................................................................ 4
NGD-4715...............................................................................................................................14
oxcarbazepine..............................................................................................................13, 14
palonosetron........................................................................................................................16
PBT2............................................................................................................................................. 4
Poly I. Poly C12U.................................................................................................................... 8
quetiapine..............................................................................................................................10
Ralivia.......................................................................................................................................12
ReN001...................................................................................................................................... 6
Serdaxin.................................................................................................................................... 8
Seroquel..................................................................................................................................10
Silenor........................................................................................................................................ 8
SSR180711................................................................................................................................. 9
Stalevo........................................................................................................................................ 3
sugammadex.......................................................................................................................11
sumatriptan...........................................................................................................................11
sumatriptan DosePro.......................................................................................................11
tetrathiomolybdate............................................................................................................. 4
tramadol.................................................................................................................................12
Trileptal.............................................................................................................................13, 14
TS-032................................................................................................................................10, 11
Tysabri....................................................................................................................................4, 5
Ultram......................................................................................................................................12
Vivitrol......................................................................................................................................13
Vyvanse...................................................................................................................................10
XP13512....................................................................................................................................16
XP19986...................................................................................................................................16
XP21279............................................................................................................................16, 17
zolpidem...............................................................................................................................7, 8
zonisamide.....................................................................................................................14, 15

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