cns issue 167

Monitoring central nervous system drug developments worldwide

CNS Drug News

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Lucy VannEditor

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Will discovery be a breakthrough for MS?The end of July has seen a major genetic advance made in multiple sclerosis (MS) - the identification of a new gene, a functional variant of which has been associated with an increased susceptibility to the disease. Dr Simon Gregory, of Duke University Medical Center, believes that the finding is important because the genetic factors that are already known to be associated with MS only explain less than half of the total genetic basis for the disease. While it has been known that there is a strong genetic basis for MS, only genes within a region of chromosome 6 have, to date, been implicated in the disease. However, the functional gene variant identified in the new research is on chromosome 5.

This will be good news for the approximately 2.5 million people worldwide affected by MS; the risk of developing MS amongst the general population is approximately 110 in 100,000, however, the prevalence may be higher because of the uncertainty in diagnosing the disease, which is the most common cause of neurological disability in young adults. Importantly, it is thought that the research may lead to novel treatments for the disease or the identification of targets for new therapies for the MS market, which was estimated to be worth US$4.9 billion in 2006, with a growth rate of 8.9 per cent year on year, and is the fifth largest segment of the CNS market (source: Espicom's CNS Drug Discoveries - What The Future Holds).

It remains to be seen whether this discovery has the impact on MS research that its coverage has suggested and it should be noted that variants of many genes are thought to be associated with the development of the disease. Nevertheless, identifying a novel gene that is associated with MS will undoubtedly help in understanding this complex disease.

In other news, scientists at deCODE genetics, in collaboration with colleagues from Emory University, have discovered the first variant in the sequence of the human genome ever linked to risk of restless legs syndrome (RLS) and periodic limb movements (PLMs). The SNP was associated with an increased risk of RLS with PLMs of 70 to 80 per cent for those who carry one copy, compared to those without the variant, and is believed to account for approximately 50 per cent of cases.

The discovery provides new evidence that RLS is a genuine disease with an identifiable biological basis, a fact that has recently been the subject of some debate. Indeed, in April last year, CNS Drug News published an editorial questioning whether the pharma industry had been exaggerating the prevalence of RLS (see CNS 136). The new research will be welcomed by the drug companies, particularly those with products either marketed or in development for the condition, such as Boehringer Ingelheim, which saw the FDA approve Mirapex (pramipexole) for the treatment of moderate-to-severe primary RLS in November last year.

THE NEXT ISSUE OF CNS DRUG NEWS WILL BE PUBLISHED ON 23RD AUGUST 2007

Issue No. 167 2nd August 2007

R&D HighlightsCompound reverses signs of AD

Page 4

TBZ protects brain cells in HD modelPage 8

deCODE discovery points to new RLS treatment approach0

Study may accelerate research into next generation of painkillers

Page 15

PRODUCT HighlightsGW withdraws European application for Sativex in MS

spasticityPage 6

Organon’s MAA for sugammadex accepted for reviewPage 16

CHMP recommends upgraded warnings for AcompliaPage 19

AGREEMENT HighlightsEisai enters partnership for Sepracor’s eszopiclone

Page 11

GSK forms US$1.5 billion CNS pact with TargaceptPage 20

EDITORLucy Vann

CONTRIBUTING EDITORSRos Smallman, Fiona Cowie,

Matthew Dennis, Johanna Shiu, Sam Turner

PUBLISHEREric Wigart

Conditions of SaleCNS Drug News must not be reproduced, abstracted, stored in a retrieval system or transmitted in any form or by any means without the written permission of the publisher. CNS Drug News must not be circulated to staff outside the address to which it is sent.

ISSN 1462-656X©Espicom Business Intelligence. All rights reserved.

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CNS Drug News

Will discovery be a breakthrough for MS? ............................................................................1

NEURODEGENERATIVE DISORDERS ......................3PARKiNSON'S DiSEASE - R&D UPDATE .......................................................3

Enrolment on target in Phase III trial of PD-0� .....................................................................3Phase III PD data for safinamide delayed .............................................................................3Proximagen awarded MJFF grant to pursue gene therapy approach for PD .....................3VASTox re-named as Summit ................................................................................................3

ALZHEiMER'S DiSEASE - R&D UPDATE .......................................................3Cortex to resume enrolment in CX717 study at all dose levels ............................................3Affiris begins clinical testing of AD vaccine ..........................................................................4Researchers shed light on how diet and exercise enhance longevity .................................4AstraZeneca initiates Phase IIb trial of AZD3480 in AD ........................................................4Compound reverses signs of AD ............................................................................................4Neurochem granted fast track designation for Alzhemed ..................................................5

PRODUCT NEWS .......................................................................................5Novartis' Exelon patch recommended for European approval ...........................................5

AGREEMENT NEWS ..................................................................................6Neuroptix receives milestone payment from Merck in AD collaboration ...........................6

MULTiPLE SCLEROSiS - R&D UPDATE .........................................................6Research identifies first new MS gene in 30 years ...............................................................6Nuon raises funds to advance tranilast development .........................................................6BioMS' RRMS trial receives positive DSMB review ...............................................................6

PRODUCT NEWS .......................................................................................6GW withdraws European application for Sativex in MS spasticity .....................................6

AGREEMENT NEWS ..................................................................................7Glenmark purchases rights to CHR-1103 and CHR-1�01 from Chromos .............................7Nuon and Kissei complete tranilast agreement ...................................................................8

OTHER NEURODEGENERATivE DiSORDERS - R&D UPDATE ..........................8TBZ protects brain cells in HD model.....................................................................................8Avicena to proceed with confirmatory Phase III ALS trial ....................................................8First patient treated in Phase II trial of Dimebon for HD ......................................................8Intellect reports positive safety data from Phase Ia Oxigon trial ........................................9

PRODUCT NEWS .......................................................................................9Neurochem receives second FDA approvable letter for Kiacta in AA amyloidosis .............9Rilutek patent ruled not invalid ............................................................................................9

AGREEMENT NEWS ..................................................................................9Biogen Idec to exercise first milestone investment in ALS collaboration with Amorfix ....9Tikvah/Academia Sinica enter licensing agreement for neurodegenerative disorders ....9

CEREBROVASCULAR DISORDERS .........................10R&D UPDATE ............................................................................................10

SYGNIS completes Phase IIa study of AX�00 in stroke .........................................................10

ANXIOLyTICS/SLEEP DISORDERS .........................10R&D UPDATE ............................................................................................10

deCODE discovery points to new RLS treatment approach .................................................10Severe trauma may affect children's brain function ............................................................10

PRODUCT NEWS .......................................................................................11Sepracor submits Lunivia MAA .............................................................................................11Caraco receives tentative FDA approval for generic Provigil ...............................................11

AGREEMENT NEWS ..................................................................................11Eisai enters partnership for Sepracor's eszopiclone .............................................................11

ANTIDEPRESSANTS ............................................12R&D UPDATE ............................................................................................12

Add-on mecamylamine treatment shows positive effects in depression..........................1�PRODUCT NEWS .......................................................................................12

Abilify sNDA granted priority review by FDA ........................................................................1�Biovail receives non-approval letter from FDA for BVF-033 ................................................1�

PSyCHOTIC DISORDERS ......................................12R&D UPDATE ............................................................................................12

BL-10�0 shows antipsychotic efficacy; enters Phase II trial in schizophrenia .....................1�Drug may help people with OCD; to be tested on smokers .................................................13Children show sustained improvement after ADHD treatment ..........................................13Progressive grey matter loss discovered in BPD ...................................................................14

PRODUCT NEWS .......................................................................................14EMEA recommends authorisation of first generic medicine for human use ......................14Shire's Vyvanse available in US pharmacies .........................................................................14

ANALGESICS/ANAESTHETICS ...............................15R&D UPDATE ............................................................................................15

Study may accelerate research into next generation of painkillers ....................................15Durect reports positive Phase IIb Posidur data ....................................................................15Newron reveals additional analyses of ralfinamide Phase II study .....................................15Meda agrees to acquire MedPointe ......................................................................................16Akela completes enrolment in Phase IIb trial of Fentanyl TAIFUN ......................................16

PRODUCT NEWS .......................................................................................16Ortho-McNeil/Par settle Ultracet patent litigation ..............................................................16Organon's MAA for sugammadex accepted for review .......................................................16RxElite launches generic sevoflurane in the US ....................................................................16US PTO allows Opana ER-related patent application ...........................................................16

AGREEMENT NEWS ..................................................................................16Hydra signs global TRPV

3 collaboration with Pfizer .............................................................16

Tikvah enters licensing agreement with Apkarian ..............................................................17

THERAPIES TO TREAT SUBSTANCE DEPENDENCE ...17R&D UPDATE ............................................................................................17

Nabi creates pharmaceuticals business unit ........................................................................17Drug may help people with OCD; to be tested on smokers .................................................17

PRODUCT NEWS .......................................................................................17UK's NICE issues guidance on Champix for smoking cessation ............................................17

ANTI-EPILEPTICS ...............................................17R&D UPDATE ............................................................................................17

Icagen files IND for novel epilepsy compound .....................................................................17

EATING DISORDERS ............................................18R&D UPDATE ............................................................................................18

Preclinical data confirm trodusquemine's potential for obesity .........................................18Orexigen reports positive Phase IIb data with Empatic for obesity ....................................18

PRODUCT NEWS .......................................................................................19CHMP recommends upgraded warnings for Acomplia .......................................................19

DRUGS USED IN NAUSEA & VERTIGO ....................19AGREEMENT NEWS ..................................................................................19

Shanghai Ethypharm signs ondansetron licence agreement with Beijing Med-Pharm ...19

GENERAL DEVELOPmENT NEwS ..........................19R&D UPDATE ............................................................................................19

Study further links addiction and memory ..........................................................................19Targacept/Abbott initiate Phase I trials of NNR modulators ...............................................19

AGREEMENT NEWS ..................................................................................20Corcept enters microdosing study agreement with Xceleron .............................................�0Penwest/Edison enter collaboration for neurological disorders.........................................�0Antares signs product development and licence agreement with Jazz .............................�0GSK forms US$1.5 billion CNS pact with Targacept ..............................................................�0

CONfERENCE LISTINGS .......................................21COmPANy INDEX ................................................22COmPOUND INDEX .............................................23

TABLE Of CONTENTSTABLE Of CONTENTS

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CNS Drug News

PARkINSON'S DISEASE - R&D UPDATEEnrolment on target in Phase III trial of PD-02

The Phase III efficacy trial of Avicena Group's lead Parkinson's disease (PD) drug candidate, PD-02 (creatine), has enrolled 288 patients in the first three months. The study, which is sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), is evaluating PD-02's potential to slow the progression of PD.

This trial will enrol over 1,720 patients at more than 50 sites in the US and Canada, making it one of the largest PD trials ever conducted. Avicena previously announced that the NINDS had awarded a grant for the study. As part of the company's collaboration with the NINDS, Avicena will supply PD-02 and placebo for use in the trial. In return, Avicena will have access to the study's data to file an NDA with the FDA for the approval of PD-02 as a treatment for PD. Avicena also holds intellectual property rights for the use of PD-02 in PD.

Data from Phase II efficacy trials conducted at the University of Rochester showed PD-02 to be safe and well tolerated. Furthermore, findings demonstrated the compound's potential to slow the rate of disease progression, as measured by the UPDRS. In preclinical studies of PD, PD-02 demonstrated significant neuroprotective properties, including protection of the dopaminergic cells that are affected in the disease.

Phase III PD data for safinamide delayed

Newron Pharmaceuticals has confirmed that the disclosure of data from a 12-month extension of a Phase III trial with safinamide, an orally-administered alpha-aminoamide derivative, in early Parkinson's disease (PD) patients will be delayed; the information had been expected by the end of June. Merck Serono (Merck KGaA) has exclusive worldwide rights to develop, manufacture and commercialise safinamide in PD, Alzheimer's disease, other cognitive disorders and restless legs syndrome.

Proximagen awarded MJFF grant to pursue gene therapy approach for PD

Proximagen Neuroscience has been awarded a Novel Approaches to Drug Discovery for Parkinson's Disease grant by the Michael J Fox Foundation (MJFF) for Parkinson's Research to pursue research into the development of a novel gene therapy approach for the treatment of Parkinson's disease (PD).

The MJFF is providing the funding under an initiative established through leadership funding from Elan. Under the terms of the agreement, Elan is given a first option to obtain an exclusive worldwide commercial licence to the programme.

The funding is to continue Proximagen's PRX4 research and development programme, which centres around a gene that produces a neuroprotective protein present in healthy individuals, but lacking in patients with PD. PRX4 is being developed using viral vector delivery technology, which delivers genetic material directly into brain cells. The combined neuroprotective gene and viral vector will be targeted to an area of the brain that degenerates in PD. If successful, the treatment may prevent the disease from causing further damage

and could restore normal brain function to patients, reversing the difficulties in movement that characterise this illness. Proximagen's preclinical studies have shown that this neuroprotective protein is implicated in the control of many mechanisms associated with the degeneration of neurons. The company has demonstrated that even in very low concentrations, PRX4 derivatives act as highly-potent inhibitors of neurodegeneration in neuronal cells.

VASTox re-named as Summit

VASTox has changed its name to Summit. The new name, which was approved by shareholders on 19th July, is aimed at encapsulating the company's ambitions, as well as providing an identity that has the flexibility to accommodate the future growth and development of the business.

The company's lead drug candidates, which are in Phase I testing for sialorrhoea and seborrhoea in Parkinson's disease, respectively, will now be known as SMT D001 (formerly DL06001) and SMT D002 (formerly DL06003). The new names for Summit's preclinical candidates are: SMT C1100 (formerly VOXC 1100), for Duchenne muscular dystrophy; SMT D003 (formerly DL06005), for glaucoma; and SMT 14400 (formerly VOX 14400) for cancer.

ALzHEImER'S DISEASE - R&D UPDATECortex to resume enrolment in CX717 study at all dose levels

Following a review of the Ampakine CX717 data package sent to the FDA's Division of Neurology Products (DNP) on 17th April, the Agency has given Cortex Pharmaceuticals the go-ahead to immediately resume enrolment in the CX717 Alzheimer's disease (AD) PET scan study at all requested dose levels. The study was originally designed with doses of 200, 600 and 1,200mg to be administered to patients, however, the FDA previously limited the dose levels such that the 600 and 1,200mg doses could not be administered. The new protocol approved by the Agency allows a return to the original dose levels.

This double-blind study will attempt to determine if Cortex can duplicate the PET scan findings in non-human primates, which correlated with increased cognitive performance. The study is being performed in mild-to-moderate AD patients who are drug naïve or stabilised on cholinesterase inhibitors at the University of Michigan Medical Center. In animal studies, cholinesterase inhibitors such as Aricept (donepezil) and Reminyl (galantamine) appear to enhance the effects of CX717.

The earlier dose limitations imposed by the FDA were related to concerns over data from preclinical studies rather than any findings from clinical trials. The DNP plans to continue its review of the data package, but saw no reason to not permit the full resumption of the current AD PET scan study. Cortex will continue to have further discussions with the DNP regarding the previously-submitted toxicology package and additional requirements may be requested by the FDA.

Cortex intends to file a second IND for CX717 with the Division of Psychiatry Products during the third quarter of 2007, to allow the company to initiate a Phase IIb study evaluating the compound for the treatment of attention deficit hyperactivity disorder.

NEURODEGENERATIVE DISORDERSNEURODEGENERATIVE DISORDERS

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CNS Drug News

Affiris begins clinical testing of AD vaccine

Affiris' Alzheimer's disease (AD) vaccine, Affitope AD01, has entered the clinical phase of its development. Up to 24 patients with AD are to be vaccinated, with the aim of this initial Phase I trial being to demonstrate the vaccine's safety and suitability for human use.

Affiris has developed the vaccine from patented Affitope technology, which is based on mimotopes and allows customised vaccines to be manufactured cost-effectively. The company's approach protects brain cells and only combats the disease-causing amyloid beta.

The vaccine is being administered at the Vienna General Hospital in Austria, to patients who have reached the mild-to-moderate disease stage. Patients will be vaccinated four times over a period of three months, and the safety and suitability of the vaccine will be analysed over six months.

Researchers shed light on how diet and exercise enhance longevity

Through studying long-lived mice, Howard Hughes Medical Institute researchers at Children's Hospital Boston and Harvard Medical School have found that sensible diet, exercise and weight control extend life by reducing signalling through a specific pathway in the brain. The investigators, whose work was published in the 20th July issue of PNAS (2007;317:369-372), believe that their findings underscore the importance of maintaining a healthy lifestyle and may also offer promising research directions for understanding and treating Alzheimer's disease (AD) and diabetes.

The insulin-like signalling pathway is known to govern growth and metabolic processes in cells throughout the body. The pathway is activated when insulin and insulin-like growth factor-1 switch on insulin receptor substrates (Irs). Other researchers had shown that reducing the activity of the pathway in Caenorhabditis elegans and Drosophila extends lifespan, however, based on previous work, the team thought that more of the lrs, Irs2, in liver and pancreatic beta cells would be beneficial. lrs2 reduces the amount of insulin needed in the body to control blood glucose, plus it promotes growth, survival and insulin secretion from beta cells.

In earlier work, the researchers had found that knocking out both copies of the Irs2 gene in mice reduces brain growth and produces diabetes due to beta cell failure. However, in the new study, when the researchers knocked out only one copy of the gene, they found that the mice lived 18 per cent longer than normal mice.

Because reducing insulin-like signalling in the neurons of roundworms and fruitflies extends their lifespan, the researchers decided to examine what would happen if one or both copies of the Irs2 gene were knocked out only in the brains of mice.

Mice lacking one copy of the Irs2 gene in brain cells also showed an 18 per cent longer lifespan and the near complete deletion of brain Irs2 had a similar effect. Further, the animals lived longer, even though they had characteristics that should shorten their lives, including being overweight, hyperinsulinaemic and glucose intolerant. However, both sets of Irs2-knockout mice exhibited other characteristics that marked them as healthier. They were more active as they aged and after eating, the animals' brains showed higher levels of the potent antioxidant enzyme, superoxide dismutase.

These findings put a mechanism behind what is already known, that eating a good diet and exercising will keep a person healthy; diet, exercise and lower weight keep peripheral tissues sensitive to insulin.

This reduces the amount and duration of insulin secretion needed to keep glucose under control after eating, therefore, the brain is exposed to less insulin. Since insulin turns on Irs2 in the brain, that means lower Irs2 activity, which the researchers have now linked to longer lifespan in the mouse.

The investigators are planning subsequent studies to better understand how healthy ageing and lifespan are co-ordinated by Irs2 signalling pathways in the body and brain. Scientists now have a greater appreciation that obesity, insulin resistance and high blood insulin levels are connected to AD, Huntington's disease and dementias in general. These researchers speculate it is possible that in people who are genetically predisposed to these disorders, too much insulin overactivates Irs2 in the brain and accelerates disease progression. Thus, insulin resistance and higher insulin levels might be the environmental influences that promote these diseases.

AstraZeneca initiates Phase IIb trial of AZD3480 in AD

Targacept's strategic collaborator, AstraZeneca, has initiated a Phase IIb trial of AZD3480 (TC-1734) in Alzheimer's disease (AD).

This double-blind, placebo-controlled study is being conducted at sites in Western and Eastern Europe, as well as Canada. The trial design provides for approximately 500 patients with mild-to-moderate AD to be randomly assigned to one of three dose groups of AZD3480, an active comparator or placebo, and to be dosed over a 12-week period. The trial is expected to complete by the end of 2008.

AZD3480 acts selectively on neuronal nicotinic receptors (NNRs) and has been evaluated in 12 clinical trials in approximately 540 subjects. In a previous Phase IIb trial conducted by Targacept in age-associated memory impairment, AZD3480 achieved statistically significant results on all of the primary endpoints, demonstrating cognitive-enhancing effects in memory-impaired older adults. Furthermore, AstraZeneca is scheduled to begin dosing in a Phase IIb trial of AZD3480 for cognitive deficits in schizophrenia in August.

For details of further NNR research and a collaboration by Targacept, see Antidepressants, R&D Update; General Development News, R&D Update; and General Development News, Agreement News.

Compound reverses signs of AD

Biologists at the University of St Andrews in the UK have developed a compound, which is capable of blocking a nerve cell interaction that is known to lead to the symptoms of Alzheimer's disease (AD), as well as shown that it is possible to reverse some of the signs associated with the disease. Dr Frank Gunn-Moore's team, in collaboration with Columbia University researchers in the US, successfully reversed a sign for the progression of AD and prevented the death of brain cells.

In AD, the amyloid protein inflicts damage by interacting with an enzyme called ABAD (amyloid beta alcohol dehydrogenase) and releasing toxic substances that kill brain cells. Gunn-Moore's research, which was published in the June issue of Molecular and Cellular Neuroscience (2007;35:377-382) and carried out in the laboratory using a model of the disease, initially focused on developing the 3D shape of ABAD and understanding how amyloid attaches itself to the structure.

Patients with AD produce too much amyloid and ABAD in their brains. Based on their knowledge of ABAD, the researchers produced an inhibitor that can prevent amyloid attaching to it in a living model and showed that it is possible to reverse some of the signs associated with the disease.

NEURODEGENERATIVE DISORDERS


CNS Drug News

The work is now being continued to try and refine the inhibitor into a potential drug. According to Gunn-Moore, the research holds a possible key for the treatment of AD, particularly in its early stages. The Alzheimer's Research Trust has awarded the St Andrews team a further grant to develop the research over the next three years.

Neurochem granted fast track designation for Alzhemed

The FDA has designated Neurochem's investigational product candidate, Alzhemed (tramiprosate), as a fast track product for the treatment of Alzheimer's disease.

As previously reported, Neurochem requested a meeting with the FDA, which is now scheduled for August, with the Division of Neurology Products. The goal of this meeting is to have a discussion on the tramiprosate Phase III programme and present an update on the work accomplished, to date, on the North American Phase III trial. Neurochem will also seek the FDA's feedback and validation on the next steps that would be acceptable to the Agency, especially with respect to the statistical models.

In relation to the ongoing European Phase III trial, patient screening activities will stop in August, as Neurochem has exceeded its original patient enrolment objectives. However, in light of the information and experience gained from the North American trial, the company is presently considering modifications that would need to be made to the design of the European study.

PRODUCT NEwSNovartis' Exelon patch recommended for European approval

A patch that delivers Novartis' Exelon (rivastigmine) has received a positive opinion for treating mild-to-moderately severe forms of Alzheimer's disease (AD) from the EMEA's CHMP and the EC is expected to issue a decision on the product within three months.

Since 1997, Exelon has been used to treat mild-to-moderate AD in more than 70 countries. The FDA approved Exelon Patch on 6th July, for the treatment of both mild-to-moderate AD and Parkinson's disease dementia. The EU positive opinion was based on results from the international IDEAL (Investigation of Transdermal Exelon in ALzheimer's disease) trial, which showed that patients receiving the patch demonstrated improved memory, overall functioning and ability to perform everyday activities compared to those taking placebo.

The patch is applied to the back, chest or upper arm, and provides smooth and continuous delivery of medication through the skin over 24 hours, with the potential for improved efficacy. A key attribute of the patch is a sharp reduction in gastrointestinal side effects commonly seen with oral forms of the cholinesterase inhibitor class of drugs. In a clinical trial, these side effects were greatly reduced, with three-times fewer reports of nausea and vomiting than with the capsule form of the drug.

Designed with compliance in mind, the patch was preferred to capsules by >70 per cent of caregivers in a clinical study as a method of drug delivery because it helped them follow the treatment schedule, interfered less with their daily life and was easier to use overall than an oral medication.

Clinical Biomarkers Forum Harnessing the potential of biomarkers from translational research, throughout clinical trials

13th – 14th September 2007, Prague

Delegates already attending have brought their queries to the table, and will benefit from case study presentations and roundtable discussions on:

Maximising the potential of biomarkers across drug

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How companies have lowered attrition, risk and costs

Development of surrogate biomarkers and companion

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How can we translate pre-clinical results into humans?

Have companies seen a real reduction in timeframes as a

direct result of biomarker implementation?

When will regulations catch up with innovation?....And

much more!

What is your number one concern or question relating to the performance of biomarkers in R&D? Make sure that it is raised and answered at this unique event by registering today.

To download a brochure, visit our website at: www.clinicalbiomarkers.net

Our expert panel of speakers includes:

Dr Stefan Scherer, Biomarker Program Leader, AVASTIN, F. Hoffmann-La Roche Dr. Stefan Sultana, Translational Medicine Leader for GU Therapeutic Area, Pfizer Dr. Orest Hurko, Assistant Vice President, Translational Research, Wyeth Clavert Louden, Head, Department of Pathology Assessment,AstraZenecaDr. Thomas Senderovitz, Vice President Global Clinical

. Pharmacology & Experimental Medicine, UCB Pharma S.ADr. Chetan Lathia, Director, Global Clinical Pharmacology,Bayer Dr. Stefan Otto Muller, Senior Toxicologist, Merck Serono KGAADr. Eric Blomme, Project Leader, Cell and Molecular Toxicology, Abbott

Go online at www.clinicalbiomarkers.net

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AGREEmENT NEwSNeuroptix receives milestone payment from Merck in AD collaboration

Neuroptix has been granted a US$1 million milestone payment under its Alzheimer's disease (AD) diagnostic collaboration with Merck & Co. Under the agreement, which was announced in December 2006, Neuroptix provides Merck with access to its laser eye-scanning technologies, which in preclinical studies, have detected AD-related amyloid protein aggregates in the lens of the eye. The quantitative technique has potential for the early detection and monitoring of AD progression.

mULTIPLE SCLEROSIS - R&D UPDATEResearch identifies first new MS gene in 30 years

A gene has been identified that may hold the promise of guiding future research into therapies for multiple sclerosis (MS). According to its discoverers, this is the first major genetic advance in 30 years for understanding the disease.

The finding, which was published in the 29th July online edition of Nature Genetics (10.1038/ng2103), demonstrates that a functional gene variant on chromosome 5 was associated with an increased susceptibility to the disease. The gene increases an individual's risk of MS by 30 per cent and this variant has an effect on the function of the gene.

First author, Dr Simon Gregory, and his colleagues at Duke University Medical Center were joined by researchers from the University of California, San Francisco and the University of Cambridge in the UK, who spearheaded the collection of MS populations over many years, and the University of Miami and Vanderbilt University. The same team was also involved in another paper replicating similar findings from a whole-genome analysis, which was published in the 29th July online edition of the NEJM (10.1056/NEJMoa073493).

Previously-discovered MS genes were all located in an area of chromosome 6 involved in the major histocompatibility complex. The gene variation discovered in the new research is located on chromosome 5 and involved in guiding the production of interleukin-7 receptor alpha (IL-7R), which is a critical receptor for the development and growth of key immune system cells.

The scientists used the technique of genomic convergence, in which they took the results of many studies looking for common elements. From studies involving patients and their families in the US and UK, they analysed more than 7,000 DNA samples from patients with confirmed MS and those without the disease.

After winnowing down 28 candidate genes to the IL-7R gene, the researchers then tested their findings on a different set of patient populations to confirm the results. They showed that the same genetic change in IL-7R increased the risk of MS to a very similar extent in four different populations.

According to Gregory, as research builds upon the altered function of IL-7R, the mechanisms involved in the development of MS will be unlocked, which may lead to novel treatments for the disease or the identification of targets for new therapies.

Nuon raises funds to advance tranilast development

Nuon Therapeutics has completed a US$5 million series A financing, capital that will support clinical studies of its orally-active lead compound, tranilast, targeting multiple sclerosis (MS), rheumatoid arthritis (RA) and pain.

Kissei Pharmaceutical has marketed tranilast (under the brandname Rizaben) in Japan and Korea for bronchial asthma since 1982. Indications for keloid and hypertrophic scar were added in 1993. In addition, a Rizaben eye drop was launched in 1995 in these markets and is widely used for allergic conjunctivitis. Tranilast is thought to act in these diseases by inhibiting the release of chemical inflammatory mediators from mast cells. Nuon's strategy is to reposition it to treat MS, RA and pain, as well as build a portfolio of additional drugs in autoimmune disease and pain. Nuon's founding scientists have conducted wide-ranging preclinical testing of tranilast, with the compound showing improvement in an animal model of MS.

The funding will enable Nuon to advance tranilast through the next phase of clinical development, as well as support the discovery and development of additional compounds. Initially, the funds will be used to develop and protect the company's intellectual property, hire staff, secure supply of drug product, undertake related licensing and open an FDA IND application.

For details of Nuon completing a licensing, supply and collaboration agreement with Kissei for tranilast, see Agreement News.

BioMS' RRMS trial receives positive DSMB review

The independent Data Safety Monitoring Board (DSMB) for BioMS Medical's Phase II MINDSET-01 trial of MBP8298 in patients with relapsing-remitting multiple sclerosis (RRMS) has completed a safety analysis and recommended that the trial continue as per the protocol. This was the first of several regularly-scheduled reviews by the DSMB that will occur over the duration of the study.

MINDSET-01 is a 15-month, double-blind, placebo-controlled trial. The objectives of the study, which is fully enrolled with approximately 215 patients at 24 sites in six countries, are to demonstrate the safety and efficacy of MBP8298 versus placebo, as measured by relapse rate, MRI activity and disease progression.

PRODUCT NEwSGW withdraws European application for Sativex in MS spasticity

GW Pharmaceuticals has chosen to withdraw its current regulatory application for Sativex, a cannabis-derived, oro-mucosal spray composed primarily of tetrahydrocannabinol and cannabidiol, in Europe, but expects to resubmit an application for approval in 2008. This follows constructive and detailed discussions with regulatory authorities in which they have provided a clear path to approval for Sativex in the treatment of multiple sclerosis (MS) spasticity.

In September 2006, GW filed an application for Sativex under the decentralised procedure in four European countries (the UK, Spain, Denmark and the Netherlands) for the relief of MS spasticity. The company has been able to successfully resolve all the major questions raised by the regulators during this process except one, and at a recent meeting with the UK assessors, it became clear that this outstanding



CNS Drug News

issue requires the generation of additional data. As European regulatory rules do not permit the introduction of new data as part of the current process, GW has elected to withdraw and resubmit its application.

The regulator's outstanding clarification relates to the fact that in a clinical trial context, the benefit obtained by "responders" can be masked by looking at the mean improvement across the entire studied patient population, which comprises both responders and non-responders. The regulators therefore wish to be able to identify Sativex responders in the first four weeks of treatment and to confirm that the improvements gained by such responders over a further 12-week period is significantly greater than placebo.

As part of the current regulatory process, GW performed analyses of existing data showing that responders can be reliably identified after four weeks and that after 12 weeks, the difference from placebo is clinically important and highly statistically significant (p=0.015). The regulators view this as acceptable evidence of efficacy in principle, but consider these analyses technically to be post hoc since they were performed at the regulator's request following completion of the trials. They require such data to be produced as part of a prospectively-planned analysis and hence GW will undertake an additional study to reconfirm this result prior to resubmitting its regulatory application.

The regulators have given GW clear guidance as to the design of the required further study, which differs from a conventional Phase III design. The study is expected to start recruiting patients in the next few months, with the results due in the second half of 2008. The regulators have specified a novel "enriched design," which first identifies responders over a four-week period and then focuses on analysing the effect of Sativex versus placebo on those responders over a further period of time. GW's clinical plans for the next 12 months already included a further MS spasticity trial, therefore the regulator's specific design requirements will be incorporated into this planned study.

There are two potential opportunities for early resubmission in Europe next year. In the indication of MS neuropathic pain, a second pivotal Phase III trial is expected to complete in early 2008, which could lead to a regulatory filing in this indication at that time. Since this is a distinct indication from MS spasticity, the outstanding issue identified as part of this recent application would not be relevant. In the event that GW does not submit for this indication, the second opportunity is to resubmit for MS spasticity later in 2008, following completion of the new study.

Elsewhere, the company anticipates receiving final regulatory approval in Canada for the cancer pain indication in the coming weeks and its first large-scale clinical trials in the US are scheduled to commence in late summer. To date, GW has entered into Sativex licence agreements with Otsuka in the US, Bayer HealthCare in the UK and Canada, and Almirall in Europe (excluding the UK).

AGREEmENT NEwSGlenmark purchases rights to CHR-1103 and CHR-1201 from Chromos

Glenmark Pharmaceuticals has completed its purchase of Chromos Molecular Systems' two new biological entities (NBEs), CHR-1103 and CHR-1201, which are humanised therapeutic monoclonal antibodies (MAbs). Under the terms of the transaction, Glenmark has purchased all rights to the two products, as well as rights to use Chromos'

3 easy ways to register Online: www.lifescienceworld.com/2007/neuroEmail: [email protected]: +44 (0) 207 539 4336 Event code: 14/1318 / Espicom

23 - 25 October 2007 The Royal Garden Hotel London, United Kingdom

CNS disorders: today’s science to tomorrow’s market

CNS disorders are one of the leading causes of mortality worldwide. According to reports, neurological disorders affect over 1 billion people globally. The prevalence of these disorders is rising, principally driven by a global aging population. However there is a lack of blockbuster drugs and targeted therapies to cater for the number of patients and range of disorders.

NeuroDrug 2007 focuses on drug discovery and development across the CNS sector. Our agenda focuses on novel therapeutic targets for neurological, neurodegenerative and psychiatric disorders. Key learning include case studies on cutting edge drugs and therapies, lead optimisation, novel biomarkers and imaging, latest approaches to drug delivery and crossing the blood brain barrier.

The best mix of expert speakers from the pharmaceutical and biotech sectors

Our senior level speakers come from world class pharmaceutical companies, leading biotechs and unrivalled medical research centres. Represented companies include GlaxoSmithKline, AstraZeneca, Johnson & Johnson, Wyeth, Eli Lilly, Boehringer Ingelheim, Schering-Plough, UCB Pharma, Lundbeck, Pierre Fabre, Otsuka Maryland Medicinal Laboratories, Oxford BioMedica and the Foundation for the NIH. 90% of speakers are CxO’s, Therapeutic Area Heads, Directors or Presidents. Advances in CNS drug discovery and development are best achieved through knowledge sharing and collaborations.

Eli Lilly explains why this is a must attend event

"Neurodrug 2007 offers an excellent insight into multiple aspects of CNS drug discovery. The meeting has topics that relate to most CNS disorders such as new technology, drug delivery, biomarkers and more specific focused topics such as small molecule, viral delivery and stem cell approaches to treat neurodegeneration. The varied approaches taken for certain diseases should make an interesting meeting with

opportunity to discuss and network".

Dr Michael J. O'Neill, Research Advisor, Neurodegeneration Drug Team, Eli Lilly



CNS Drug News

proprietary ACE System technology for cell line development for use with respect to the two NBEs. Glenmark holds the worldwide rights for further development, registration and commercialisation of these products. Further terms were not disclosed.

The NBEs are part of a validated class of drugs known as selective adhesion molecule inhibitors. CHR-1103 is a broad anti-inflammatory agent with a novel mechanism of action that is initially being developed to treat acute multiple sclerosis. Glenmark plans to initiate Phase I trials in 2008 and complete this stage of development with CHR-1103 by March 2009. CHR-1201 is an antithrombolytic humanised MAb that Glenmark initially plans to develop to treat acute stroke; the company plans to start Phase I development with CHR-1201 by March 2009.

Nuon and Kissei complete tranilast agreement

Nuon Therapeutics has completed a licensing, supply and collaboration agreement for tranilast with Kissei Pharmaceutical. The agreement will enable Nuon to advance tranilast through the next phase of clinical development, while giving Kissei the exclusive option right for research, development and marketing of tranilast in Japan and Korea in the autoimmune disease field, including multiple sclerosis (MS). The partnership will enable multiple Phase II development programmes.

The terms of the agreement include provisions for Kissei to supply tranilast to Nuon for clinical trials and license Nuon-related intellectual property (IP) on the compound. The agreement also establishes a collaborative relationship between the companies for the development of additional portfolio products. Nuon has licensed and developed worldwide IP for the use of tranilast to treat MS, rheumatoid arthritis, pain and other indications.

For details of Nuon raising funds to advance tranilast's development, see R&D Update.

OTHER NEURODEGENERATIVE DISORDERS - R&D UPDATE

TBZ protects brain cells in HD model

University of Texas Southwestern Medical Center researchers have found that a drug used in some countries to treat the symptoms of Huntington's disease (HD) prevents the death of brain cells in mice genetically engineered to mimic the hereditary condition. The research, which was published in the 25th July issue of the Journal of Neuroscience (2007;27:7899-7910), sheds light on the biochemical mechanisms involved in the disease and suggests new avenues of study for preventing brain cell death in at-risk people before symptoms appear.

The drug, called tetrabenazine (TBZ), is commercially distributed as Xenazine or Nitoman and blocks the action of dopamine. TBZ is approved for use in several countries, but not the US, to treat uncontrollable muscle movements in HD and other neurological conditions.

In the study, the researchers used mice that were genetically engineered to carry the mutant human gene for HD, causing symptoms and the death of brain cells similar to those seen in the disease. The study focused on the striatum, which is primarily made up of medium spiny neurons that undergo widespread death in HD.

The researchers conducted various co-ordination tests on both normal and genetically-manipulated mice. Engineered mice given a drug that increased brain dopamine levels performed worse on these tasks, while TBZ protected against this effect. Most importantly, TBZ appeared to significantly reduce cell loss in the striatum of the engineered mice.

More research is needed to determine whether this protective effect might also be present in humans and if at-risk people would benefit from the drug. However, senior author, Dr Ilya Bezprozvanny, believes that clinical trials would be difficult, because they require many participants and there is no easy way to score the effectiveness of a presymptomatic drug. Thus, his future studies in animals will look at the effectiveness of TBZ given just after initial symptoms have developed, a situation that simulates what would probably happen in a human trial.

Editor's note: Cambridge Laboratories has worldwide rights to TBZ and markets the product itself in the UK and Eire, and through marketing partners in Europe and other global markets.

Avicena to proceed with confirmatory Phase III ALS trial

Avicena Group has met with the FDA and plans to proceed with a confirmatory Phase III trial of its lead drug candidate, AL-02, for the treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease).

Two completed Phase III studies demonstrated a positive trend towards increased survival at nine months and Avicena will be analysing the data at the 18-month time point to confirm a longer-term survival benefit. These data will be used to support the new Phase III study, which is planned to commence in 2008 and will be designed to evaluate AL-02's potential to increase survival.

First patient treated in Phase II trial of Dimebon for HD

The first patient has been treated in Medivation's Phase II trial of Dimebon to treat Huntington's disease (HD), plus the company has expanded enrolment in the study by 20 per cent (to 90 patients) in order to enhance the ability to detect differences between the compound and placebo.

Medivation is conducting the trial in collaboration with the Huntington Study Group (HSG). The Phase II portion will be conducted at approximately 17 HSG sites in the US and Europe, and is a randomised, placebo-controlled, double-blind evaluation of the safety and preliminary efficacy of Dimebon in 90 patients with HD after three months of dosing. The primary efficacy endpoint of the Phase II portion is the UHDRS and Medivation expects to report study data in the first half of 2008. According to the company, the results from the Phase I portion of the study have allowed it to move forward to the preliminary efficacy phase.

Dimebon is an orally-available small molecule that has been shown to prevent the death of brain cells in preclinical models of HD and Alzheimer's disease, making it a novel potential treatment for these and other neurodegenerative diseases. Based on the clinical and preclinical data generated, to date, Medivation believes that Dimebon operates by a novel mechanism of action and may exert a neuroprotective effect in multiple areas of the CNS. Dimebon appears to block a new target that involves mitochondrial pores, which are thought to play a role in the cell death that is associated with neurodegenerative diseases and the ageing process.



CNS Drug News

Intellect reports positive safety data from Phase Ia Oxigon trial

Intellect Neurosciences has obtained validated data and an audited report describing the results of a Phase Ia trial of Oxigon, which indicate no serious adverse effects in any of the subjects throughout the dose levels.

This double-blind, randomised, placebo-controlled, single escalating-dose study in 54 elderly healthy volunteers was conducted in the Netherlands under Ethics Committee approval in Utrecht. Intellect designed the trial to determine the safety, tolerability and pharmacokinetics of Oxigon with and without food interactions.

Oxigon is a chemically-synthesised form of a small, naturally-occurring molecule that has unique antifibrillogenic, neuroprotectant and antioxidant properties. Oxigon can reduce the accumulation of toxic soluble amyloid beta peptides and inhibit plaque deposition. Simultaneously, it acts as a neuroprotectant, preventing neuronal damage from amyloid beta-induced oxidative stress. Preclinical studies using transgenic mouse models have provided evidence that the compound has the potential to reduce brain amyloid burden and improve cognition in Alzheimer's disease, while additional studies have demonstrated its potential utility to treat indications and conditions such as Parkinson's, Huntington's and other diseases in which oxidative stress is believed to be a significant contributing factor.

Intellect is the exclusive licensee of patents related to the use of Oxigon, which are owned jointly by New York University and the University of South Alabama. Patents have been granted in Europe, the US and several other countries.

PRODUCT NEwSNeurochem receives second FDA approvable letter for Kiacta in AA amyloidosis

Neurochem has received a second approvable letter from the FDA for Kiacta (eprodisate), for the treatment of amyloid A (AA) amyloidosis.

In its action letter, the FDA indicated that the Phase II/III trial provided some evidence of the effectiveness of Kiacta, which has received orphan drug status in the US, EU and Switzerland, for the treatment of the renal manifestations of amyloidosis, however, the Agency also indicated that an additional efficacy trial with a target p-value of 0.05 will be necessary before it could approve the investigational product candidate.

Furthermore, the approvable letter stated that additional submissions, filed by Neurochem as part of its complete response to this approvable letter, may address issues raised in this letter. The FDA has indicated that such additional submissions could persuade it to eliminate the requirement for an additional trial. The Agency also asked for additional information, including further pharmacokinetic studies, and again acknowledged that a QT clinical study should be submitted as part of a Phase IV commitment. The company expects to file a complete response to this approvable letter in the near future.

Rilutek patent ruled not invalid

The US District Court for the District of Delaware has ruled that Aventis Pharmaceutical's (sanofi-aventis) Patent No. 5,527,814 related to the use of Rilutek (riluzole) for the treatment of amyotrophic lateral

sclerosis (Lou Gehrig's disease), is not invalid on the grounds of anticipation. This decision comes following a remand from the Court of Appeals for the Federal Circuit in November 2006, in which the Court had vacated an earlier decision of patent validity and remanded for further findings relating to a specific validity issue of anticipation by a prior art patent.

Impax Laboratories' ANDA for its generic version of Rilutek 50mg tablets was approved on 29th January 2003 by the FDA, but the product has never been sold due to an injunction entered in this patent litigation.

AGREEmENT NEwSBiogen Idec to exercise first milestone investment in ALS collaboration with Amorfix

Amorfix Life Sciences has received notice from Biogen Idec that it will be exercising the first milestone investment under an August 2006 research and investment agreement.

The milestone investment allows Biogen Idec to retain its exclusive worldwide option to license Amorfix' therapeutic candidates for amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease). Biogen Idec will subscribe for 91,445 shares of Amorfix at a price of C$1.76 per share for gross proceeds to Amorfix of US$150,000; the shares are subject to a four-month hold period.

The companies entered into the agreement to develop and commercialise Amorfix' technology directed against ALS, which includes an option for Biogen Idec to license the exclusive worldwide rights to the technology. According to Amorfix, which has achieved the first of three predefined milestones for its therapeutic ALS programme with Biogen Idec, the research is focused on the role of monoclonal antibodies (Abs) targeted to misfolded superoxide dismutase-1 (SOD1) for the treatment of ALS.

Amorfix has demonstrated that a targeted immunotherapy approach can diminish the motor neuron effects of ALS in animals. Its approach is based on the premise that the misfolding and aggregation of SOD1 is a principal agent in the death of motor neurons in all types of ALS disease. Amorfix believes that if the misfolded SOD1 could be specifically recognised and neutralised by Abs prior to aggregation, the disease could be effectively treated. This approach could be extended beyond ALS to other misfolded protein diseases, such as Alzheimer's and Parkinson's, where misfolded proteins have been identified.

Tikvah/Academia Sinica enter licensing agreement for neurodegenerative disorders

Tikvah Therapeutics has entered into an exclusive licensing agreement for a number of patent and patent applications with Academia Sinica encompassing the diagnosis, methods of use and treatments of a variety of neurodegenerative disorders, including, amongst others, spinal muscular atrophy (SMA). The subject of this agreement is technology developed at Academia Sinica.

Under the terms agreed, Tikvah will be conducting the clinical development of agents. Tikvah will pay a licensing fee, potential milestones and royalty payments in exchange for an exclusive licence to pursue the commercial development of the technology for the treatment of SMA and other neurodegenerative diseases.



CNS Drug News

CEREBROVASCULAR DISORDERSR&D UPDATE

SYGNIS completes Phase IIa study of AX200 in stroke

SYGNIS Pharma has successfully completed a multi-centre, double-blind, placebo-controlled, dose-escalation, Phase IIa study of AX200 in stroke. A comprehensive analysis of the AXIS study data show that the primary and secondary endpoints were achieved and that the use of AX200 in stroke patients can be considered safe. Although the focus of the study was the collection of data regarding safety and tolerability, data on the efficacy of AX200 were also monitored. Due to the small number of patients involved in such a safety study, a

significant difference between AX200- and placebo-treated patients could not be observed in the overall consideration of the usual clinical endpoints. However, a detailed statistical evaluation of the data provided has suggested that certain stroke patients may benefit from a treatment with AX200.

Besides stroke, SYGNIS is currently preclinically testing the endogenous protein, AX200, in further neurodegenerative indications, such as amyotrophic lateral sclerosis (Lou Gehrig's disease).

Following the positive results of the AXIS study, SYGNIS is in the process of designing and preparing a Phase IIb trial, the aim of which will be to demonstrate the efficacy of AX200 in stroke patients.

ANXIOLyTICS/SLEEP DISORDERSR&D UPDATE

deCODE discovery points to new RLS treatment approach

Scientists at deCODE genetics, in collaboration with colleagues from Emory University, have discovered the first variant in the sequence of the human genome ever linked to risk of restless legs syndrome (RLS) and periodic limb movements (PLMs).

The SNP in the BTBD9 gene on chromosome 6 was associated in Icelandic and US cohorts with an increased risk of RLS with PLMs of 70 to 80 per cent for those who carry one copy, compared to those without the variant. It is believed to account for approximately 50 per cent of cases and was shown to associate with decreased stores of iron in the body.

The discovery, which was published in the 18th July online edition of the NEJM (10.1056/NEJMoa072743), provides new evidence that RLS is a genuine disease with an identifiable biological basis. deCODE plans to analyse the BTBD9 pathway to begin a drug-discovery programme targeting the underlying causes of disease.

The deCODE team analysed more than 300,000 SNPs in a total of 1,000 Icelandic RLS patients and controls, leading to the identification of a single SNP on chromosome 6p21. The strongest association was between allele A of SNP rs3923809 and the combined phenotype of RLS with PLMs.

The rs3923809 is located within the BTBD gene, which is widely expressed in the brain and other organs. The finding was subsequently confirmed in a case-control cohort from the Emory Healthcare Program in Sleep in Atlanta, GA.

The variant identified also confers risk of PLMs without RLS, with individuals carrying two copies of the at-risk variant having two-fold risk of PLMs compared to those that do not carry a copy of the variant. Analysis of the impact of the variant on serum ferritin levels, a principal indicator of iron stores in the body, showed that serum ferritin was 13 per cent lower per copy of the variant carried compared to controls. Hence, this discovery supports an old notion that the pathogenesis of RLS may involve iron metabolism.

Severe trauma may affect children's brain function

The first study to examine brain activity patterns in severely-traumatised children has suggested that their brains function differently than those of healthy children, according to researchers at the Stanford University School of Medicine and Lucile Packard Children's Hospital.

The study, which was published in the 27th June online edition of Depression and Anxiety (10.1002/da.20346), hints at the biological underpinnings of post-traumatic stress disorder (PTSD), as well as provides a valuable benchmark with which to assess the effectiveness of potential therapies. However, it is not yet clear whether the brain differences are caused by the interpersonal trauma experienced by the children or if pre-existing differences make some children more susceptible to developing PTSD after traumatic events than their more resilient peers.

The researchers used functional MRI (fMRI) to compare brain activation patterns in 16 children with symptoms of PTSD to the patterns seen in 14 age- and gender-matched non-traumatised children as they performed a simple decision-making task. It was found that although the two groups accomplished the task equally well, they used different parts of their brains to do so. The children with PTSD symptoms showed less activity than their non-traumatised peers in the left middle frontal cortex, an area known to be involved in response inhibition, and more activity in several other areas of the brain, including the insula.

People with PTSD often have trouble paying attention and responding appropriately to experimental tasks, perhaps due to heightened physiological arousal arising from their traumatic experience. As a result, many children with PTSD symptoms are diagnosed with attention deficit hyperactivity disorder, but it is difficult to tell whether the two disorders are truly related, or if they simply have overlapping symptoms; functional imaging such as fMRI may allow researchers to solve this mystery, plus it may help doctors to devise better therapies.

According to lead author, Dr Victor Carrion, it may be possible to redirect the brain's altered processing functions. Ideally, people will one day be able to compare brain images from before and after treatment to determine what does or does not work for children with PTSD.

CEREBROVASCULAR DISORDERS / ANXIOLyTICS/SLEEP DISORDERS


CNS Drug News

PRODUCT NEwSSepracor submits Lunivia MAA

Sepracor has submitted an MAA for Lunivia (eszopiclone) to the EMEA for review under the centralised procedure, with EU approval targeted for the second half of 2008. Eszopiclone is known in the US as Lunesta and indicated for the treatment of insomnia.

The MAA contains results from 122 preclinical and 35 clinical studies, which included more than 5,500 adult and older adult (>65 years of age) subjects, including patients with transient or chronic insomnia. In addition to studies of the drug in patients with insomnia and co-existing conditions, two six-month, placebo-controlled studies in primary insomnia, as well as two driving studies that Sepracor believes will support a European labelling claim that Lunivia shows no effect on next-day driving (as measured by brake reaction time) in healthy subjects or subjects with insomnia, were included as part of the submission.

Sepracor has also commenced enrolment in its six-month, Pan-European study of Lunivia co-administered with Wyeth Pharmaceuticals' Effexor XR (venlafaxine) in subjects with insomnia and co-existing major depressive disorder. This 640-patient trial seeks to assess the potential benefit of Lunivia in the reduction of symptoms of depression and in relapse prevention.

For details of an agreement for the development and commercialisation of eszopiclone for the Japanese market, see Agreement News.

Caraco receives tentative FDA approval for generic Provigil

On 18th July, the FDA granted tentative approval for Caraco Pharmaceutical Laboratories' ANDA for modafinil tablets 100 and 200mg, which is indicated to improve wakefulness in patients with excessive sleepiness associated with narcolepsy and is bioequivalent to Cephalon's Provigil.

AGREEmENT NEwSEisai enters partnership for Sepracor's eszopiclone

Eisai has entered into an agreement for the development and commercialisation of Sepracor's insomnia product, eszopiclone, which is known as Lunesta in the US and Lunivia in Europe, for the Japanese market. Under the terms agreed, Eisai will be responsible for completing the remaining clinical trials necessary for attaining marketing approval from the Japanese regulatory authorities and contingent on regulatory approval, commercialisation of the product in Japan.

Sepracor anticipates that the Japanese marketing application will be submitted in 2010 or 2011. In exchange, the company is entitled to receive an initial milestone payment and subsequent payments upon the accomplishment of various development, regulatory and pricing milestones, as well as royalties on product sales and compensation for providing the product's active ingredient.

For details of Sepracor submitting an MAA for Lunivia, see Product News.

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An expanding market, a growing

population, a regulatory

regime supportive of the generics sector, robust

domestic production and many untapped opportunities.

Is Brazil the place for generic companies to be?

The world’s major emerging economies are attracting much investment and interest. Brazil is not least among them, and it is easy to see why with a population of 189 million and a GDP of US$978 billion in 2007.

www.espicom.com/brazilgen

Key areas addressed:5-year market forecast to 2012The generics market in contextReview of the product registration procedurePricing issues and reimbursementPolitical, legal and economic assessmentInsightful review of 20 major domestic and foreign players in the marketDetailed product registration dataWho produces what?

•••

••

•

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Includes A weAlth of InformAtIon not AvAIlABle In

englIsh elsewhere!

Marketforecasts andtrend analysis!

All this and more can be found in this new 200-page management

report, published in April 2007

ANXIOLyTICS/SLEEP DISORDERS

©Espicom Business IntelligencePage 1� �nd August �007

CNS Drug News

R&D UPDATEBL-1020 shows antipsychotic efficacy; enters Phase II trial in schizophrenia

BioLineRx has successfully completed a study determining the clinical binding properties of BL-1020 to dopamine receptors in the brain. The study has shown that BL-1020, an orally-available, GABA-enhanced antipsychotic clinical candidate for the treatment of schizophrenia, blocks dopamine receptors in the human brain, providing direct evidence of antipsychotic efficacy. The study further supports the safety of BL-1020, as well as provides evidence that 32mg will be clinically efficacious and that the compound can be given once daily.

The study's primary objective was to investigate the receptor occupancy of BL-1020 in the human brain, however additional safety, tolerability and pharmacokinetic data were also generated. The study was conducted in Uppsala, Sweden, and designed as a single-centre, randomised, open-label evaluation performed on three cohorts, each with four healthy male subjects (aged 21 to 35 years) receiving a single dose of BL-1020 16, 24 or 32mg. Receptor occupancy was assessed using PET scans at 1.5, six or 24 hours post-dosing. The PET data demonstrated a dose-dependent increase in dopamine

occupancy that supports the 32mg dose as being able to achieve clinically-efficacious dopamine blockade. The efficacy of BL-1020 was also demonstrated by measuring the elevation in prolactin levels, an accepted marker for dopamine activity. There was a dose-dependent change in prolactin level at four hours post-dosing, further validating earlier Phase I results. Safety and tolerability data show that there have been no significant changes in ECG, vital signs or physical examination, clinical chemistry or haematology values.

In addition...

BioLineRx has initiated a Phase II trial to determine the maximal tolerated dose of BL-1020 in 60 patients with schizophrenia or schizo-affective disorder. This open-label, multi-centre, six-week, sequential cohort study is expected to be conducted at five centres in Israel and 12 centres in Romania. The dose ranges are based on results in previous studies performed on healthy volunteers.

BL-1020 is being developed by BioLineRx under a worldwide exclusive licence from Ramot at Tel Aviv University and Bar-Ilan Research & Development, the technology transfer arms of Tel Aviv University and Bar-Ilan University, respectively. Data from preclinical and Phase I studies demonstrated that the compound may retain the efficacy of currently-available typical and atypical antipsychotic drugs, while

ANTIDEPRESSANTSR&D UPDATE

Add-on mecamylamine treatment shows positive effects in depression

At the Summer Meeting of the British Association for Psychopharmacology (BAP), held from 22nd to 25th July, in Harrogate, the UK, Targacept presented positive research findings suggesting that an add-on treatment of mecamylamine, a broad-spectrum nicotinic antagonist, improved symptoms of depression in patients who were inadequate responders to first-line citalopram therapy.

The study included an open-label citalopram phase and a subsequent double-blind, placebo-controlled phase in which the effects of mecamylamine taken with citalopram, a treatment combination known as Tridmac, were evaluated in patients who did not respond adequately to citalopram alone. In the trial, the treatment combination of mecamylamine and citalopram was generally well tolerated. Also, patients showed greater improvement on symptoms of depression and irritability when augmented with mecamylamine, as compared to placebo. Patients for the trial were recruited from nine out-patient facilities, one in the US and eight in India. Of the 472 subjects screened, 450 entered the trial and 192 were randomised to double-blind medication. Mecamylamine represents a new class of promising antidepressant medications that target the brain's neuronal nicotinic receptors (NNRs). Targacept's depression programme also includes TC-5214, one of the enantiomers of mecamylamine hydrochloride and a preclinical product candidate as an augmentation therapy, and TC-2216, a product candidate as a monotherapy for depression and anxiety disorders that is currently in an ongoing Phase I trial.

For details of further NNR research and a collaboration by Targacept, see Neurodegenerative Disorders, Alzheimer's Disease - R&D Update; General Development News, R&D Update; and General Development News, Agreement News.

PRODUCT NEwSAbilify sNDA granted priority review by FDA

The FDA has accepted for filing and granted a priority review of the sNDA for Bristol-Myers Squibb/Otsuka Pharmaceutical's atypical antipsychotic, Abilify (aripiprazole), for the treatment of adults with major depressive disorder (MDD) as adjunctive to antidepressant therapy (ADT). The application is based on data from two six-week, double-blind, randomised, placebo-controlled, multi-centre trials (n=743) evaluating the use of adjunctive Abilify in adult patients with a primary diagnosis of MDD who had an inadequate response to monotherapy with one or more ADTs.

Biovail receives non-approval letter from FDA for BVF-033

Biovail has received a non-approval letter from the FDA for its NDA for BVF-033, a novel, once-daily salt formulation of bupropion for the treatment of depression. The main issue raised by the Agency in its letter related to the design of the pharmacokinetic studies required to support the NDA.

Biovail believes that the studies were appropriate, but is evaluating the issue and will meet with the FDA as soon as possible to discuss the necessary steps to resolve this matter.

PSyCHOTIC DISORDERS

ANTIDEPRESSANTS / PSyCHOTIC DISORDERS


CNS Drug News

achieving a higher safety profile, as evidenced by a lack of metabolic or extrapyramidal side effects. Based on its previous results, the company believes that BL-1020 has the potential to be clinically efficacious, with minimal therapy-limiting side effects, and expects Phase IIa trial results during the fourth quarter of 2007.

Drug may help people with OCD; to be tested on smokers

Researchers at the University of Minnesota have found that a drug originally developed to fight tuberculosis may help people with obsessive-compulsive disorder (OCD) to make more progress in therapy sessions. The drug, D-cycloserine, is believed to help accelerate ''extinction learning'' and the team now wants to see if it could have a similar effect on people who want to quit smoking.

In this research project, which was led by Dr Matt Kushner and published in the 22nd June online edition of Biological Psychiatry (10.1016/j.biopsych.2006.12.020), investigators separated patients with OCD into two groups. One group received the drug and the other received placebo, several hours before psychotherapy.

It was found that those who took D-cycloserine made progress in therapy more quickly and were less likely to quit therapy compared with the placebo group. The research subjects who took the drug reported feeling less distress or anxiety due to their obsessions or compulsions. The drug seemed to be most effective in the first few therapy sessions. Over time, people in the placebo group could catch up in terms of therapy goals, but more study participants in the placebo group dropped out of therapy. The drop-out rate decreased dramatically; typically, approximately 20 to 30 per cent of people with OCD drop out of therapy, but only 7 per cent of people who took D-cycloserine did so.

According to Kushner, the drug must be taken in conjunction with therapy to be effective. His team is now studying how it will effect smokers who want to quit and is seeking participants. This project will investigate whether or not a similar extinction learning effect will be seen in people who smoke.

Study participants will be given nicotine-extracted cigarettes to smoke and similar to the previous study, one group will receive the drug and another placebo, prior to therapy sessions. Participants will attend sessions once weekly for four weeks and be asked to smoke only the nicotine-extracted cigarettes in between the sessions.

Children show sustained improvement after ADHD treatment

It has been reported that most children treated in a variety of ways for attention deficit hyperactivity disorder (ADHD) showed sustained improvement after three years in a major follow-up study funded by the National Institute of Mental Health, yet increased risk for behavioural problems, including delinquency and substance use, remained higher than normal.

The study followed-up children who had participated in the Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder (MTA). Initial advantages of medication management alone or in combination with behavioural treatment over purely behavioural or routine community care waned in the years after 14 months of controlled treatment ended. However, Dr Peter Jensen of Columbia University and colleagues emphasised that it would be incorrect to conclude from these results that treatment

Many claim the BRIC countries present the most exciting opportunity for pharmaceutical manufacturers. Maybe, but separating the fact from the fiction is essential in making sound business judgements.

These leading emerging and rapidly-growing economies represented a total market of 2.7 billion people and a combined GDP of US$5.2 trillion in 2006. But where do commercial opportunities exist for pharmaceutical companies now?

COMPARATIVE OVERVIEW

This extensive section compares and contrasts the economic, health and pharmaceutical operating environment in the 4 markets.

COUNTRY ANALYSIS

Key National IndicatorsHealthcare SystemThe Pharmaceutical MarketAccessing the Pharma MarketContact Details

QUARTERLY UPDATE REPORTS INCLUDED!

Buyers of this report will receive, for each market, 4 quarterly reportscovering:

Current market sizeUnique 5-Year market projections to 2011Market outlook & structureComment & ratingImports & export dataMarket developments, covering recent and impending developments with respect to key issues such as regulation, health facilities, and funding

Copies of The Market for Pharmaceuticals in Brazil, Russia, India & China 2007

are available for £1295 / $2655 / €2330 from Espicom in either print or pdf format. For

ordering details please see the back page of this issue.

Alternatively call ourUK office on tel: +44 (0) 1243 533322

US office on tel: +1 609 951 2227

www.espicom.com/bricp

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CNS Drug News

makes no difference or is not worth pursuing. Their report is among four on the outcome of the MTA study published in the August issue of the Journal of the American Academy of Child and Adolescent Psychiatry (2007;46:989-1002). According to Jensen, the results suggest that medication can make a long-term difference for some children if it is continued with optimal intensity and not started or added too late in a child's clinical course.

Progressive grey matter loss discovered in BPD

Researchers at the University of Edinburgh have found that people with bipolar disorder (BPD) suffer from an accelerated shrinking of their brain. The study shows for the first time that BPD is associated with a reduction in brain tissue and proves that the changes get progressively worse with each relapse.

Furthermore, the findings, which were published in the 9th July online edition of Biological Psychiatry (10.1016/j.biopsych.2007.03.005), show that the loss of grey matter tissue is concentrated in areas of the brain that control memory, face recognition and co-ordination, namely the hippocampus, fusiform gyrus and cerebellum, respectively.

According to lead researcher, Dr Andrew McIntosh, this discovery has implications for the way the disease is researched and may also impact the way it is treated. The amount of brain tissue that is lost is greater in people with multiple episodes of illness and is associated with a decline in some areas of mental ability. However, McIntosh believes another possibility is that the brain changes are caused by stress or genetic factors, which tend to lead both to more frequent illness episodes and to greater brain loss, thus further research will be required.

PRODUCT NEwSEMEA recommends authorisation of first generic medicine for human use

The EMEA has adopted a positive opinion recommending, for the first time, the granting of a marketing authorisation for a generic of a centrally-authorised medicine for human use. The recommendation was made by the Agency's CHMP at its July meeting.

This first positive opinion is for Zalasta (olanzapine), from Krka, which is intended for the treatment of schizophrenia and moderate-to-severe manic episode. The reference product for Zalasta is Eli Lilly's Zyprexa (olanzapine), which has been authorised in the EU since 1996. The CHMP recommendation will now be forwarded to the EC for adoption of a decision.

Shire's Vyvanse available in US pharmacies

Shire's Vyvanse (lisdexamfetamine dimesylate), a new once-daily medication approved to treat the symptoms of attention deficit hyperactivity disorder (ADHD), is now available in US pharmacies nationwide. The FDA approved Vyvanse on 23rd February and the product is now available in retail pharmacies in 30, 50 and 70mg dosage strengths.

Vyvanse works with the patient's natural metabolism to deliver active medication and significantly improves core ADHD symptoms of inattention and behaviour. In a randomised, double-blind, placebo-controlled, Phase III study, all three doses of the drug demonstrated significant improvements in ADHD Rating Scale-IV scores compared

After years of anticipation and encouraging responses

to pathfinder products, monoclonal antibodies are now set to realise their true

clinical and commercial potential. But what are the prospects for the products that will lead the market?

HUGE POTENTIALWhile large pharma companies predictably take aim at the largest treatable populations (breast cancer, colorectal disease, NHL, leukaemia), there is an abundance of niches for monoclonal antibody therapy applications and a staggering number of potential disease targets. Smaller developer companies are likely to become more visible as their products move closer to regulatory approval.

That is why this new management report, published in April 2007 is essential for everyone working in the field. The report covers over 30 leading compounds originating from the largest blue-chip multinationals to smaller developer companies.

KEY EVALUATION FOR EACH PRODUCT

It is vital that new compounds can be seen in the wider competitive/development landscape. For that reason we have established a unique competitor analysis based on each of the following criteria:

Novelty/rationale for mechanism of actionProof of concept/clinical dataManagement/clinical expertiseCompetition within the marketplaceRisks associated with developing a drug within a therapeutic class

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Monoclonalantibodies:what the futureholds

Order your copy todaywww.espicom.com/mab

ANTICANCER PRODUCTSAbegrin

MedImmuneACA 125

Cell Control Biomedical adecatumumab

Micromet/Merck KGaAAntibody 3F8

MSKCCBB-10901

ImmunoGenBrevaRex

Virexxcatumaxomab

Fresius Biotech/TRION PharmaCNT0328

CentocorCotara

Peregrine Pharmadaclizumab

PDL BioPharma/Rocheepratuzumab

Immunomedicsertumaxomab

Fresius Biotech/TRION Pharmagaliximab

Biogen IdecHA20/IMMV-106

ImmunomedicsHuMax-EGFr

Genmabipilimumab

Bristol-Myers SquibbKW-2871

Kyowa Pharmaceuticalmatuzumab

EMD Pharma/Merck/TakedaMDX-060

Medarexofatumumab

Genmaboregovomab

UnitherRencarex

Wilex CentocorSGN-30

Seattle Geneticsticilimumab

Pfizer/Amgenvolociximab

PDL BioPharma zanolimumab

Genmab/Merck KGaA

RHEUMATOLOGY PRODUC TS

belimumabHuman Genome Sciences/GSK

certolizumab pegolUCB

golimumabCentocor/Schering Plough

HuMax CD-20 Genmab

tocilizumabChugai/Roche

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CNS Drug News

R&D UPDATEStudy may accelerate research into next generation of painkillers

Scientists studying amoeboid organisms commonly known as slime moulds have helped to unravel the structure of a key molecule that controls pain in humans. It is thought that the findings, published in the 12th July issue of Nature (2007;448:200-203), could rapidly advance research into the next generation of painkillers for the relief of chronic conditions, such as migraine and backache.

Chronic pain has no apparent physiological benefit, often being referred to as the ''disease of pain.'' Complete and lasting relief of chronic pain is rare and often, the clinical goal is pain management through one or more medications. But now, researchers at the University of Manchester have examined the microscopic amoeboid organisms in a bid to gain greater insight into pain molecules known as P2X receptors.

In humans, P2X receptors look identical to one another, therefore scientists have had difficulty understanding how they function. The researchers discovered that there was only a 10 per cent similarity between human P2X and the slime mould equivalent, and were therefore able to deduce from evolutionary theory that it was these similar parts of the molecule that probably regulate pain in humans.

This is thought to be a big step forward in understanding how the molecule works and should make it possible to develop drugs that block the receptors' actions. Inhibiting P2X as a potential pain-relief therapy could revolutionise the way that chronic pain conditions are managed.

Durect reports positive Phase IIb Posidur data

Durect has reported positive results from a 122-patient, Phase IIb trial of Posidur (SABER-bupivacaine) for the treatment of postoperative pain in patients undergoing inguinal hernia repair, where the long-acting local anaesthetic demonstrated statistically significant reductions in pain and total consumption of supplemental opioid analgesic medications versus placebo.

The multi-centre, double-blind, placebo-controlled study was conducted in Australia and New Zealand, and designed to evaluate the tolerability, activity, dose response and pharmacokinetics of Posidur in patients undergoing open inguinal hernia repair. Participants were randomised into three treatment groups: Posidur 2.5mL (n=43), Posidur 5mL (n=47) and placebo (n=32).

In relation to the co-primary endpoint of pain reduction, as measured by Mean Pain Intensity on Movement area under the curve (AUC) one to 72 hours post-surgery, the patient group treated with Posidur 5mL reported 31 per cent less pain versus placebo (p=0.0033), plus a 35 per cent reduction of pain as measured by Mean Pain Intensity on Movement AUC for the period one to 48 hours post-surgery, a secondary endpoint measure, was reported between the

Posidur 5mL treatment group versus placebo (p=0.0007). A total of 53 per cent of the study patients in the Posidur 5mL group took supplemental opioid analgesic medications versus 72 per cent of the placebo patients (p=0.0909). During the periods of one to 24 hours, 24 to 48 hours and 48 to 72 hours after surgery, placebo patients consumed approximately 3.5- (p=0.0009), 2.9- (p=0.0190) and 3.6-times (p=0.0172) more supplemental opioid analgesic medications, respectively, than the Posidur 5mL treatment group. In addition, the median time to first use of supplemental opioid analgesic medication after surgery for the placebo patients was 2.7 hours versus >72 hours for the Posidur 5mL treatment group (p=0.0197).

The patient groups treated with Posidur showed comparable safety profiles to those treated with placebo and the drug administration appeared to be well tolerated. Additionally, the side effects commonly observed with opioid medication use were less frequent in the Posidur treatment groups compared to placebo.

Durect has scheduled an end-of-Phase II meeting with the FDA in preparation for the Phase III programme, for which it intends to select Posidur 5mL, as this dose showed statistically significant activity relative to placebo, whereas Posidur 2.5mL showed a positive trend relative to placebo on certain parameters, but the results were not statistically significant.

The decision for advancing Posidur into Phase III trials was based on this study and the successful results trigger an US$8 million milestone payment from Nycomed to Durect under the parties' collaborative agreement. Durect has licensed Nycomed the exclusive commercialisation rights to Posidur in the EU and select other countries, plus will manufacture and supply the product to Nycomed. The company may earn additional milestone payments of up to US$180 million, due upon the achievement of additional defined development, regulatory and sales milestones, in addition to blended royalties.

Durect has also been conducting smaller exploratory Phase II studies in hernia, shoulder arthroscopy and appendectomy surgeries to evaluate different application techniques, clinical design and conduct, as well as other investigational factors. In all of the exploratory studies, patient groups treated with Posidur showed comparable safety profiles as the placebo groups and the drug administration appeared well tolerated. Some treatment groups from the hernia and shoulder exploratory studies utilising Posidur have shown positive activity as measured by a reduction of pain or the consumption of supplemental opioid analgesic medication versus placebo, while other treatment groups have not.

Newron reveals additional analyses of ralfinamide Phase II study

Newron Pharmaceuticals has reported further results from the first placebo-controlled, randomised treatment trial of ralfinamide in patients with various types of neuropathic pain, including diabetic neuropathy. Previously-announced results indicated the statistically significant superiority (p=0.019; 95% CI -14.9, -1.4) of ralfinamide compared with placebo on the patient-rated Visual Analogue Scale

with placebo (p<0.0001) after four weeks of once-daily treatment. The effects were maintained throughout the day based on parent ratings reported at approximately 10am, 2pm and 6pm using the Connors'

Parent Rating Scale. The most common side effects reported in this study were decreased appetite, difficulty falling asleep, stomach ache and irritability.

ANALGESICS/ANAESTHETICS



CNS Drug News

(VAS), while showing good tolerability at the doses tested (see CNS 165). Additional analyses have revealed that ralfinamide treatment is associated with multiple statistically significant differences and clinically-relevant benefit over placebo, as judged by:

responder analysis using multiple definitions of the magnitude of pain relief, as judged on the VAS (overall p<0.05);significant improvement in the mean ratings of the patient-rated Daily Pain Diary (p=0.003; 95% CI -1.5, -0.3);significant improvement in the quality of sleep, as judged by the patient (p=0.002; 95% CI -1.5, -0.4); andsignificant improvement in daily activities (p=0.033; 95% CI -1.4, -0.1).

Meda agrees to acquire MedPointe

Meda AB has agreed to acquire MedPointe for US$520 million in cash and 17.5 million newly-issued Meda shares. With approximately 710 employees and headquartered in Somerset, NJ, MedPointe is focused on two of Meda's priority areas, pain and allergy/respiratory.

With the acquisition, Meda will have full marketing coverage in both the US and Europe, with revenues approaching US$1.4 billion, and the acquisition is expected to be accretive to Meda's EPS, at the latest, during 2009.

Akela completes enrolment in Phase IIb trial of Fentanyl TAIFUN

Akela Pharma (formerly LAB International) has completed patient enrolment in its Phase IIb trial of Fentanyl TAIFUN, a fast-acting fentanyl formulation that is delivered using the company's TAIFUN dry powder inhaler platform.

This is a multi-centre, multi-national trial in cancer patients with severe persistent pain on maintenance opioid therapy. The first part of the trial is a single-arm, open-label dose titration to evaluate the effective individual dose for significant pain relief with Fentanyl TAIFUN in the treatment of breakthrough cancer pain.

The second part includes 28 responders from the open-label arm who are randomised to receive the titrated doses or placebo. It is expected that safety and efficacy data from this double-blind, placebo-controlled extension arm will be available by early September.

PRODUCT NEwSOrtho-McNeil/Par settle Ultracet patent litigation

Ortho-McNeil Pharmaceutical (Johnson & Johnson) has settled patent litigation against the generic drug manufacturer, Par Pharmaceutical Companies, and its subsidiaries, Par Pharmaceutical and Kali Laboratories, regarding their infringement of the patent for Ultracet (tramadol+acetaminophen). Par received FDA approval and began marketing its generic version of the product, which is indicated for the short-term management of acute pain, in April 2005.

As part of the settlement, Par/Kali acknowledged that the re-issue patent for Ultracet is valid and enforceable, and that they infringed it by selling generic versions of the product on the US market. Par/Kali will pay to Ortho-McNeil a lump sum for past damages and will have a royalty-bearing licence until their product's agreed-upon exit from the market on 15th November 2007.

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Organon's MAA for sugammadex accepted for review

Organon's (Akzo Nobel) MAA for sugammadex has been accepted for review by the EMEA. This novel selective relaxant-binding agent is specifically designed to reverse the effects of the muscle relaxant, rocuronium bromide (Esmeron/Zemuron), used as part of general anaesthesia during surgical procedures.

The MAA is based on safety and efficacy data from over 1,700 patients, including data from ten global Phase III trials. The results of four of these studies were presented at the 14th Annual Euroanaesthesia 2007 Congress in June (see CNS 164).

Sugammadex works by encapsulating the muscle relaxant molecule and forming a tight complex. The encapsulation of the muscle relaxant by sugammadex removes the drug from its site of action and renders it inactive. In clinical trials conducted, to date, sugammadex has generally demonstrated the ability to reverse shallow and profound depths of rocuronium-induced neuromuscular blockade within three minutes, 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 vecuronium-induced (Norcuron) neuromuscular blockade. Sugammadex' global Phase III development programme, consisting of five US and five European trials, completed recruitment in late 2006. The anticipated submissions for the US and Japan are proceeding in line with the previously-disclosed timelines.

RxElite launches generic sevoflurane in the US

RxElite Holdings (Southridge Technology) has launched Sojourn (sevoflurane), a generic inhalation anaesthetic, in the US. The company is Minrad International's exclusive commercial partner for the product in this market, where it received FDA approval on 2nd May. RxElite currently markets three anaesthetic gases in the partnership with Minrad: sevoflurane, isoflurane and enflurane. RxElite is the third entrant into the US sevoflurane market, following Abbott (with Ultane) and Baxter.

US PTO allows Opana ER-related patent application

The US PTO has indicated that Penwest Pharmaceuticals' patent application claiming the sustained-release formulation of oxymorphone related to Opana ER (oxymorphone) extended-release tablets CII has been allowed. Penwest received a final rejection from the PTO for this application on 15th March, however in response to the rejection, the company amended the claims and the PTO examiner found these allowable.

Opana ER, which is marketed by Endo Pharmaceuticals, uses Penwest's TIMERx technology and is indicated for the treatment of moderate-to-severe pain in patients requiring continuous, around-the-clock opioid treatment for an extended period of time. The patent, once issued, will be scheduled to expire in 2022 and Penwest expects that Endo will list this patent at the earliest opportunity in the FDA's Orange Book.

AGREEmENT NEwSHydra signs global TRPV3 collaboration with Pfizer

Hydra Biosciences has signed a collaboration agreement with Pfizer Global Research & Development that will be focused on TRPV

3

antagonist product candidates for pain. The transient receptor



CNS Drug News

potential (TRP) channel family comprises a novel group of non-selective cation channels that are distinct from classical voltage-gated ion channels. Under the terms agreed, Hydra will receive up-front and success-based development milestone payments totalling US$195 million for the first developed product launched, with upside potential for additional approved indications. Furthermore, there are opportunities for the development of additional products. Pfizer will fund all research and development under the agreement, plus receive exclusive access to Hydra's current TRPV

3 patents, as well

as an exclusive licence to commercialise any compound from the collaboration. Once the products are on the market, Pfizer will pay worldwide royalties to Hydra.

Tikvah enters licensing agreement with Apkarian

Tikvah Therapeutics has entered into an exclusive licensing agreement with Apkarian Technologies for patents and patent applications involving certain agonists of specific sites of the NMDA receptor. These

newly-acquired rights provide Tikvah with claims encompassing the chronic treatment of pain and pain-related indications with glycine receptor agonists as monotherapy or in combination with certain other agents.

The subject of this agreement is technology developed by researchers at Northwestern University in the area of pain and perception. This work has suggested that treatment with certain classes of glycine receptor agonists, alone or in combination with other agents, can be used to treat chronic pain, as well as modify the structural brain changes that occur under conditions of chronic pain.

The studies of various brain processes in humans and animals using non-invasive brain imaging techniques, coupled with brain electrophysiology and knowledge of neural networks, afford a differentiated approach to understanding the perception of touch and pain.

THERAPIES TO TREAT SUBSTANCE DEPENDENCER&D UPDATE

Nabi creates pharmaceuticals business unit

Nabi Biopharmaceuticals has created the second of its two planned strategic business units, Nabi Pharmaceuticals, which will be responsible for the NicVAX (nicotine conjugate vaccine) and StaphVAX (Staphylococcus aureus polysaccharide conjugate vaccine) development programmes, as well as the continuing milestone-related development obligations following the sale of PhosLo (calcium acetate).

The company announced in June that it had created the Nabi Biologics units, as well as a Corporate Shared Services group to support these business units.

In connection with the reorganisation required to support the business strategy of this latest unit, the company eliminated 33 positions in its Rockville, MD, research and development facility. This reduction of approximately 5 per cent of the company's total current workforce is expected to yield approximately US$3.3 million in savings on an annualised basis.

Editor's note: NicVAX is Nabi's innovative and proprietary investigational vaccine that is being developed to treat nicotine addiction and prevent smoking relapse.

Drug may help people with OCD; to be tested on smokers

For details, see Psychotic Disorders, R&D Update.

PRODUCT NEwSUK's NICE issues guidance on Champix for smoking cessation

The UK's National Institute for Health and Clinical Excellence (NICE) has issued guidance recommending Pfizer's Champix (varenicline) as an effective treatment for helping smokers to quit. The drug, within its licensed indications, is recommended as an option for smokers who have expressed a desire to quit smoking, but should normally be prescribed only as part of a programme of behavioural support. These recommendations are part of a suite of guidance being produced by NICE on the most effective methods of tackling smoking and what works to help people quit.

ANTI-EPILEPTICSR&D UPDATE

Icagen files IND for novel epilepsy compound

Icagen has filed an IND application with the FDA for ICA-105665, a novel small-molecule compound for the treatment of epilepsy.

ICA-105665 is an activator of subtypes of KCNQ ion channels, which are attractive targets for the treatment of epilepsy based on their function and genetic linkage to a seizure disorder. In preclinical studies, ICA-105665 was active in animal models predictive of

efficacy for the treatment of partial seizures, generalised seizures and treatment-resistant seizures. In addition, ICA-105665 has also been shown to have activity in models of neuropathic and inflammatory pain.

ICA-105665 will be administered orally and is intended to be developed as a chronic therapy for patients with epilepsy. Provided that the IND is accepted, Icagen plans to initiate a Phase I trial during the third quarter of 2007; this will be a double-blind, placebo-controlled study conducted in healthy male volunteers to assess the safety, tolerability and pharmacokinetics of the compound.

THERAPIES TO TREAT SUBSTANCE DEPENDENCE / ANTI-EPILEPTICS


CNS Drug News

EATING DISORDERSR&D UPDATE

Preclinical data confirm trodusquemine's potential for obesity

At the Center for Business Intelligence's 3rd Annual Obesity Drug Development Summit, held from 26th to 27th July, in Arlington, VA, Genaera presented new data from preclinical studies with trodusquemine (MSI-1436) for the treatment of obesity and Type II diabetes.

The preclinical data demonstrated that MSI-1436 is a potent, highly-selective and reversible inhibitor of protein tyrosine phosphatase-1B (PTP-1B), an enzyme central to the function of both the leptin and insulin pathways. The mechanism of this inhibition, as indicated by in vitro kinetics, is through binding to a site different from the catalytic site of PTP-1B. The in vitro kinetics demonstrate that MSI-1436 is an allosteric, non-competitive inhibitor of PTP-1B. Data also indicated that MSI-1436 crosses the blood-brain barrier and is both centrally and peripherally active. These dual locations of MSI-1436 action make the drug a promising therapeutic candidate for both obesity and Type II diabetes.

As previously disclosed, preclinical studies have also demonstrated that MSI-1436 suppresses appetite and causes differential weight loss in a mouse model of diet-induced obesity. In addition, MSI-1436

was shown to reduce the size of adipocytes, reduce body fat with no reduction of lean mass and improve glucose tolerance via inhibition of a unique combination of signalling pathways in this model. MSI-1436 is currently being evaluated in obese, but otherwise healthy volunteers for a Phase I safety and pharmacokinetics study.

Orexigen reports positive Phase IIb data with Empatic for obesity

Orexigen Therapeutics has reported positive top-line results at the 24-week primary endpoint of its Phase IIb trial of Empatic (bupropion+zonisamide; formerly Excalia), one of the company's two obesity drug candidates. The trial demonstrated, across each of the six Empatic treatment arms, statistically significant weight loss compared to placebo (p<0.001).

The randomised, double-blind, placebo-controlled trial was conducted with the company's novel sustained-release (SR) formulation of zonisamide paired with bupropion SR, and evaluated various ratios of bupropion and zonisamide in 620 patients. At the highest dose tested, patients experienced 8.6 per cent weight loss from baseline, compared to 1.1 per cent weight loss for placebo in the intent-to-treat group, and 10.3 per cent weight loss from baseline, compared to 1.2 per cent weight loss for placebo in the completer group. In addition, the trajectory of weight loss for all treatment arms appeared to continue downward through 24 weeks.

Results of the trial indicate that Empatic is safe and generally well tolerated. The pooled discontinuation rate for adverse events (AEs) across the six Empatic dosages was 14 per cent, which was meaningfully lower than the rate in the company's previous trial employing an older immediate-release form of zonisamide (37 per cent). The pooled discontinuation rate due to AEs across the six Empatic dosage groups was not statistically different than the rate seen with placebo. AEs were consistent with the existing package labels for the two constituents and most commonly included headache, nausea, insomnia, anxiety or dry mouth.

Empatic employs a proprietary formulation of the CNS molecules, bupropion and zonisamide, which have been independently approved by the FDA in other indications. Orexigen developed its own proprietary SR version of zonisamide to improve drug tolerability. Bupropion and zonisamide each target reciprocal pathways in the hypothalamus that separately mediate appetite and energy expenditure. The unique combination of these molecules is designed to provide more clinically-meaningful weight loss for patients by both initiating weight loss and sustaining it over a longer period of time.

Orexigen's approach is designed to achieve and sustain weight loss by enhancing satiety, diminishing appetite, improving energy expenditure and counteracting the body's efforts to compensate for weight loss. According to the company, if the magnitude of weight loss evident in this trial continues to be seen, Empatic may be particularly useful in severely obese individuals.

Additional safety and efficacy data will be reported following the completion of an ongoing 24-week trial extension. Primary trial results are to be presented at the Annual Scientific Meeting of the North American Association for the Study of Obesity, to be held from 20th to 24th October, in New Orleans, LA.

Company AnalysisRegularly updated and detailed analysis of 135 leading companies’ strategy, research, products and agreements

R&D and Product DevelopmentsR&D and product developments in all major cancer areas.

Market StatisticsDemography, disease incidence and cause of death for 20 markets.

Latest NewsTrack over 2,000 companies and organisations involved with cancer drugs.

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For full details about this report’s content, pricing and availability go to:

www.espicom.com/cio

The authoritative online business resource for everyone involved in

this high growth area, providing:

EATING DISORDERS


CNS Drug News

PRODUCT NEwSCHMP recommends upgraded warnings for Acomplia

Following an assessment of the information on psychiatric adverse events associated with sanofi-aventis' first-in-class CB

1 blocker,

Acomplia (rimonabant), the EMEA's CHMP has recommended the addition of a contraindication in patients with ongoing major depression or who are being treated with antidepressants, because of the risk of psychiatric side effects. Finalising its assessment of the available data at its 16th to 19th July meeting, the CHMP did, however, conclude that except in these patients, the benefits of Acomplia continue to outweigh its risks.

Acomplia has been authorised in the EU since June 2006 and is marketed in 13 European countries as an adjunct to diet and exercise for the treatment of obese or overweight adult patients. Psychiatric side effects, in particular depression, were identified as the main safety issue at the time of approval and reflected in the medicine's product

information. The CHMP has now recommended upgrading this warning, suggesting that treatment with Acomplia should be stopped if a patient develops depression, as well as the inclusion of additional information on the psychiatric safety of the drug.

Acomplia's labelling has been updated based on data reflecting a year of post-marketing experience, mainly from Germany, France and the UK, as well as the results of five additional clinical trials completed since the original dossier was approved.

Editor's note: earlier in July, sanofi-aventis decided to withdraw the NDA for rimonabant in the US, where it is branded Zimulti, following a decision by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee to not recommend the product's approval. Additionally, in February 2006, the company received a non-approvable letter from the FDA's Division of Metabolism and Endocrinology Products for smoking cessation and in May that year, the CHMP adopted a negative opinion for Acomplia for this indication. This most recent decision for rimonabant in obesity is unlikely to improve its chances as an approved smoking cessation product.

DRUGS USED IN NAUSEA & VERTIGOAGREEmENT NEwS

Shanghai Ethypharm signs ondansetron licence agreement with Beijing Med-Pharm

Shanghai Ethypharm Pharmaceutical (Ethypharm) has signed an exclusive licence agreement under which Beijing Med-Pharm will market and distribute ondansetron Flashtab (4 and 8mg) in China once the drug is approved in this market. Under the terms agreed, Shanghai

Ethypharm will pursue registration of ondansetron Flashtab in China, a process that is expected to be completed in 2009. Beijing Med-Pharm will then be responsible for sales, marketing, distribution and supply.

Ondansetron is a member of the 5-HT3 antagonist class of anti-emetics

and marketed under the tradename, Zofran, by GlaxoSmithKline. The drug is indicated to reduce nausea and vomiting (N&V) induced by cytotoxic chemotherapy and radiotherapy, as well as prevent postoperative N&V. Ethypharm manufactures the product using its proprietary Flashtab orally-disintegrating tablet technology.

GENERAL DEVELOPmENT NEwSR&D UPDATE

Study further links addiction and memory

People's experiences can trigger long-term changes in the strength of connections between nerve cells in the brain and these persistent changes are how the brain encodes information as memory. Now, Johns Hopkins researchers have discovered a new biochemical mechanism for memory storage, one that may have a connection with addictive behaviour.

Previously, the long-term changes in connection were thought to only involve a fast form of electrical signalling in the brain, however neuroscience professor, Dr David Linden, and his colleagues have shown that another, much slower form of electrical signalling lasting approximately a second, can also be persistently changed by experience.

The researchers, whose work was published in the 19th July issue of Neuron (2007;55:277-287), simulated natural brain activity by applying short electrical jolts to slices of rat brain and measuring the current flowing across the cells. After repeated jolting, the strength of the slow nerve signals had dramatically decreased and remained at a low

intensity for 30 minutes after electrical jolts ceased. These slow signals are produced by a nerve cell receptor called mGluR1, which has been associated with addiction and epilepsy. Both of these conditions also involve long-term changes in the function of nerve connections, therefore in addition to furthering the basic understanding of memory storage, Linden believes the team's work suggests that drugs designed to alter mGluR1 are promising candidates for the treatment of addiction, epilepsy and diseases of memory.

Targacept/Abbott initiate Phase I trials of NNR modulators

Targacept has initiated a Phase I trial of TC-5619, a novel small molecule that modulates the activity of the neuronal nicotinic receptor (NNR) subtype, alpha7. The double-blind, placebo-controlled study is designed to evaluate the safety, tolerability and pharmacokinetics of TC-5619, with single escalating doses administered orally to healthy volunteers.

TC-5619 was discovered using Targacept's proprietary drug design technology known as Pentad and is the lead product candidate in its alpha7 NNR programme. The alpha7 NNR is associated with a variety of biological functions. In particular, it has been shown in animal studies to be an essential regulator of both inflammation arising from

DRUGS USED IN NAUSEA & VERTIGO / GENERAL DEVELOPmENT NEwS

©Espicom Business IntelligencePage �0 �nd August �007

CNS Drug News

injury or infection and cognitive functions. Published in vitro studies have also suggested that the alpha7 NNR plays a role in protecting neuronal cells from deterioration and death, however Targacept has not yet definitively selected the indication for which it will pursue the development of TC-5619.

For details of further NNR research and a collaboration by Targacept, see Neurodegenerative Disorders, Alzheimer's Disease - R&D Update; Antidepressants, R&D Update; and General Development News, Agreement News.

In addition...

NeuroSearch's development and licence partner, Abbott, has enrolled and dosed the first patients in a Phase I study with the drug candidate, ABT-560, which has treatment potential within a variety of CNS disorders. The initiation of this study releases a milestone payment to NeuroSearch.

ABT-560 is also an NNR modulator that has shown promise in preclinical models relevant for the treatment of cognitive deficits. According to the terms of the companies' licence agreement, Abbott has all rights to ABT-560 and will finance all costs relating to the development and commercialisation of the drug. NeuroSearch will receive milestone payments, as well as royalties on Abbott's global sales, if the drug is successfully commercialised.

AGREEmENT NEwSCorcept enters microdosing study agreement with Xceleron

Corcept Therapeutics has entered into an agreement for a human microdosing study of one of its new chemical entities, a selective GR-II antagonist, utilising Xceleron's accelerator mass spectrometry (AMS) technology. GR-II antagonists have potential to be used in treating numerous neurological disorders, including early dementia (including Alzheimer's disease), psychosis associated with cocaine addiction and the weight gain associated with antipsychotic medication.

Cortex initiated a discovery research programme to identify and patent selective GR-II antagonists to develop a pipeline of products for proprietary use. Three distinct series of GR-II antagonists were identified that appear to be as potent as Corcept's Corlux (mifepristone) in blocking cortisol, but unlike this product, they do not block progesterone and other steroid receptors. The company will evaluate the compound that develops particularly high plasma and brain concentrations in an animal model, in a human microdosing study using Xceleron's AMS technology. Under the terms agreed, Xceleron will carry out the work using ultra-sensitive AMS, which enables human drug-metabolite profiling to be performed in the early stages of clinical development.

Penwest/Edison enter collaboration for neurological disorders

Penwest Pharmaceuticals has entered into a research, development, commercialisation and licence agreement with Edison Pharmaceuticals for the treatment of neurological disorders resulting from defects in cellular energy metabolism.

The initial focus of the collaboration is to pursue treatments for orphan diseases of the mitochondria. Under the terms agreed, Penwest has obtained exclusive worldwide rights to develop and

commercialise Edison's drug candidate, EPI-A0001, in all fields of use. EPI-A0001 has been granted orphan drug status by the FDA for the treatment of inherited mitochondrial respiratory chain diseases, and Penwest intends to submit an IND application and commence clinical development of the compound in early 2008. Additionally, Penwest has the exclusive worldwide rights to develop and commercialise one additional drug candidate to be selected from those identified by Edison during the term of the sponsored research collaboration.

The financial terms of the agreement call for Penwest to provide Edison with an up-front payment, a US$1 million loan and sponsored research funding for the next 18 months. The aggregate total of these payments and the loan is US$7.5 million. Penwest may, at its sole discretion, extend the term of the sponsored research period by up to an additional 18 months. The agreement also provides for payments upon the exercise of certain options, success-based milestones payments and royalties on net sales of any products commercialised as a result of the collaboration.

Antares signs product development and licence agreement with Jazz

Antares Pharma has signed a worldwide product development and licence agreement with Jazz Pharmaceuticals, which demonstrates the successful completion of a feasibility agreement that was initiated between the companies in December 2005. The product candidate underlying this agreement is being developed to treat a significant CNS disorder and is based on Antares' proprietary ATD (advanced transdermal delivery) system.

Under the terms agreed, Jazz will pay Antares up-front and product development milestone payments, in addition to payments for any future development activities. Antares will also receive royalties on product sales upon commercialisation, including minimum royalties. Total milestone and minimum royalty payments could add up to US$16.5 million or more over the life of the agreement. Jazz is responsible for the development and commercialisation of this product candidate and will cover the costs of clinical trials, regulatory filings, plus all manufacturing and marketing associated with the product.

GSK forms US$1.5 billion CNS pact with Targacept

GlaxoSmithKline and Targacept have formed a strategic alliance that is valued at up to approximately US$1.5 billion, to discover, develop and market novel therapeutics that selectively target specified neuronal nicotinic receptors (NNRs) to treat CNS conditions such as pain, smoking cessation, obesity, addiction and Parkinson's disease. GSK will participate in the alliance through its Center of Excellence for External Drug Discovery.

Under the terms agreed, GSK will make an initial up-front payment of US$35 million to Targacept, which includes an investment of US$15 million for the purchase of 1,275,502 shares of Targacept common stock. In addition, Targacept is eligible to receive up to US$1.5 billion in payments from GSK, contingent upon the achievement of specified discovery, development, regulatory and commercial milestones across five therapeutic focus areas, as well as tiered double-digit royalties dependent on sales achieved.

The alliance includes Targacept's lead product candidates for pain, TC-2696, which is currently in a Phase II trial for acute postoperative pain, and TC-6499, a preclinical product candidate that is currently planned for development for neuropathic pain. Targacept has retained an option to co-promote the aforementioned drugs to specialists and

GENERAL DEVELOPmENT NEwS

Page �1©Espicom Business Intelligence�nd August �007

CNS Drug News

hospital-based physicians in the US. In the alliance, Targacept will utilise its proprietary Pentad drug-discovery technology to discover novel small-molecule product candidates that target specified NNR subtypes and will then develop the most promising product for each therapeutic focus area through a proof-of-concept, Phase II trial. Targacept is eligible to receive success-based progress milestones from GSK as product candidates are advanced. Upon Targacept's achievement of clinical proof-of-concept for a lead product candidate for a particular therapeutic focus area, GSK would have an exclusive

option to license product candidates in development in the alliance from that programme. GSK would then assume full responsibility for funding of further clinical development and commercialisation on a worldwide basis.

For details of further NNR research by Targacept, including the initiation of clinical studies, see Neurodegenerative Disorders, Alzheimer's Disease - R&D Update; Antidepressants, R&D Update; and General Development News, R&D Update.

CONfERENCE LISTINGS

CNS CONFERENCES - NOVEMBER 2007

DATE CONFERENCE TITLE CONTACT TEL/FAX/E-MAIL1-3 10th International Conference on

the Mechanisms and Treatment of Neuropathic Pain, Salt Lake City, UT, US

Continuing Professional Education, 601 Elmwood Ave, Box 677 Rochester, NY 14642-8677, US

Tel:Fax:E-mail:

1 585 275 43921 585 275 [email protected]

2-4 Association of Anesthesiology Program Directors/Society of Academic Anesthesiology Chairs Annual Meeting, Washington DC, US

Denise M Jones Tel:Fax:E-mail:

1 847 825 55861 847 825 [email protected]

8-11 5th International Congress on Vascular Dementia, Budapest, Hungary

Meeting Organiser Tel:E-mail:

41 229 080 [email protected]

15-18 57th Annual Meeting of the Canadian Psychiatric Association, Montréal, QC, Canada

CPA Head Office, 260-441 MacLaren, Ottawa, ON, K2P 2H3, Canada

Tel:Fax:E-mail:

1 613 234 28151 613 234 [email protected]

17-18 1st Annual NYSORA (New York School of Regional Anesthesia) Europe Symposium, London, UK

Jo Watling Tel:Fax:E-mail:

44 870 013 293044 870 013 [email protected]

18-21 12th Asian-Australasian Society of Neurological Surgeons/13th World Federation of Neurosurgical Societies Interim Meeting, Nagoya, Japan

Congress Secretariat, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Aichi-Ken 470-1192, Japan

Tel:Fax:E-mail:

81 562 93 925381 562 93 [email protected]

28/11-2/12 3rd International Congress on Brain & Behaviour, Thessaloniki, Greece

Global Events, 177 Egnatias str, 546 35 Thessaloniki, Greece

Tel:Fax:E-mail:

30 2310 247 734/30 2310 247 74330 2310 247 [email protected]

29/11-2/12 American Academy of Addiction Psychiatry 18th Annual Meeting & Symposium, Coronado, CA, US

American Academy of Addiction Psychiatry, 345 Blackstone Blvd, 2nd Floor RCH, Providence, RI 02906, US

Tel:Fax:E-mail:

1 401 524 30761 401 272 [email protected]

30/11-4/12 61st Annual Meeting of the American Epilepsy Society, Philadelphia, PA, US

Meeting Organiser Tel:E-mail:

1 860 586 [email protected]

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

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CONfERENCE LISTINGS

©Espicom Business IntelligencePage �� nd August �007

CNS Drug News

Abbott .......................................................................................................................16, 19, 20Academia Sinica ................................................................................................................... 9Affiris ..........................................................................................................................................4Akela Pharma .......................................................................................................................16Akzo Nobel ...........................................................................................................................16Almirall ......................................................................................................................................7Amorfix Life Sciences ........................................................................................................ 9Antares Pharma ..................................................................................................................20Apkarian Technologies ...................................................................................................17AstraZeneca ........................................................................................................................... 4Avicena Group ..................................................................................................................3, 8Bar-Ilan Research & Development ............................................................................12Baxter.......................................................................................................................................16Bayer ..........................................................................................................................................7Beijing Med-Pharm ..........................................................................................................19Biogen Idec .............................................................................................................................9BioLineRx ...............................................................................................................................12BioMS Medical ...................................................................................................................... 6Biovail ......................................................................................................................................12Boehringer Ingelheim ....................................................................................................... 1Bristol-Myers Squibb .......................................................................................................12Cambridge Laboratories .................................................................................................8Caraco Pharmaceutical Laboratories ......................................................................11Cephalon ...............................................................................................................................11Children’s Hospital Boston .............................................................................................. 4Chromos Molecular Systems ......................................................................................... 7Columbia University ...................................................................................................4, 13Corcept Therapeutics ......................................................................................................20Cortex Pharmaceuticals ................................................................................................... 3deCODE genetics.......................................................................................................... 1, 10Duke University ................................................................................................................1, 6Durect......................................................................................................................................15Edison Pharmaceuticals .................................................................................................20Eisai ...........................................................................................................................................11Elan ............................................................................................................................................. 3Eli Lilly ......................................................................................................................................14Emory University .......................................................................................................... 1, 10Endo Pharmaceuticals ....................................................................................................16Ethypharm ............................................................................................................................19Genaera ..................................................................................................................................18GlaxoSmithKline .........................................................................................................19, 20Glenmark Pharmaceuticals ............................................................................................ 7GW Pharmaceuticals ..........................................................................................................6Harvard Medical School ................................................................................................... 4Howard Hughes Medical Institute .............................................................................. 4Hydra Biosciences .............................................................................................................16Icagen ......................................................................................................................................17Impax Laboratories ............................................................................................................ 9Intellect Neurosciences .................................................................................................... 9Jazz Pharmaceuticals .......................................................................................................20Johns Hopkins .....................................................................................................................19Johnson & Johnson ..........................................................................................................16Kali Laboratories ................................................................................................................16

Kissei Pharmaceutical ....................................................................................................6, 8Krka ...........................................................................................................................................14Lucile Packard Children’s Hospital ............................................................................10Meda AB .................................................................................................................................16Medivation ..............................................................................................................................8MedPointe.............................................................................................................................16Merck & Co ..............................................................................................................................6Merck KGaA ............................................................................................................................3Merck Serono ........................................................................................................................3Minrad .....................................................................................................................................16Nabi Biopharmaceuticals ..............................................................................................17Neurochem ........................................................................................................................5, 9Neuroptix................................................................................................................................. 6NeuroSearch ........................................................................................................................20New York University ...........................................................................................................9Newron Pharmaceuticals .........................................................................................3, 15Northwestern University ...............................................................................................17Novartis ....................................................................................................................................5Nuon Therapeutics .........................................................................................................6, 8Nycomed ...............................................................................................................................15Orexigen Therapeutics ...................................................................................................18Organon .................................................................................................................................16Ortho-McNeil Pharmaceutical ....................................................................................16Otsuka .................................................................................................................................7, 12Par Pharmaceutical Companies .................................................................................16Penwest Pharmaceuticals ..................................................................................... 16, 20Pfizer .................................................................................................................................16, 17Proximagen Neuroscience ............................................................................................. 3RxElite ......................................................................................................................................16sanofi-aventis ................................................................................................................. 9, 19Sepracor .................................................................................................................................11Shire ..........................................................................................................................................14Southridge Technology .................................................................................................16Southwestern Medical Center ...................................................................................... 8Stanford University ...........................................................................................................10Summit ..............................................................................................................................3, 18SYGNIS Pharma ...................................................................................................................10Targacept .....................................................................................................4, 12, 19, 20, 21Tel Aviv University .............................................................................................................12Tikvah Therapeutics.................................................................................................... 9, 17University of California ..................................................................................................... 6University of Cambridge .................................................................................................. 6University of Edinburgh .................................................................................................14University of Manchester ..............................................................................................15University of Miami............................................................................................................. 6University of Minnesota .................................................................................................13University of South Alabama ......................................................................................... 9University of St Andrews.................................................................................................. 4University of Texas ..............................................................................................................8Vanderbilt University ......................................................................................................... 6VASTox ......................................................................................................................................3Xceleron .................................................................................................................................20

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CNS Drug News

Abilify .......................................................................................................................................12ABT-560 ..................................................................................................................................20acetaminophen ..................................................................................................................16Acomplia ................................................................................................................................19Affitope AD01 ........................................................................................................................ 4AL-02 .......................................................................................................................................... 8Alzhemed ................................................................................................................................5aripiprazole ...........................................................................................................................12AX200 ......................................................................................................................................10AZD3480 ..................................................................................................................................4BL-1020 .............................................................................................................................12, 13bupivacaine ..........................................................................................................................15bupropion ......................................................................................................................12, 18BVF-033...................................................................................................................................12calcium acetate...................................................................................................................17cannabidiol ............................................................................................................................. 6Champix .................................................................................................................................17CHR-1103 ..............................................................................................................................7, 8CHR-1201 ..............................................................................................................................7, 8citalopram .............................................................................................................................12Corlux ......................................................................................................................................20creatine .....................................................................................................................................3CX717 .........................................................................................................................................3D-cycloserine .......................................................................................................................13Dimebon ..................................................................................................................................8Empatic ...................................................................................................................................18enflurane ...............................................................................................................................16EPI-A0001 ..............................................................................................................................20eprodisate ...............................................................................................................................9eszopiclone ..........................................................................................................................11Excalia ......................................................................................................................................18Exelon ........................................................................................................................................5fentanyl ...................................................................................................................................16Fentanyl TAIFUN .................................................................................................................16ICA-105665 ............................................................................................................................17isoflurane ...............................................................................................................................16Kiacta .........................................................................................................................................9lisdexamfetamine dimesylate ....................................................................................14Lunesta ...................................................................................................................................11Lunivia .....................................................................................................................................11MBP8298 ..................................................................................................................................6mecamylamine ...................................................................................................................12mifepristone .........................................................................................................................20Mirapex ..................................................................................................................................... 1modafinil ................................................................................................................................11MSI-1436 .................................................................................................................................18nicotine ............................................................................................................................13, 17NicVAX ....................................................................................................................................17Nitoman ...................................................................................................................................8olanzapine ............................................................................................................................14ondansetron ........................................................................................................................19Opana ......................................................................................................................................16Oxigon ...................................................................................................................................... 9oxymorphone .....................................................................................................................16PD-02 .........................................................................................................................................3PhosLo .....................................................................................................................................17Posidur ....................................................................................................................................15pramipexole ...........................................................................................................................1Provigil ....................................................................................................................................11PRX4 ........................................................................................................................................... 3ralfinamide .....................................................................................................................15, 16Rilutek ........................................................................................................................................ 9riluzole .......................................................................................................................................9

rimonabant ...........................................................................................................................19rivastigmine ...........................................................................................................................5Rizaben .....................................................................................................................................6safinamide .............................................................................................................................. 3Sativex ...................................................................................................................................6, 7sevoflurane ...........................................................................................................................16SMT 14400 ...............................................................................................................................3SMT C1100 ............................................................................................................................... 3SMT D001................................................................................................................................. 3SMT D002 ................................................................................................................................3SMT D003 ................................................................................................................................ 3Sojourn ...................................................................................................................................16StaphVAX ...............................................................................................................................17sugammadex.......................................................................................................................16TC-1734 ...................................................................................................................................... 4TC-2216 ....................................................................................................................................12TC-2696 ...................................................................................................................................20TC-5214 ....................................................................................................................................12TC-5619 .............................................................................................................................19, 20TC-6499 ...................................................................................................................................20tetrabenazine ........................................................................................................................ 8tetrahydrocannabinol ....................................................................................................... 6tramadol.................................................................................................................................16tramiprosate........................................................................................................................... 5tranilast .................................................................................................................................6, 8Tridmac ...................................................................................................................................12trodusquemine...................................................................................................................18Ultane ......................................................................................................................................16Ultracet ...................................................................................................................................16varenicline .............................................................................................................................17Vyvanse ..................................................................................................................................14Xenazine................................................................................................................................... 8Zalasta .....................................................................................................................................14Zimulti .....................................................................................................................................19Zofran ......................................................................................................................................19zonisamide ...........................................................................................................................18Zyprexa ...................................................................................................................................14

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