cns issue 178

Monitoring central nervous system drug developments worldwide

CNS Drug News

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Lucy VannEditor

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Issue No. 178 17th January 2008

R&D HighlightsStudy offers new clue to cause of PD

Page 3

Baylor study suggests new treatments for HDPage 5

Addex’ ADX10059 fails to reduce acute anxiety in Phase IIa study

Page 7

Progress reported with new treatment mechanisms for schizophrenia

Page 9

PRODUCT HighlightsForest/Merz file lawsuits for Namenda patent

infringementPage 4

Breckenridge/Taro settle litigation with Novartis over generic Trileptal

3

AGREEMENT HighlightsPfizer/Taisho finalise agreement for novel schizophrenia

drug candidatePage 10

Janssen enters supply agreement for ER tramadol; expands Fentanyl TAIFUN deal

Page 12

Sepracor enters deal for Bial’s anti-epileptic compoundPage 14

EDITORLucy Vann

CONTRIBUTING EDITORSRos Smallman, Fiona Cowie,

Matthew Dennis, Johanna Shiu, Andrew Way

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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Can AD symptoms be reversed within minutes?The beginning of 2008 has seen a potentially groundbreaking development in Alzheimer's disease (AD) research - a study has documented marked improvement in AD within minutes of the administration of a therapeutic molecule.

The study, which was published in the 9th January online edition of the Journal of Neuroinflammation (10.1186/1742-2094-5-2), highlights the importance of cytokines in AD and focused on TNF alpha in particular. Normally, TNF alpha finely regulates the transmission of neural impulses in the brain, but in AD, the study authors hypothesised that elevated levels of TNF alpha interfere with this regulation. To reduce these elevated levels, patients received an injection of Enbrel (etanercept), which was discovered by Immunex (Amgen) and jointly developed with Wyeth.

This therapeutic, which binds and inactivates excess TNF alpha, is FDA approved to treat a number of immune-mediated disorders and was used off-label in the new research. In the study, a dramatic and unprecedented therapeutic effect in an AD patient was observed: improvement within minutes following delivery of perispinal etanercept. While the article discusses one patient, many other subjects with mild-to-severe AD received the treatment, and all have shown sustained and marked improvement.

According to Dr Sue Griffin, of the University of Arkansas for Medical Sciences: “It is unprecedented that we can see cognitive and behavioural improvement in a patient with established dementia within minutes of therapeutic intervention.” She believes that it is imperative that the medical and scientific communities immediately undertake to further investigate and characterise the physiologic mechanisms involved, adding that: ”Even though this report predominantly discusses a single patient, it is of significant scientific interest because of the potential insight it may give into the processes involved in the brain dysfunction of Alzheimer's.”

Despite the positive results and their potential impact on sales of Enbrel, Amgen has remained cautious in its response. In a statement on the company's website, Amgen has commented: ''It is important to note that the study published was a case study involving a single patient. This study was not supported nor endorsed by Amgen. While Amgen and others have long recognized the potential for tumor necrosis factor (TNF) inhibitors to have an effect on neurological conditions, we have carefully examined this study and believe that at this time there is insufficient scientific data to support the use of a TNF inhibitor as a means of treating Alzheimer's disease. Amgen will continue to review data on the use of Enbrel (etanercept) and other anti-inflammatory agents for the treatment of Alzheimer’s disease.''

As stated in Espicom's 4D Pharma, Enbrel has benefited from continuous development, leading to a number of new launches and approvals in recent years. The product's sales growth has profited from its competitive profile and significant increases in the usage of biologics in both rheumatology and dermatology settings. In 2006, Enbrel sales reached US$2,879 million and Espicom recently anticipated that sales would increase to US$4,409 million by 2011. However, if these results are replicated and lead to an approval for AD, Amgen could see Enbrel sales rocket.

http://www.4dpharma.com

©Espicom Business IntelligencePage � 17th January �008

CNS Drug News

Can AD symptoms be reversed within minutes? .................................................................1

NEURODEGENERATIVE DISORDERS ......................3PARkINSoN'S DISEASE - R&D UPDATE .......................................................3

Study offers new clue to cause of PD ....................................................................................3Alnylam and collaborators receive MJFF grant to develop RNAi therapeutic for PD..........3

PRoDUCT NEwS .......................................................................................3Sun amends ANDA for generic Stalevo Tablets ....................................................................3

AlzHEIMER'S DISEASE - R&D UPDATE .......................................................3CoMentis reports positive Phase I data with beta-secretase inhibitor ...............................3Prana completes Phase IIa trial of PBT� in early AD .............................................................4Pipex initiates Phase II trial of Coprexa for AD ......................................................................4

PRoDUCT NEwS .......................................................................................4Forest/Merz file lawsuits for Namenda patent infringement .............................................4Eisai introduces new Aricept dose formulations for severe AD in Japan.............................4

MUlTIPlE SClERoSIS - PRoDUCT NEwS ....................................................4Biogen Idec/Elan provide update on Tysabri's utilisation, safety and exposure ................4

oTHER NEURoDEgENERATIvE DISoRDERS - R&D UPDATE ..........................5Baylor study suggests new treatments for HD.....................................................................5Amarin to commence Phase IIa trial with AMR-101 in AAMI ..............................................5

AgREEMENT NEwS ..................................................................................5Yissum licenses small molecule for neurodegenerative diseases to Eucalyptus................5

CEREBROVASCULAR DISORDERS ..........................6R&D UPDATE ............................................................................................6

ReNeuron provides update on IND application for SC therapy trials...................................6UCLA discovery offers promise for SCI patients ....................................................................6Alseres concludes enrolment in Phase I/IIa trial of Cethrin for acute SCI ............................6Study identifies new gene for CVT ........................................................................................6

AgREEMENT NEwS ..................................................................................7BrainStorm/Rutgers expand collaboration for spinal cord injury cure ...............................7

ANXIOLyTICS/SLEEP DISORDERS ..........................7R&D UPDATE ............................................................................................7

Addex' ADX10059 fails to reduce acute anxiety in Phase IIa study .....................................7Ambien CR improves chronic insomnia in patients with co-morbid GAD ..........................7Somaxon plans Silenor NDA submission following mouse carcinogenicity study ............8

PRoDUCT NEwS .......................................................................................8Hemispherx addresses FDA questions on Ampligen NDA ...................................................8

ANTIDEPRESSANTS .............................................8R&D UPDATE ............................................................................................8

Rexahn raises funds for compound development ...............................................................8

PSyCHOTIC DISORDERS .......................................9

R&D UPDATE ............................................................................................9Progress reported with new treatment mechanisms for schizophrenia ............................9Chromosome abnormality may increase autism risk; UCLA study identifies new genetic link .............................................................................................................................9

PRoDUCT NEwS .......................................................................................10AstraZeneca submits sNDAs for Seroquel XR in bipolar mania and depression .................10FDA approves additional dosage strengths of Shire's Vyvanse ...........................................10

AgREEMENT NEwS ..................................................................................10Addex/Merck forge deal over schizophrenia drug candidate .............................................10Pfizer/Taisho finalise agreement for novel schizophrenia drug candidate ........................10

ANALGESICS/ANAESTHETICS ...............................11R&D UPDATE ............................................................................................11

Dosing commences in US Phase II trial of Innocoll's bupivacaine implant .........................11Arcion raises funds to continue development of ARC-4558 .................................................11Zogenix raises funds for pain compound development ......................................................11

PRoDUCT NEwS .......................................................................................11Sugammadex NDA assigned FDA priority review status .....................................................11FDA accepts BEMA Fentanyl NDA for filing ...........................................................................1�

AgREEMENT NEwS ..................................................................................12Janssen enters supply agreement for ER tramadol; expands Fentanyl TAIFUN deal .........1�

THERAPIES TO TREAT SUBSTANCE DEPENDENCE ...12R&D UPDATE ............................................................................................12

Evotec successfully completes Phase I study with EVT 30� .................................................1�AgREEMENT NEwS ..................................................................................13

Alkermes enters agreement with Cilag for Vivitrol in Russia/CIS ........................................13

ANTI-EPILEPTICS ...............................................13R&D UPDATE ............................................................................................13

FDA grants ODD to Ovation's clobazam for LGS and Jazz' JZP-8 for recurrent ARS ............13Amarin reports completion of preclinical nasal lorazepam study ......................................13

PRoDUCT NEwS .......................................................................................13Breckenridge/Taro settle litigation with Novartis over generic Trileptal ...........................13

AgREEMENT NEwS ..................................................................................14Sepracor enters deal for Bial's anti-epileptic compound .....................................................14

EATING DISORDERS ............................................14R&D UPDATE ............................................................................................14

Neurogen opts not to advance NGD-4715 to Phase II testing .............................................14Stimulation of brain CPT-1 decreases food intake and body weight ..................................14Orexigen reports 48-week results of Phase IIb Empatic trial ..............................................14Brain-imaging study offers new clues to overeating ..........................................................15

DRUGS USED IN NAUSEA & VERTIGO ....................16PRoDUCT NEwS .......................................................................................16

Generic Kytril approved following patent expiry .................................................................16Aloxi Capsules sNDA accepted for review by FDA .................................................................16

GENERAL DEVELOPmENT NEwS ..........................16R&D UPDATE ............................................................................................16

XenoPort provides clinical trial update .................................................................................16Lundbeck moves compound into clinical development but discontinues other ...............17Researchers elucidate mechanisms behind fragile X syndrome .........................................17

AgREEMENT NEwS ..................................................................................17£4 million consortium investment to accelerate research into mental illness ...................17Medistem modifies licence agreement with ICM ................................................................17

COmPANy INDEX ................................................18COmPOUND INDEX .............................................19

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PARkINSON'S DISEASE - R&D UPDATEStudy offers new clue to cause of PD

A glitch in the mechanism by which cells recycle damaged components may trigger Parkinson's disease (PD), according to a study by scientists at the Albert Einstein College of Medicine of Yeshiva University.

Senior author, Dr Ana Maria Cuervo, previously showed that mutant forms of alpha-synuclein (found in the 5 to 10 per cent of patients who have familial PD) are poorly digested via autophagy and block the breakdown of other substances. While these mutations are rare, other modifications of alpha-synuclein (eg, phosphorylated and oxidised forms) can be found in the brains of all PD patients.

In this study, which was published in the 2nd January online edition of the Journal of Clinical Investigation (10.1172/JCI32806), Cuervo and her colleagues looked at how several different modified forms of alpha-synuclein affected autophagy in vitro and in tissue culture. One particular modification of alpha-synuclein was found to interfere with autophagy: the compound created by the interaction of alpha-synuclein with dopamine (DA).

Alpha-synuclein molecules modified by DA bound tightly to the lysosomal membrane, but got stuck there and were not effectively transported into the lysosome. As a result, the alpha-synuclein molecules altered by DA were poorly degraded and the presence of these molecules on the lysosomal membranes also interfered with the autophagic digestion of other compounds.

The researchers propose that inhibition of autophagy caused by DA's alteration of alpha-synuclein could explain the selective death of DA-producing nerve cells in PD. Indeed, interference with autophagy has also been implicated in other neurodegenerative disorders, including Alzheimer's disease. It is thought that by devising strategies for boosting autophagy in nerve cells or suppressing the chemical reactions that interfere with the process, for example by lowering alpha-synuclein expression, researchers may be able to treat patients who have these conditions.

Alnylam and collaborators receive MJFF grant to develop RNAi therapeutic for PD

Alnylam Pharmaceuticals is part of a research team that has been awarded a new US$3.8 million grant from the Michael J Fox Foundation (MJFF) to further develop an RNA interference (RNAi) therapeutic for the treatment of Parkinson's disease (PD). The four-year grant, which is part of the Foundation's LEAPS (Linked Efforts to Accelerate Parkinson's Solutions) initiative, was awarded to Alnylam, Mayo Clinic, and the Parkinson's Institute and Clinical Center of Sunnyvale, CA.

The LEAPS award will fund research focused on the further development of an RNAi therapeutic targeting alpha-synuclein. Continued research will look at whether reducing levels of alpha-synuclein in the brain can slow or halt the progression of PD. Alnylam and collaborators have designed and synthesised small interfering RNAs (siRNAs) that are specific to the alpha-synuclein gene. Previously-reported in vivo data show that siRNAs administered into the brain

were effective in reducing alpha-synuclein levels, thus suggesting the applicability of RNAi therapeutics as a possible disease-modifying therapy for PD.

PRODUCT NEwSSun amends ANDA for generic Stalevo Tablets

Orion has been informed that Sun Pharmaceutical Industries has amended its ANDA with the FDA seeking authorisation to produce and market generic versions of Stalevo Tablets (carbidopa+levodopa+entacapone) 25/100/200 and 37.5/150/200mg in the US. Sun's amendment to its ANDA involves a Paragraph IV challenge to Orion's US Patent No. 5,446,194.

Stalevo is an enhanced levodopa treatment originated by Orion and marketed in the US by its exclusive licensee, Novartis, for the treatment of Parkinson's disease. Sun previously filed Paragraph IV certifications against Orion's US Patent Nos. 6,500,867 and 6,797,732, and Orion subsequently sued Sun (November 2007) in the US for patent infringement. Of the six Orion patents listed in the FDA's Orange Book, three have not received Paragraph IV certifications from Sun (US Patent Nos. 4,963,590, 5,112,861 and 5,135,950), and the latest of these expires on 31st October 2010. Together with Novartis, Orion is currently evaluating its legal options to protect its rights.

ALzHEImER'S DISEASE - R&D UPDATECoMentis reports positive Phase I data with beta-secretase inhibitor

CoMentis has completed a Phase I study of its proprietary, orally-bioavailable, small-molecule beta-secretase inhibitor, CTS-21166, which is being developed as a disease-modifying treatment for Alzheimer's disease (AD).

This was designed as a dose-escalation study to assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of CTS-21166 in healthy volunteers following intravenous administration. Forty-eight subjects received one of six different doses or placebo, and the study measured levels of CTS-21166 and levels of amyloid beta (Abeta) in the plasma.

The results indicate that CTS-21166 is safe and well tolerated. Pharmacodynamic proof of activity was achieved as subjects displayed a robust, sustained and dose-related reduction in plasma Abeta in both area-under-curve (AUC) reduction and peak reduction, with effects lasting over 72 hours. Single-dose administration of CTS-21166 produced a >60 per cent reduction of plasma Abeta measured either by AUC over 24 hours or as a maximal reduction relative to pre-dose levels. The highest doses of CTS-21166 further demonstrated a sustained reduction in AUC that was >40 per cent over 72 hours.

CTS-21166 demonstrated good PK properties, including dose-proportional exposure and very low inter-subject PK variability. In addition, the PK profile is consistent with once-daily dosing and will support a commercial product. Inhibition of beta-secretase reduces Abeta production and could slow the progression of AD. CTS-21166 is the first of several highly-selective, potent and orally-active beta-

NEURODEGENERATIVE DISORDERSNEURODEGENERATIVE DISORDERS

©Espicom Business Intelligence 17th January �008

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secretase inhibitors being developed by CoMentis that show positive efficacy in preclinical models of AD. CoMentis anticipates launching a Phase II study of oral CTS-21166 in AD patients during 2008, plus in an effort to accelerate the development of this platform, the company is in advanced partnership negotiations with multiple parties and expects to complete a transaction during the first quarter of the year.

Prana completes Phase IIa trial of PBT2 in early AD

Prana Biotechnology has completed its Phase IIa trial of PBT2 in patients with early Alzheimer's disease (AD). This double-blind, placebo-controlled study exploring the safety and tolerability of PBT2, also measured the drug's effects on the mechanism and progression of the disease, by investigating biomarkers of AD, as well as measures of cognition. All patients have completed their final clinical assessment. The data are being analysed and results are expected in the first quarter of 2008.

Pipex initiates Phase II trial of Coprexa for AD

Pipex Pharmaceuticals has initiated a Phase II trial of its lead anticopper drug candidate, Coprexa (oral tetrathiomolybdate), for the treatment of Alzheimer's disease (AD). The study is being led by the clinical research group that first discovered and has most extensively studied and published findings of elevated toxic free copper levels in the serum of AD patients. The trial is also being partially supported by a grant from the Italian Ministry of Health, which is expected to fund approximately 30 per cent of the cost.

Coprexa is an oral, small-molecule agent that is highly specific for the reduction of free copper in serum, the most toxic form of copper in the body, and is thus ideally suited for the treatment of CNS diseases in which abnormal serum and CNS copper homeostasis are implicated. The double-blind, placebo-controlled, Phase II trial is intended to enrol 150 mild-to-moderate AD patients who have elevated levels of free copper. Patients will be randomised on a 1:1 basis to receive either Coprexa plus an acetylcholineserase inhibitor or placebo plus an acetylcholineserase inhibitor during the course of the study. The primary endpoint is to evaluate cognition at 24 and 52 weeks utilising the ADAS-Cog, while secondary endpoints will evaluate changes in hippocampal volume measured by MRI, as well as other advanced neuroimaging markers of AD progression. The study is being conducted at four sites throughout Italy.

PRODUCT NEwSForest/Merz file lawsuits for Namenda patent infringement

Forest Laboratories and Merz have filed lawsuits in the US District Court for the District of Delaware against several companies for infringement of US Patent No. 5,061,703 (the '703 patent), which relates to Forest's Namenda (memantine), an NMDA receptor antagonist indicated for the treatment of moderate-to-severe dementia of the Alzheimer's disease type. The defendants named in the lawsuits include Barr Laboratories, Cobalt Laboratories (Cobalt Pharmaceuticals), Lupin, Orchid Chemicals & Pharmaceuticals, Teva Pharmaceuticals USA (Teva Pharmaceutical Industries), Upsher-Smith Laboratories, Wockhardt, and related companies and subsidiaries thereof.

The '703 patent expires in April 2010, however, Forest has applied for patent term extension, which if granted, would extend this patent until September 2013. As previously reported, Forest had received

notification from several companies that they had filed ANDAs with Paragraph IV certifications to obtain approval to market generic versions of Namenda (see CNS 177).

Editor's note: Forest markets memantine as Namenda in the US, whilst Lundbeck markets the product as Ebixa, both under licence from Merz, which markets it as Axura/Akatinol in a number of markets worldwide.

Eisai introduces new Aricept dose formulations for severe AD in Japan

Eisai has introduced new dose formulations of Aricept (donepezil), Aricept Tablet 10mg and Aricept D Tablet 10mg, for the treatment of severe Alzheimer's disease (AD), in Japan.

On 23rd August 2007, Eisai obtained approval of additional efficacy and dosage for Aricept in the treatment of severe AD, as well as marketing authorisation for the new 10mg dose formulations, in Japan. These new formulations were added to the National Health Insurance drug price list as of 21st December.

Aricept, an acetylcholinesterase inhibitor developed by Eisai, is the only approved prescription medicine for the treatment AD in Japan. In the US, where it is co-promoted with Pfizer, Aricept received approval for the treatment of severe AD in October 2006. Since then, this indication has been approved in India, the Philippines, New Zealand, Canada, Australia and Thailand.

mULTIPLE SCLEROSIS - PRODUCT NEwSBiogen Idec/Elan provide update on Tysabri's utilisation, safety and exposure

Biogen Idec and Elan have reported new data on the global utilisation, safety and overall patient exposure of Tysabri (natalizumab). As of late December, more than 21,000 patients were on commercial and clinical therapy worldwide. To date, the safety data continue to support a favourable benefit-risk profile for the drug.

According to data available to the companies as of late December:

in the US, approximately 12,900 patients were on Tysabri therapy commercially and approximately 2,500 physicians have prescribed the therapy;internationally, approximately 7,500 patients were on Tysabri therapy commercially;in global clinical trials, approximately 700 patients were on Tysabri therapy; andthere have been no cases of progressive multifocal leukoencephalopathy since re-launch in the US and launch internationally in July 2006.

In addition, as of mid-December:

cumulatively, in the combined clinical trial and post-marketing settings, up to 30,900 patients have been treated with Tysabri; and of those patients, up to 6,300 have received at least one year of therapy with the drug.

Tysabri, which was discovered by Elan and co-developed with Biogen Idec, is approved for relapsing forms of multiple sclerosis (MS) in the US and relapsing-remitting MS in the EU. It is available in the US through the TOUCH Prescribing Program; all US prescribers, infusion

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sites and patients receiving the drug are required to enrol in TOUCH. Safety information is also collected through ongoing clinical trials and registries, including TYGRIS (Tysabri Global ObseRvation Program In Safety) and the pregnancy registry, making this the largest long-term patient follow-up effort undertaken for any MS therapy. In addition to the US and EU, Tysabri is also approved for MS in Switzerland, Canada, Australia, New Zealand and Israel.

OTHER NEURODEGENERATIVE DISORDERS - R&D UPDATE

Baylor study suggests new treatments for HD

Working with fruit flies, researchers at the Baylor College of Medicine have discovered a new mechanism by which the abnormal protein in Huntington's disease (HD) causes neurodegeneration. They have also manipulated the flies to successfully suppress that neurodegeneration, which suggests potential treatments to delay the onset and progression of the disease in humans.

HD is caused by a mutation in the gene for the huntingtin (htt) protein that causes an abnormally long number of glutamine repeats at one end of the protein. Previous studies had concentrated on the toxicity that the abnormal protein produces by forming cell-clogging aggregates in the nuclei of neurons, however, most studies in animals had not involved introducing the gene for full-length htt; instead, they involved only a fragment.

In experiments reported in the 10th January issue of Neuron (2008;57:27-40), the researchers introduced the gene for full-length abnormal human htt into the fruit fly, Drosophila, and studied its early effects on neural function. They found that before the abnormal protein produced any toxic effects in the nuclei of neurons, it caused abnormally high transmission of neurotransmitters among neurons. Besides abnormal synaptic transmission, mutant htt also caused neurodegeneration and degeneration in the flies' motor ability. The researchers found that they could suppress these abnormalities by introducing other mutations into the fly genome that either reduced neurotransmission or reduced the activity of calcium channels in the membranes of neurons.

These findings unveil a mechanism of pathogenesis for expanded htt that does not require its nuclear accumulation in detectable amounts. Instead, it is thought that the increased neurotransmission likely represents a mechanism of pathogenesis taking place at early stages of disease progression. Furthermore, the results point to increased synaptic transmission as a therapeutic target with the potential of delaying HD onset and thus likely impacting disease progression. According to the researchers, the ability to genetically suppress the abnormal neurotransmission and neurodegeneration further defines specific therapeutic targets and supports the idea that calcium channel antagonists, and perhaps other inhibitors of neurotransmission, offer an attractive therapeutic option due to their specificity and wide usage.

Amarin to commence Phase IIa trial with AMR-101 in AAMI

Amarin has received the necessary regulatory and ethical approvals to commence a Phase IIa trial in age-associated memory impairment (AAMI) with AMR-101 (ultra-pure ethyl-eicosapentanoic acid). The company previously reported positive results from a preclinical programme in memory and cognition using AMR-101.

This double-blind, placebo-controlled study will enrol 96 patients with AAMI, who will be randomised to receive AMR-101 1, 2 or 4g, or placebo twice daily over a six-week period. Efficacy will be assessed by a computerised battery of cognition tests designed by Cognitive Drug Research. The study is being conducted in the UK and patient recruitment is expected to commence shortly, with initial results anticipated in the second half of 2008.

AGREEmENT NEwSYissum licenses small molecule for neurodegenerative diseases to Eucalyptus

Yissum, the technology transfer company of the Hebrew University of Jerusalem, has licensed an orally-available small molecule for several biological indications to Eucalyptus. The molecule, N-acetylcysteine amide (AD4), is an antioxidant in development for the prevention and treatment of Parkinson's disease (PD), Alzheimer's disease, multiple sclerosis (MS) and other neurodegenerative diseases that are linked to oxidative stress, plus has broader applications in biology. AD4 is administered orally and able to cross the blood-brain barrier.

Under the terms agreed, Eucalyptus has acquired exclusive worldwide rights to develop and commercialise the molecule. Yissum, together with Ramot, the technology transfer company of Tel Aviv University, and Mor Research Applications, the technology transfer company of Clalit Health Services, will receive up-front and milestone payments in accordance with development progress, plus royalties from sales of final products.

Preclinical data showed the ability of AD4 to protect cells in culture from oxidative damage. Furthermore, the molecule was shown to protect neuronal cells from damage in rodent models of both PD and MS. It is anticipated that the low toxicity of AD4, as evidenced in the laboratory, together with its neuroprotective function and high bioavailability, will make it highly suitable for the treatment of CNS disorders.

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R&D UPDATEReNeuron provides update on IND application for SC therapy trials

ReNeuron has provided an update on progress with its IND application to the FDA to commence initial clinical trials in the US with its ReN001 stem cell (SC) therapy for stroke.

On 3rd December, the company revealed that it had submitted its responses to the requests made by the FDA in respect of the original IND application. ReNeuron has subsequently been notified that the IND currently remains on clinical hold. While most of the substantive issues raised by the Agency in the original IND hold letter have been satisfactorily addressed in the amended IND package, there is a small number of further hold issues that remain to be resolved. The company intends to meet with the FDA shortly to discuss and agree an approach to resolving these remaining issues in a timely fashion. Indeed, based on the proof-of-concept, safety and product manufacturing data package that it has and is continuing to build for ReN001, ReNeuron remains confident that this therapy can be taken into the clinic during 2008.

In the meantime, ReNeuron is continuing its preparations for the clinical phase of development with its ReN001 therapy. These preparations include continuing dialogue with regulatory authorities in other key territories such as the UK, with a view to further clinical trial applications in these territories in due course.

UCLA discovery offers promise for SCI patients

A University of California, Los Angeles (UCLA) study has shown that the CNS can re-organise itself and follow new pathways to restore the cellular communication required for movement. Published in the January issue of Nature Medicine (2008;14:69-74), the discovery could lead to new therapies for people with traumatic spinal cord injuries (SCIs).

Using a mouse model, the researchers blocked half of the long nerve fibres in different places and at different times on each side of the spinal cord. They left untouched the spinal cord's centre, which contains a connected series of shorter nerve pathways. The latter convey information over short distances up and down the spinal cord. Suprisingly, most of the mice regained the ability to control their legs within eight weeks; they walked more slowly and less confidently than before their injury, but still recovered mobility.

When the researchers blocked the short nerve pathways in the centre of the spinal cord, the regained function disappeared, returning the animals' paralysis. This step confirmed that the nervous system had re-routed messages from the brain to the spinal cord via the shorter pathways and that these nerve cells were critical to the animals' recovery.

This study has identified cells that researchers can target in their attempts to restore communication between the brain and spinal cord. The UCLA team's next step will be to learn how to entice nerve cells in the spinal cord to grow and form new pathways that connect across or around the injury site, enabling the brain to direct these cells. If the researchers succeed, the findings could lead to the development of new strategies for restoring mobility following SCI.

Alseres concludes enrolment in Phase I/IIa trial of Cethrin for acute SCI

Alseres Pharmaceuticals has concluded enrolment in a Phase I/IIa trial of Cethrin for acute spinal cord injury (SCI). A total of 48 subjects have been enrolled at nine sites in the US and Canada. Interim reported data from the trial have demonstrated encouraging safety and efficacy results over a 30-fold dose range. The company expects to release periodic updates of the data in 2008, following protocol-specified patient evaluations, and plans to begin a placebo-controlled, Phase IIb trial in acute SCI at sites in the US, Canada, Europe and other countries in the first half of the year.

Cethrin, which has been granted orphan drug status in the US, contains a proprietary protein that inactivates the action of Rho, a key enzyme that prevents axon regeneration and recovery after an SCI. In February 2005, enrolment began in the open-label, non-placebo-controlled, dose-escalating, Phase I/IIa trial in subjects with acute SCI at sites in the US and Canada. The study assessed five dose levels of Cethrin from 0.3 to 9mg in both thoracic and cervical injuries.

The trial design includes a number of post-treatment evaluations of the subjects for safety and efficacy, for up to one year after treatment. The efficacy measurements assess changes in subjects' sensory and motor functions, as well as overall recovery, as measured by the American Spinal Injury Association (ASIA) Impairment Scale. Subjects in the trial suffered a complete thoracic or cervical SCI and were thus classified as an A on the ASIA Impairment Scale at the time of enrolment into the study.

The six-month interim data on 37 of these subjects treated with doses of up to 6mg indicate that 27 per cent of the Cethrin-treated subjects improved from ASIA A to ASIA B or better. When subjects with cervical injuries who were treated with Cethrin were analysed separately, approximately 46 per cent exhibited a conversion rate from ASIA A to ASIA B or better. Moreover, approximately 18 per cent of subjects overall and 38 per cent of subjects with cervical injuries improved to ASIA C or better over the six months, the hallmark of which is recovery of some motor function. In subjects with cervical injuries, the interim efficacy data also suggest that the response rate observed is dose-dependent at doses up to 6mg.

To date, the safety and tolerability data for dose levels up to 6mg indicate that Cethrin appears to be safe and well tolerated. There have been no serious adverse events related to Cethrin as determined by the investigators and the independent Data Safety Monitoring Board (DSMB). There were two deaths of subjects enrolled in the trial, which the DSMB and clinical investigators attributed to causes related to the subjects' initial SCI, other injuries or pre-existing conditions, and not related to Cethrin.

Study identifies new gene for CVT

Researchers have identified a new gene linked to cerebral venous thrombosis (CVT). The study, which was published in the 8th January issue of Neurology (2008;70:129-132), compared 78 people with CVT in Germany to 201 healthy people. It was found that a variant of the gene known as Factor XII C46T is more common in people with this condition than in healthy people. A total of 16.7 per cent of those with CVT had the gene variant, compared to 5.5 per cent of those without the condition. The results were the same after adjusting for factors that could affect blood clotting, such as age, gender, smoking and use of oral contraceptives. Study author, Dr Christoph Lichy, of the

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University of Heidelberg, believes that although these results need to be confirmed, it appears that people with CVT should be tested for this gene and be considered for use of blood-thinning medication to prevent future blood clots.

AGREEmENT NEwSBrainStorm/Rutgers expand collaboration for spinal cord injury cure

BrainStorm Cell Therapeutics has expanded its collaboration with Rutgers, The State University of New Jersey in an effort to cure spinal cord injuries through the company's adult stem cell (SC) research.

BrainStorm is developing adult SC therapeutic products, derived from autologous bone marrow (BM) cells, for the treatment of neurodegenerative diseases. The NurOwn patent-pending technology allows for the differentiation of BM-derived SCs into functional neurons and astrocytes, as demonstrated in animal models.

This study, combined with BrainStorm's unique differentiation process, uses SCs derived from human BM that are expanded and induced to secrete neurotrophic factors.

Preliminary evidence has indicated that transplantation of differentiated human BM-derived SCs improved the motor behaviour of subjects used in animal studies, as measured by motor and walking analysis.

ANXIOLyTICS/SLEEP DISORDERSR&D UPDATE

Addex' ADX10059 fails to reduce acute anxiety in Phase IIa study

Addex Pharmaceuticals has revealed that ADX10059 did not reduce acute anticipatory anxiety in a small Phase IIa study in patients with dental anxiety, however, some signs of anxiolytic activity were observed. The development of ADX10059 for migraine and gastro-oesophageal reflux disease (GORD) is continuing as planned.

This double-blind, placebo-controlled trial was conducted at specialist UK dental centres. It included 50 patients with moderately-severe dental anxiety who underwent a routine dental procedure. Patients received a single dose of ADX10059 250mg or placebo 60 minutes prior to a dental procedure. Anxiety was measured at specific time points before, during and after the procedure using the Visual Analogue Scale of anxiety (VAS anxiety). Skin conductance, an objective measure of the physiological response to stress and patient ratings of study medication effectiveness were also collected.

The primary endpoint, VAS anxiety at 60 minutes after dosing (immediately prior to the start of the dental procedure), did not show a statistical difference between ADX10059 and placebo (mean VAS 4.81 vs 4.67cm, respectively). However, signs of anxiolytic activity were observed in the trial. Although the differences were not statistically significant, patients in the ADX10059 group had lower increases in skin conductance at all time points from 30 minutes post-dose, suggesting a lower level of stress. In addition, patients rated ADX10059 as more effective, with 56 per cent rating it as good or excellent, compared to 30 per cent of those who received placebo. Also, 15 per cent of patients receiving ADX10059 rated it as poor, compared to 39 per cent of patients receiving placebo; statistical analyses of the patient ratings are ongoing. ADX10059 was generally well tolerated in the study and there were no serious adverse events.

ADX10059 is a negative allosteric modulator of metabotropic glutamate receptor 5. Fenobam, a product with a similar mechanism of action, demonstrated efficacy in patients with generalised anxiety disorder after repeated administration in studies conducted in the 1980s. Although ADX10059 did not demonstrate efficacy in this clinical model of acute anticipatory anxiety, Addex believes that the compound has potential for other types of human anxiety, especially where therapeutic administration of a longer duration is necessary. Addex will complete analysis of the data from this study before

announcing further plans for ADX10059 in the anxiety indication. The company noted that although VAS anxiety is a well-recognised way to measure response to anxiolytics, it is a subjective measure and consequently, can make interpretation of drug activity challenging, particularly in smaller studies.

Addex intends to start Phase IIb testing of ADX10059 in both migraine and GORD in mid-2008, as planned. In preparation for the Phase IIb programme, ADX10059 formulation work is nearing completion and the first galenic formulation of the product is expected to enter a confirmatory Phase I programme around the end of the first quarter of the year. An unformulated version of ADX10059 (ie, the active pharmaceutical ingredient in capsule) met primary endpoints in separate proof-of-concept, Phase IIa studies in migraine and GORD in 2007.

Ambien CR improves chronic insomnia in patients with co-morbid GAD

Results from a new study have shown that sanofi-aventis' Ambien CR (zolpidem extended-release [ER]) tablets CIV provided improvement in sleep onset, sleep maintenance and total sleep time (TST) for patients with co-morbid chronic insomnia and generalised anxiety disorder (GAD) compared to placebo. Zolpidem ER also improved sleep-related next-day functioning measures.

This was a multi-centre, double-blind, parallel-group, randomised, placebo-controlled trial in 381 adults aged 21 to 64 years with co-morbid chronic insomnia and GAD. The study evaluated the overall improvement of insomnia, as measured by TST, in patients treated with zolpidem ER and the antidepressant, Lexapro/Cipralex (escitalopram), compared to treatment with placebo and escitalopram. Patients received zolpidem ER 12.5mg (n=191) or placebo (n=190) each night, followed by escitalopram 10mg each day during the eight-week study, followed by a one-week period of escitalopram only.

Researchers assessed treatment efficacy during clinic visits at weeks one, two, four, six and eight, and through daily patient-reported Morning Sleep Questionnaires (MSQ). The MSQ measured the primary efficacy outcome of TST, in addition to measurements of sleep onset latency, wake time after sleep onset, number of awakenings, quality of sleep and sleep-related next-day functioning.

TST was increased in the zolpidem ER group throughout the study. At week eight, such patients reported sleeping an average of 106 minutes more than baseline, while placebo-treated patients reported

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CNS Drug News

sleeping an average of 68 minutes more (p<0.0001). On average, zolpidem ER-treated patients reported falling asleep sooner and exhibited improved sleep maintenance, based upon fewer night-time awakenings and decreased wake time after sleep onset compared to placebo-treated patients (p<0.0001). At week eight, the number of night-time awakenings decreased in the zolpidem ER+escitalopram group (-1.33+/-1.26) compared to the placebo+escitalopram group (-0.76+/-1.02), and time to sleep onset was reduced by 55.1 (+/-67.3) minutes with zolpidem ER, compared to a reduction of 26.8 (+/-58.7) minutes with placebo (p<0.0001). In addition, patients reported improvements in secondary measures relating to daytime functioning, including morning energy, morning concentration and sleep impact on daily activities.

Treatment was well tolerated during the study and adverse events (AEs) were similar between treatment groups. AEs occurred in 76 per cent of patients treated with zolpidem ER+escitalopram and 71 per cent of the patients treated with placebo+escitalopram. The most frequent AEs experienced by both treatment groups were nausea, dizziness and fatigue. These AEs have been reported in previous studies of both zolpidem ER and escitalopram, and are known to be part of the safety profile of both treatments. One patient in each treatment group experienced different serious AEs.

Somaxon plans Silenor NDA submission following mouse carcinogenicity study

Somaxon Pharmaceuticals has completed a 26-week, transgenic mouse carcinogenicity study of Silenor (doxepin). Based on the results of this study and a review of such results with its consultant toxicologists, Somaxon intends to proceed with the submission of an NDA for Silenor, which is now estimated to occur by mid-February.

Somaxon has completed four successful Phase III trials of Silenor for the treatment of insomnia. As previously disclosed, based on a request from the FDA in May 2006, the company initiated a

preclinical programme for Silenor consisting of standard genotoxicity, reproductive toxicology and carcinogenicity studies. The results of the transgenic mouse carcinogenicity study will be included in the company's planned NDA submission, which will also include the results of reproductive toxicology studies that were completed in June. In August, Somaxon initiated a two-year rat carcinogenicity study and the company plans to submit the results of that study as a post-approval commitment.

PRODUCT NEwSHemispherx addresses FDA questions on Ampligen NDA

Hemispherx Biopharma has formally submitted to the FDA detailed responses to all of the 14 questions posed by the Agency concerning the company's NDA for Ampligen (Poly I. Poly C12U) to treat chronic fatigue syndrome (CFS). Hemispherx received the questions from the FDA on 5th December, at which point the application was deemed by the Agency as ''not sufficiently complete'' to permit substantive review under 21 CFR 314.101(R). Consequently, the FDA's consideration of the NDA was postponed, pending receipt of the company's answers to the questions (see CNS 176).

With the exception of a topical product for skin cancer, no Toll-like receptor-type compounds have yet received full regulatory clearance; Ampligen is the first in this class of RNA molecules now seeking commercialisation. A recent independent study enumerated three primary causes of early death in CFS populations at large (without administration of Ampligen) that may be attributable to the disease: 1) cardiovascular events; 2) suicide; and 3) untreatable life-threatening malignancies/tumours. In response to the FDA's questions, as well as within the body of its NDA, Hemispherx has discussed how Ampligen may address these and other high-risk aspects of CFS.

ANTIDEPRESSANTSR&D UPDATE

Rexahn raises funds for compound development

Rexahn Pharmaceuticals has raised net proceeds of US$6.8 million in a private placement of its common stock and three-year warrants to purchase its common stock for a group of accredited investors in Korea. The company expects to raise an additional US$1.8 million in a second tranche, which is scheduled to close on 29th February. The proceeds will be used for general corporate purposes, including the company's

ongoing research and development programmes relating to a number of compounds, such as Serdaxin. Rexahn intends to initiate Phase II trials for Serdaxin, a compound for the treatment of depression, in 2008.

Serdaxin acts on the neurotransmission systems of serotonin and dopamine, which are key controlling mechanisms of anxiety and mood disorders. In animal models, the compound increased levels of serotonin and dopamine in the brain, exhibited potent anxiolytic activities, and induced significant active imaging changes in the rat brain. Furthermore, Serdaxin did not disrupt learning and memory functions unlike current anxiolytic drugs.

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R&D UPDATEProgress reported with new treatment mechanisms for schizophrenia

All treatments for schizophrenia approved by the FDA have had a single treatment mechanism at their core, the blockade of the dopamine D

2 receptor. However, the introduction of clozapine in

the 1980s suggested that other brain targets might complement the blockade of dopamine D

2 receptors to treat symptoms that failed to

respond to the typical antipsychotics. Indeed, new research related to three new treatment approaches has been reported in the 1st January issue of Biological Psychiatry.

In the first study (2008;63:86-91), a Georgetown University-led research team tested a novel drug that inhibits the breakdown of the transmitter, N-acetylaspartylglutamate (NAAG), which activates a receptor that reduces schizophrenia-like behaviours in some animal models. The findings indicate that this drug is effective in an animal model of schizophrenia and support the conclusion that NAAG peptidase inhibitors represent a breakthrough in the discovery of a completely novel means of adjunct therapy for schizophrenia that is analogous to the use of selective serotonin reuptake inhibitors for the treatment of depression.

In the second article (2008;63:92-97), Chiba University researchers and colleagues demonstrated that repeated administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), decreased the density of alpha7 nicotinic receptors (alpha7 nAChRs) in the mouse brain, and that the novel alpha7 nAChR agonist, SSR180711, could ameliorate PCP-induced cognitive deficits in mice. These findings suggest that alpha7 nAChR agonists, including SSR180711, could be potential therapeutic drugs for cognitive deficits in schizophrenic patients.

Finally, in the third investigation (2008;63:98-105), University of California researchers and colleagues found that the recently-discovered 5-HT

7 receptor might be of importance for understanding

certain aspects of schizophrenia. Their study focused on sensory input processing, which is often impaired in schizophrenia, and found that blockade of this particular serotonin receptor in mice alleviates this impairment. The results indicate that atypical antipsychotics may promiscuously exert some of their beneficial effects through the 5-HT

7 receptor, and suggest that further exploration of this receptor as a

treatment target may lead to more specific and better medications for disorders such as schizophrenia.

Chromosome abnormality may increase autism risk; UCLA study identifies new genetic link

A multi-institutional study involving Massachusetts General Hospital researchers has identified a chromosomal abnormality that appears to increase susceptibility to autism. The investigators, whose work was published in the 9th January online edition of the NEJM (10.1056/NEJMoa075974), found that a segment of chromosome 16 is either missing or duplicated in approximately 1 per cent of individuals with autism or related disorders, a frequency that is comparable to other genetic syndromes associated with the disorder. Population studies indicate that up to 90 per cent of cases of autism and autism spectrum disorders (ASDs) have some genetic component, but only 10 per cent can be attributed to known genetic and chromosomal syndromes.

Since several of those conditions involve deletions or duplications of chromosomal segments, including an inherited deletion of a region of chromosome 15, the investigators conducted a complete genome scan of samples from the Autism Genetic Resource Exchange, which contains DNA from families in which at least one child has autism or a related disorder.

The scan of more than 1,400 affected individuals and a similar number of their unaffected parents revealed that an identical region of chromosome 16 was deleted in five individuals with an ASD, but not in any of the parents, implying that the deletion had occurred spontaneously and was not inherited. To confirm this observation, clinical testing data from almost 1,000 patients from the Children's Hospital Boston, approximately half of whom had been diagnosed with autism or a related developmental delay, were evaluated. Among those with a developmental disorder, five children had the same deletion and in another four, the chromosome segment was duplicated. Again, no abnormalities were seen in the DNA of children without autism or developmental delay.

Confirmatory data were also obtained by colleagues from deCODE genetics, who found the same deletion in three out of almost 300 individuals with an ASD, as well as in a few with other psychiatric or language disorders. Among almost 20,000 members of the deCODE database who had not been evaluated for language or psychiatric disorders, the deletion was seen in only two individuals. Results from the deCODE scan indicate that, while this chromosomal deletion occurs in only 0.01 per cent of the general population, it is 100-times more prevalent in those with ASDs.

These large, non-inherited chromosomal deletions are extremely rare, so finding precisely the same deletion in such a significant proportion of patients suggests that it is a very strong risk factor for autism. The researchers are now pursuing more detailed genetic studies to determine which genes in this region are responsible for this effect in order to gain a better understanding of the underlying biology and potential clues to therapeutic approaches.

In addition...

University of California, Los Angeles (UCLA) scientists have used language onset as a tool for identifying a new gene linked to autism. The research team also discovered that the gene is most active in brain regions involved with language and thought. Interestingly, evidence for the genetic link came from the DNA of families with autistic boys rather than those with autistic girls. The findings were published in the January issue of the American Journal of Human Genetics (2008;82:150-159), which also featured two studies from research teams at Yale University and Johns Hopkins University that used different methods to pinpoint the same gene (2008;82:160-164 & 165-173). The coincidences suggest that the gene, called contactin-associated protein-like 2 (CNTNAP2), likely plays a key role in the development of autism. According to Dr Daniel Geschwind, the study's principal investigator, this gene may not only predispose children to autism, but may also influence the development of brain structures involved in language, providing a tangible link between genes, the brain and behaviour. Late language onset is a symptom shared by most children with autism. In an earlier study, the UCLA investigators studied the DNA of 291 families nationwide who had donated blood samples to the

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CNS Drug News

Autism Genetic Resource Exchange. Each family had at least one autistic child; youngsters who had never spoken were excluded. The findings connected a specific region of chromosome 7 known as 7q35 to autism. In the current study, the researchers scrutinised every gene in the 7q35 region using DNA samples from 172 families. They identified four promising genes; one of the candidates was CNTNAP2. To verify their findings, the scientists conducted a second test on a new group of 304 families. The CNTNAP2 gene showed up consistently, confirming its implication in language development. In a second approach, the researchers examined CNTNAP2's presence in early brain tissue and discovered that the gene was most active in developing brain structures involved in language and thought. In an unexpected third finding, the scientists found that statistical evidence for the gene was strongest in families with autistic boys.

Less of an association appeared in families with autistic boys and girls, or in families with autistic girls only. Autism strikes boys three-times as often as girls and it is thought that this finding may partly explain why. The researchers' next step will be to identify more traits, such as seizures or other symptoms, that will help them to track down additional genes linked to the disorder.

PRODUCT NEwSAstraZeneca submits sNDAs for Seroquel XR in bipolar mania and depression

AstraZeneca has submitted two separate sNDAs to the FDA for once-daily Seroquel XR (quetiapine) Extended-Release Tablets to seek approval for the treatment of manic and depressive episodes associated with bipolar disorder.

Seroquel XR is currently approved in eight countries, including the US, Canada and the Netherlands, for the acute and maintenance treatment of schizophrenia in adults. The bipolar mania submission is based on a clinical study of once-daily treatment with Seroquel XR compared to placebo, with a primary endpoint of change in YMRS total score (week three), in 316 patients with bipolar mania. Meanwhile, the bipolar depression submission is supported by a clinical study of once-daily treatment with Seroquel XR compared to placebo, with a primary endpoint of change from baseline in MADRS total score after eight weeks of treatment, in 280 patients diagnosed with bipolar depression.

Doses of Seroquel XR administered in both the bipolar mania (400 to 800mg/day) and bipolar depression (300mg/day) studies were comparable to the FDA-approved recommended doses for Seroquel immediate-release tablets in those indications. Both studies met their primary endpoint and it is expected that they will be presented at major scientific congresses in 2008.

FDA approves additional dosage strengths of Shire's Vyvanse

On 10th December, Shire received FDA approval for three additional dosage strengths of the attention deficit hyperactivity disorder (ADHD) treatment, Vyvanse (lisdexamfetamine dimesylate). Shire expects the additional dosage strengths of 20, 40 and 60mg to be available in retail pharmacies in the second quarter of 2008, to supplement the existing 30, 50 and 70mg dosage strengths currently available in pharmacies throughout the US.

Vyvanse is currently approved in the US for the treatment of ADHD in children aged six to 12 years. An sNDA for the drug, for the treatment of ADHD in adults, is currently under review by the FDA.

AGREEmENT NEwSAddex/Merck forge deal over schizophrenia drug candidate

Addex Pharmaceuticals has entered into an exclusive worldwide licence agreement with Merck & Co to develop ADX63365, an orally-available drug candidate for the potential treatment of schizophrenia and other undisclosed indications. Currently in preclinical development, ADX63365 is a positive allosteric modulator (PAM) that targets the metabotropic glutamate receptor 5 (mGluR5), which is believed to be important as a target for the treatment of schizophrenia and other conditions. The deal also includes mGluR5 PAM back-up compounds discovered by Addex.

Under the terms agreed, Addex will receive US$22 million up-front and is eligible for up to US$455 million in research, development, regulatory and sales milestones for the first product developed for two indications, plus up to US$225 million in additional development, regulatory and sales milestones for a second product developed in two indications.

Addex is eligible to receive royalties on the sales of any products resulting from this collaboration. In addition, the company has an option to co-promote in certain EU countries and will participate in the joint oversight committee for further development that will be led by Merck.

Preclinical research has shown that the activation of mGluR5 using PAMs can act as an antipsychotic and reverse cognitive dysfunction of schizophrenia. As a result, a product like ADX63365 could become a first-line antipsychotic therapy that also improves cognitive dysfunction, thereby offering advantages over other therapies on the market or in development. On 3rd December, Addex announced a separate collaboration with an affiliate of Merck (Merck Sharp & Dohme Research) to discover and develop PAMs targeting mGluR4 for the treatment of Parkinson's disease and other undisclosed indications (see CNS 176).

Pfizer/Taisho finalise agreement for novel schizophrenia drug candidate

Pfizer and Taisho Pharmaceutical have signed a definitive agreement, which replaces the letter of intent previously signed between the companies, for a worldwide (excluding Japan) collaboration to research, develop and commercialise TS-032, a new schizophrenia drug candidate discovered by Taisho that is currently in preclinical development (see CNS 174).

TS-032 is a novel metabotropic glutamate receptor (mGluR) agonist that may offer a new treatment option for CNS disorders. Although the characteristics of mGluR are still only partly understood, this receptor is believed to play a role in the transmission of glutamate and other substances in the brain.

Abnormalities in the neurotransmission through mGluR may be one cause for symptoms related to schizophrenia, as well as other CNS disorders, and data show that mGluR agonists, such as TS-032, offer potential as new treatments for schizophrenia.

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R&D UPDATEDosing commences in US Phase II trial of Innocoll's bupivacaine implant

The first in a series of planned Phase II trials to investigate Innocoll's CollaRx bupivacaine surgical implant for the management of postoperative pain has commenced dosing.

The implant is a biodegradable and fully-bioresorbable matrix of purified fibrillar collagen impregnated with the local anaesthetic, bupivacaine, which has been specifically developed and formulated using Innocoll's proprietary CollaRx sponge technology. It is under development in the US and Europe for the management of postoperative pain following moderate/major abdominal, gynaecological, abdominal, thoracic and orthopaedic surgeries. The implant is intended to provide pain control directly at the surgical site and thus reduce the level of additional analgesia required following surgery. The collagen matrix naturally biodegrades over a few days and the bupivacaine is released to provide local analgesia for up to 96 hours postoperatively.

Innocoll recently completed a Phase II trial in patients undergoing hysterectomy surgery in the absence of gynaecological cancers at Wexham Park Hospital in Slough, the UK. The results of this trial provided evidence of sustained, postoperative analgesia for approximately 96 hours, as measured by Visual Analogue Scale scores and reduced dependence on systemic morphine administered by patient-controlled analgesia.

This extended action was achieved despite a low total bupivacaine dose (150mg as the hydrochloride salt), which is well below the allowable daily dose and equivalent to that used by some practitioners for a once-off wound infiltration with bupivacaine solution prior to wound closure.

For the planned series of multi-centre, controlled, Phase II trials to be performed in the US, Innocoll has appointed Premier Research Group to co-ordinate up to five trials in a variety of soft and hard tissue procedures, including hysterectomy, herniorrhaphy, open gastrointestinal surgery and orthopaedic surgery. The first of these trials that has commenced dosing will compare the analgesic effect of the bupivacaine surgical implant versus a placebo implant and current standard-of-care in patients undergoing abdominal hysterectomy at eight different US sites. The other Phase II soft tissue trials in herniorrhaphy and open gastrointestinal surgeries are expected to commence in early 2008.

Arcion raises funds to continue development of ARC-4558

Arcion Therapeutics has raised US$8.8 million in a series A round of financing, which will help the company to continue its work with ARC-4558 (topical clonidine gel), a treatment for alleviating moderate and severe pain associated with diabetic neuropathy. ARC-4558 offers an

alternative to current systemic treatments for neuropathic pain, which often induce serious side effects. Arcion is expected to conduct a late-stage clinical trial to demonstrate safety and efficacy. The company is also evaluating other topical treatments in addition to ARC-4558, to further its goal of providing pain relief with a favourable risk to benefit ratio.

Zogenix raises funds for pain compound development

Zogenix has raised US$18 million in a private placement of preferred stock. Proceeds from the financing will be used to support the commercialisation of sumatriptan DosePro (previously known as Intraject), for which the company submitted an NDA with the FDA in December. Proceeds will also be used to fund the development of the company's late-stage, controlled-release (CR) opioid product that was recently in-licensed from Elan (see CNS 176).

Zogenix' sumatriptan DosePro is a needlefree, single-use, easy-to-use, subcutaneous delivery system for sumatriptan that will compete in the triptan segment of the migraine market, while the CR opioid product utilising the Elan SODAS technology will compete in the strong opioid market for chronic pain.

PRODUCT NEwSSugammadex NDA assigned FDA priority review status

The FDA has assigned priority review status to Schering-Plough's NDA for sugammadex. The product, which Schering-Plough acquired through its combination with Organon BioSciences in November (see CNS 175), was designed to reverse the effects of rocuronium bromide (Zemuron/Esmeron/Eslax) or vecuronium bromide, muscle relaxants commonly used during surgeries that require profound muscle relaxation. If approved, sugammadex will be the first in a new selective relaxant binding agent class of drugs, which work in an entirely new and unique way to encapsulate the muscle relaxant molecule and render it inactive.

According to Schering-Plough, sugammadex has the potential to change the way that doctors practice anaesthesia as it will allow anaesthesiologists to rapidly and safely reverse both shallow and profound levels of muscle relaxation, which is not possible with current reversal agents. In clinical trials, to date, sugammadex has demonstrated the ability to rapidly reverse shallow and profound depths of rocuronium-induced neuromuscular blockade (NMB), thereby enabling control of the onset and offset of skeletal muscle relaxation through the use of both drugs.

Sugammadex has also demonstrated the ability to reverse the effects of NMB induced by vecuronium bromide. In a Phase III trial, the most frequently-reported adverse events associated with sugammadex regardless of relationship to the study drug were procedural pain and nausea.

Through the definitive licence agreement, Taisho will grant exclusive development and commercialisation rights outside of Japan for TS-032 to Pfizer. Taisho will receive from Pfizer an initial payment of US$22

million, plus milestone payments tied to the progress of development, as well as royalties and milestone payments tied to sales if TS-032 is approved by regulatory authorities and launched.

ANALGESICS/ANAESTHETICS

ANALGESICS/ANAESTHETICS

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CNS Drug News

FDA accepts BEMA Fentanyl NDA for filing

The FDA has accepted for filing BioDelivery Sciences International's (BDSI) NDA for BEMA Fentanyl, which was submitted on 31st October, for the management of breakthrough cancer pain in opioid-tolerant patients (see CNS 174). A final decision by the Agency is expected in August.

BEMA Fentanyl consists of a small, dissolvable, polymer disc, formulated with the opioid narcotic, fentanyl, for application to the buccal membranes. The efficacy results from a pivotal Phase III efficacy trial in patients with breakthrough pain associated with cancer demonstrated that subjects treated with BEMA Fentanyl had a significantly greater reduction in pain as early as 15 minutes (study primary endpoint) compared to those treated with placebo. A subsequent safety study demonstrated a good tolerability profile, including a lack of oral irritation or ulceration related to product administration and use.

If BEMA Fentanyl is approved by the FDA, BDSI is expected to receive milestone payments from its commercial partner, Meda AB, totalling US$30 million and could begin receiving royalty revenues from the product as early as the fourth quarter of 2008. In September, BDSI reported a licensing agreement with Meda for the distribution rights in the US, Canada and Mexico for BEMA Fentanyl (see CNS 170). This followed Meda securing from BDSI the rights to distribute the product in Europe; plans for submitting a regulatory application in Europe are under way.

AGREEmENT NEwSJanssen enters supply agreement for ER tramadol; expands Fentanyl TAIFUN deal

Janssen Pharmaceutica (Johnson & Johnson) has entered into an exclusive supply agreement for the marketing and distribution of Biovail's once-daily, extended-release (ER) formulation of tramadol

in 86 countries in two regions, Central and Eastern Europe, and the Middle-East and Latin America. Under the terms of the ten-year agreement, Biovail Laboratories International will manufacture and supply to Janssen once-daily ER tramadol tablets in dosage strengths of 100, 200 and 300mg at contractually-determined prices. Janssen affiliates will be responsible for all related promotional costs, as well as all regulatory filings and the management of the regulatory approvals process.

In February 2007, Ortho-McNeil (J&J) launched Biovail's ER version of tramadol for the treatment of moderate-to-moderately severe chronic pain under the brandname, Ultram ER, in the US and Puerto Rico. Ultram ER, which is available in 100, 200 and 300mg dosage strengths, is the only once-daily tramadol formulation that has been approved by the FDA. In November, Biovail Pharmaceuticals Canada, Biovail's sales and marketing division, launched the product in Canada under the brandname, Ralivia. Ralivia is indicated for the management of moderate severity pain in patients who require continuous treatment for several days or more. With respect to other regions, Biovail is evaluating potential commercialisation options in Western Europe.

In addition...

Akela Pharma has extended the territory coverage of the initial licence and development agreement it has with Janssen for Fentanyl TAIFUN, to include Canada.

Fentanyl TAIFUN is a fast-acting fentanyl formulation delivered using Akela's TAIFUN dry-powder inhaler for the treatment of breakthrough cancer pain. The existing agreement already covers the EU, Eastern Europe, Russia, the Middle-East and Africa. All the commercial and contractual conditions remain in effect.

The product will be distributed by Janssen-Ortho (J&J) for the Canadian market. Akela will receive a signing fee, development and regulatory milestones, as well as commercial sales milestones that are in line with current commercial expectations regarding the Canadian market as compared with the EU market.

THERAPIES TO TREAT SUBSTANCE DEPENDENCER&D UPDATE

Evotec successfully completes Phase I study with EVT 302

Evotec has successfully completed a Phase I safety and tolerability study of EVT 302, with the preliminary results confirming the compound's good tolerability profile.

EVT 302, an orally-active, potent, highly-selective and reversible inhibitor of MAO-B that is in development for smoking cessation, was investigated in this ascending-dose study with repeated daily dosing, in a total of 84 healthy young and elderly subjects. Healthy young male subjects were treated with EVT 302 2.5, 5 or 15mg, or placebo for two weeks, while healthy elderly male and female subjects were treated with EVT 302 2.5 or 10mg, or placebo for four weeks. Each treatment was received by 12 young and/or elderly subjects as appropriate. The highest dose levels exceed the expected maximum therapeutic dose planned to be used in further clinical trials. For the treatment period and part of the subsequent washout phase, the subjects were confined to the clinical research unit.

The study was aimed at investigating safety/tolerability, pharmacokinetics and pharmacodynamics (inhibition of MAO-B in platelets) during prolonged dosing with EVT 302 as compared to placebo, and was conducted and successfully completed as planned per protocol. The results are still blinded and will become available as final evaluated data over the next two months, however the preliminary data indicate that EVT 302 was well tolerated in young and elderly subjects up to the highest dose levels tested in this study. Adverse events (AEs) classified as possibly treatment-related were transient and mostly of mild intensity; only very few moderate AEs were reported. No severe or serious AEs occurred and no clinically-relevant changes in laboratory values of haematology or clinical chemistry were noted. In particular, there were no changes in liver function tests in any subjects.

EVT 302's preclinical profile supports the potential for a superior safety profile over marketed MAO-B inhibitors and better tolerability compared to current treatments. In a single ascending-dose, Phase I study by Roche (from whom the compound was in-licensed), EVT 302 was safe and well tolerated up to high dose levels and showed positive pharmacokinetic properties with prolonged MAO-B inhibition, offering the potential for once-weekly dosing at very low exposure levels.

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R&D UPDATEFDA grants ODD to Ovation's clobazam for LGS and Jazz' JZP-8 for recurrent ARS

Ovation Pharmaceuticals has been granted orphan drug designation (ODD) by the FDA for clobazam as an adjunctive treatment for Lennox-Gastaut syndrome (LGS), which is one of the most severe forms of childhood epilepsy that frequently persists into adulthood.

Clobazam is a 1,5-benzodiazepene and has a distinctive chemical structure compared to other currently-available benzodiazepines. It was initially developed to reduce the adverse events (AEs) associated with 1,4-benzodiazepines, while still maintaining efficacy. In animal models, clobazam has been shown to work both by intensifying GABA-mediated inhibitory effects and by increasing the activity of glutamate transporters. In a Phase II trial, clobazam significantly reduced drop seizures compared to baseline. The majority of AEs observed in this trial were mild or moderate in severity and no serious AEs resulted in premature discontinuation of drug treatment.

Clobazam is widely available, with approvals in more than 100 countries for various uses in both children and adults, including the adjunctive treatment of epilepsy and anxiety. Though not currently approved for any use in the US, Ovation plans to seek FDA approval for clobazam as adjunctive treatment for patients with LGS. To support this development programme, a global multi-centre, Phase III trial is currently under way and enrolling patients.

In addition...

Jazz Pharmaceuticals has received ODD from the FDA for JZP-8, its product candidate for the treatment of recurrent acute repetitive seizures (ARS). JZP-8 is a novel drug-delivery formulation incorporating clonazepam, a widely-prescribed benzodiazepine. The product candidate is designed to be a fast-acting intranasal spray for the treatment of recurrent ARS in patients with epilepsy. Jazz previously completed development activities to select the active pharmaceutical

ingredient for the product, to determine its formulation, and to assess its safety and tolerability in early-stage studies. In December, the company dosed the first patient in a Phase II trial of JZP-8.

Amarin reports completion of preclinical nasal lorazepam study

Amarin has reported the successful completion of a preclinical proof-of-concept study using a novel nasal formulation of lorazepam. The study evaluated the extent of lorazepam's absorption after nasal administration and the pharmacokinetics of the formulation.

This nasal lorazepam formulation utilises Elan's proprietary NanoCrystal Technology and is in development for the out-patient treatment of emergency seizures in epilepsy patients, specifically status epilepticus and acute repetitive seizures. Amarin is now working with a subsidiary of Elan to prepare the formulation for clinical pharmacokinetic trials.

PRODUCT NEwSBreckenridge/Taro settle litigation with Novartis over generic Trileptal

Breckenridge Pharmaceutical has settled a Paragraph IV litigation with Novartis concerning Trileptal (oxcarbazepine), plus on 11th January, the FDA approved the company's ANDA for oxcarbazepine 150, 300 and 600mg tablets in the US. Breckenridge enjoys a shared 180-day exclusivity period and will immediately launch its oxcarbazepine tablets, which are AB-rated to Novartis' Trileptal and used in treating seizures.

In addition...

Taro Pharmaceutical Industries has settled a pending lawsuit with Novartis and plans to launch oxcarbazepine 150, 300 and 600mg tablets in the US.

Two further Phase I studies with EVT 302 are currently ongoing. In March 2007, Evotec initiated a PET study that is designed to assess the occupancy of MAO-B in the brain after oral administration of EVT 302 in patients, which helps to determine the therapeutic dose range of EVT 302 for subsequent safety and efficacy trials; this study is expected to be completed in early 2008. Furthermore, in November, Evotec initiated a Phase I tyramine interaction study to confirm that there was no cardiovascular liability with foods that contain high amounts of tyramine. A first Phase II study to examine the effects of EVT 302 on craving following smoking cessation is planned to start in the first quarter of 2008.

AGREEmENT NEwSAlkermes enters agreement with Cilag for Vivitrol in Russia/CIS

Alkermes has entered into an exclusive agreement with Cilag (Johnson & Johnson) to commercialise Vivitrol (naltrexone for extended release injectable suspension) for the treatment of alcohol and opioid

dependence in Russia and other countries in the Commonwealth of Independent States (CIS). As part of the agreement, Cilag will pay up-front and milestone payments up to US$39 million, as well as ongoing royalties on commercial sales of Vivitrol in this territory, and the product will be commercialised by Janssen-Cilag.

Alkermes will retain exclusive development and marketing rights to Vivitrol in all markets outside of the US, Russia and other countries in the CIS. In the US, Vivitrol is commercialised primarily by Cephalon.

Under the terms agreed, Cilag will have primary responsibility for filing the NDA for Vivitrol in Russia and other countries in the CIS. Alkermes will be responsible for manufacturing Vivitrol, and will receive from Cilag manufacturing revenues and a royalty based on product sales.

Cilag will make an initial payment of US$5 million cash to Alkermes and up to an additional US$34 million in cash payments upon regulatory approvals for the product, certain agreed-upon events and levels of Vivitrol sales. Additional terms were not disclosed.

ANTI-EPILEPTICS

ANTI-EPILEPTICS


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Taro recently settled litigation with Novartis regarding its Paragraph IV certification challenging the latter's patent protection on Trileptal. On 15th November, Taro received FDA approval of its ANDA for oxcarbazepine tablets, but did not immediately launch the product at that time, pending settlement of the litigation with Novartis.

These generic versions of Trileptal will no doubt further impact Novartis' sales of the drug. As reported in Espicom's 4D Pharma, in 2006, Trileptal posted sales of US$721 million, an increase of 17.2 per cent compared to 2005, whilst during 2007, the drug continued to generate growth until the onset of generic competition in the latter half of the year. Indeed, Espicom forecasts that Trileptal sales will decrease to US$403 million by 2011.

AGREEmENT NEwSSepracor enters deal for Bial's anti-epileptic compound

Sepracor has entered into an exclusive licensing agreement for the development and commercialisation of Bial's anti-epileptic compound, BIA 2-093 (eslicarbazepine acetate), in the US and Canada.

Under the terms agreed, Sepracor will be responsible for filing the NDA and seeking marketing approval from the FDA, and contingent on obtaining regulatory approval, commercialisation of the product in

the US. Sepracor anticipates that the NDA will be submitted to the FDA in late 2008 or early 2009, with a potential product launch in late 2009 or early 2010, subject to FDA approval. In exchange, Bial is entitled to receive an up-front payment of US$75 million and subsequent payments upon the accomplishment of various development and regulatory milestones, which could include up to an additional US$100 million if all milestones are met. Bial will also receive compensation for providing finished product and milestone payments upon FDA approval of additional indications, if any.

BIA 2-093 is a new chemical entity that has been designed to offer patients with partial epilepsy additional control of their seizures and improved quality of life. Bial is currently completing clinical evaluation of BIA 2-093 for adjunctive use in partial seizures in adults with epilepsy.

Eslicarbazepine acetate has been shown in clinical studies to be safe and effective in the control of seizures as adjunctive therapy in adults. Bial has tested the compound in three Phase III trials in 22 countries, with over 1,000 patients randomised to an 18-week, acute double-blind therapy and subsequently followed in a one-year, open-label extension study. The potential for once-daily administration could be an important clinical advantage for patients with epilepsy.

In addition, there may be benefits to patients such as reduced drug-drug interactions, which may distinguish this drug from commonly-used compounds such as carbamazepine.

EATING DISORDERSR&D UPDATE

Neurogen opts not to advance NGD-4715 to Phase II testing

Neurogen has completed the follow-up component of a multiple ascending-dose (MAD), Phase I study with NGD-4715, a melanin-concentrating hormone-1 (MCH-1) receptor antagonist being investigated for the treatment of obesity.

The initial phase of the study utilised three-times daily dosing for 14 days in healthy obese subjects exposed to a high caloric diet. As previously reported, during this phase, moderate induction of the liver enzyme, CYP3A4, occurred, increasing the probability of accelerating the metabolism of other drugs administered concomitantly. In addition, during the initial phase of the MAD study, lipid-lowering effects were observed.

The follow-up study was designed to test the effect of twice-daily (bid) dosing in healthy obese subjects on a restricted caloric diet for 14 days. Using bid dosing, CYP3A4 induction was substantially reduced, as measured by treatment with midazolam, a drug sensitive to changes in CYP3A4 levels. With less frequent dosing and caloric restriction in the current trial, no effect on lipids was observed. As in the initial Phase I studies, no serious adverse events were observed, however, vivid dreams and awakenings were reported by half of the drug-treated subjects during the first week of dosing.

These results suggest that the effect of MCH-1 receptor antagonism on caloric regulation and sleep architecture requires further study in humans. Based on the results of the MAD studies, Neurogen has

determined that it will not advance the compound into Phase II testing at this time, but will consider out-licensing its MCH programme for potential development with a partner.

Stimulation of brain CPT-1 decreases food intake and body weight

FASgen has reported new research results in the obesity field using FAS89B, one of its proprietary compounds.

FASgen has conducted extensive research in the area of metabolic disease disorders, specifically for the treatment of obesity and fatty liver disease. The company has a long-standing co-operation with the Johns Hopkins University and that joint research has produced discoveries in the regulation of weight loss by the stimulation of carnitinepalmitoyl-transferase-1 (CPT-1). FAS89B was characterised in vitro as a selective inhibitor of brain CPT-1 and produced in vivo results in mice of decreased feeding for three days and persistent weight loss for six days, with no evidence of conditioned taste aversion.

This discovery, which was published in the 5th December online edition of the American Journal of Physiology - Regulatory, Integrative and Comparative Physiology (10.1152/ajpregu.00862.2006), adds another tool for FASgen to use in its ongoing programme of research into the field of treatment for obesity and fatty liver disease.

Orexigen reports 48-week results of Phase IIb Empatic trial

Orexigen Therapeutics has reported 48-week results from a Phase IIb trial of Empatic (bupropion+zonisamide; formerly Excalia), one of its two obesity drug candidates. Weight loss through 48 weeks for the highest Empatic dosage arm, in the intent-to-treat (ITT) double-

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blind extension and completer groups, was 14 and 15.1 per cent, respectively. This double-blind, placebo-controlled trial was the company's first large, multi-centre trial of its novel sustained-release (SR) formulation of zonisamide paired with bupropion SR. The primary objective was to determine the optimal dose ratios of bupropion and zonisamide. The trial randomised 623 obese patients, and included only a minimal diet and exercise intervention.

The trial protocol permitted all patients who completed 24 weeks of treatment to continue on their existing double-blind therapy for an additional 24 weeks. Alternatively, patients who failed to achieve at least a 5 per cent response 24 weeks after the start of treatment were

permitted to switch to the highest Empatic dose in a 24-week, open-label extension. Most patients receiving Empatic therapy elected to continue on their existing double-blind therapy for an additional 24 weeks and continued to lose weight in the time period from weeks 24 to 48. Analysis of their weight loss, as specified by the study protocol, is referred to as the ITT - double-blind extension. Patients from this group who completed treatment through week 48 are referred to as completers - double-blind extension. Except with respect to the placebo patients, only data for patients remaining on double-blind treatment beyond week 24 were included in the analysis and data from patients discontinuing blinded therapy through week 24 were not imputed. The double-blind extension results are as follows:

Weight loss at 48 weeks (per cent)

zonisamide SR (mg) bupropion SR (mg) ITT - double-blind extension

completers - double-blind extension

Group 1 120 280 10.1 12.1Group 2 120 360 12.1 11.8Group 3 240 280 11.8 12.4Group 4 240 360 12 12.5Group 5 360 280 10.8 11Group 6 360 360 14 15.1Group 7* placebo placebo 1.1 1.2

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

Results of this trial also indicate that Empatic was safe and generally well tolerated. As previously reported, the overall rate of discontinuation due to adverse events (AEs) for the Empatic treatment arms through the primary endpoint at 24 weeks was not statistically different to the rate seen with placebo. This was also true with the highest Empatic dose as compared to placebo. Between 24 and 48 weeks, the overall rate of discontinuation due to AEs among the double-blind extension group receiving Empatic was <2 per cent. Moreover, the discontinuation rate due to AEs in the double-blind group of patients receiving the highest Empatic dose between weeks 24 and 48 was 0 per cent. AEs were consistent with the existing package labels for one or both of the Empatic constituents and most commonly included headache, insomnia, nausea or dry mouth. There were no serious AEs that were attributed by investigators to Empatic.

Orexigen recently submitted to the FDA the results of this trial at 24 weeks, which was the primary endpoint of the study. In subsequent correspondence, the FDA confirmed the design of the company's next planned Phase IIb trial; Orexigen plans to initiate this trial in the second quarter of 2008. This study will be designed to evaluate Empatic against individual monotherapies and placebo. Based on the above results of the completed Phase IIb trial, the company expects to take the highest dose ratio of Empatic, and possibly one lower dose ratio, into this upcoming study.

Brain-imaging study offers new clues to overeating

Researchers at the US Department of Energy's Brookhaven National Laboratory have found new clues as to why some people overeat and gain weight while others do not. Examining how the human brain responds to satiety messages delivered when the stomach is in various stages of fullness, the scientists have identified brain circuits that motivate the desire to overeat; treatments that target these circuits may prove useful in controlling chronic overeating.

The researchers studied the brain metabolism of 18 individuals with body mass indices (BMI) ranging from 20 to 29. Each study participant swallowed a balloon, which was then filled with water, emptied and refilled again at volumes that varied between 50 and 70 per cent. During this process, the researchers used functional MRI to scan the subjects' brains. Subjects were also asked throughout the study to describe their feelings of fullness.

By simulating feelings of fullness with the expandable balloon, the researchers saw the activation of different areas of the brain in normal weight and overweight people. The overweight subjects had less activation in parts of the brain that signal satiety in normal weight subjects and were also less likely than normal weight subjects to report satiety when their stomachs were moderately full.

It is thought that these findings, which were published in the 22nd November online edition of NeuroImage (10.1016/j.neuroimage.2007.11.008), provide new evidence for why some people will continue to eat despite having eaten a moderate-size meal.

One notable region of the brain, the left posterior amygdala, was activated less in the high BMI subjects, but activated more in their thinner counterparts. This activation was turned "on" when study subjects reported feeling full. Subjects who had the highest scores on self-reports of hunger had the least activation in the left posterior amygdala.

This study is thought to provide the first evidence of the connection of the left amygdala and feelings of hunger during stomach fullness, demonstrating that activation of this brain region suppresses hunger. The findings indicate a potential direction for treatment strategies targeting this brain region. The scientists also looked at a range of hormones that regulate the digestive system, to see whether they played a role in responding to feelings of fullness. Ghrelin, a hormone

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R&D UPDATEXenoPort provides clinical trial update

XenoPort has initiated a Phase II trial of XP19986 in spinal cord injury (SCI) patients with spasticity, as well as the first clinical trial of XP21279, a drug candidate designed to treat Parkinson's disease.

In addition, XenoPort has confirmed plans to release top-line data from two Phase III trials of XP13512 in patients with restless legs syndrome (RLS) in the first quarter of 2008. The company also stated that GlaxoSmithKline, its partner for XP13512 in the US and other countries worldwide, excluding certain Asian countries, plans to file an NDA for the compound in RLS with the FDA in the third quarter of 2008. GSK also intends to initiate two polysomnography studies of XP13512 in RLS patients in the second half of 2008, in order to explore XP13512's potential benefits in sleep.

XenoPort also reiterated GSK's plans to initiate additional clinical trials of XP13512 in other CNS-related disorders. GSK intends to initiate separate dose-ranging, Phase II trials of XP13512 in post-herpetic

neuralgia (PHN) and painful diabetic neuropathy, as well as a Phase II trial in PHN patients who have not responded to treatment with gabapentin, all in the first quarter of 2008. In addition, GSK expects to initiate, after discussion with the FDA, two pivotal dose-ranging efficacy studies and an open-label, long-term study of XP13512 for migraine prophylaxis in the second half of this year.

XP19986 Phase II trial in SCI patients with spasticity

XenoPort's multiple-dose, placebo-controlled, Phase II trial of XP19986 is designed to evaluate the efficacy, safety and tolerability of a sustained-release (SR) formulation (designated as SR1) of XP19986 in patients with spasticity due to SCI. XenoPort believes that the SR1 formulation of XP19986, which provides sustained drug exposure over 12 hours, could provide improved therapy when dosed twice daily (bid) in spasticity patients.

The trial is being conducted at multiple study centres in the US. Three doses of XP19986 are being assessed in a randomised, crossover comparison versus placebo, with 12 subjects to be enrolled at each dose level. Eligible subjects undergo a washout and baseline period, followed by XP19986 (10, 20 or 30mg) or placebo, administered bid in the first treatment segment. After a washout period, each subject

known to stimulate the appetite and cause short-term satiety, showed the most relevance. It was found that individuals who had greater increases in ghrelin levels after their stomachs were moderately full

also had greater activation of the left amygdala, which indicates that ghrelin may control the reaction of the amygdala to satiety signals sent by the stomach.

DRUGS USED IN NAUSEA & VERTIGOPRODUCT NEwS

Generic Kytril approved following patent expiry

Following the expiration of patent protection on 28th December, numerous companies have received final FDA approval for generic versions of Roche's Kytril (granisetron). The drug is indicated for the prevention of: nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin; and, nausea and vomiting associated with radiation, including total body irradiation and fractionated abdominal radiation. Companies receiving approvals included:

Company Dosage and form Approval dateAPP Pharmaceuticals 0.1mg base/mL injection 31st DecemberApotex 0.1mg base/mL injection 31st DecemberBarr Laboratories 1mg tablet 28th DecemberBaxter Healthcare 1mg base/mL injection 31st DecemberCorePharma 1mg tablet 31st DecemberRoxane Laboratories (Boehringer Ingelheim)

1mg tablet 31st December

Teva Pharmaceutical Industries

1mg tablet 28th December

Teva Pharmaceutical Industries

0.1mg base/mL injection 31st December

Watson Laboratories 0.1mg base/mL injection 31st December

As the first company to file an ANDA with a Paragraph IV patent certification for granisetron injection, Teva has been awarded 180 days of marketing exclusivity for this product.

Aloxi Capsules sNDA accepted for review by FDA

The FDA has accepted for filing MGI Pharma/Helsinn Healthcare's sNDA for the 5-HT

3 receptor antagonist, Aloxi (palonosetron) Capsules

for oral administration. Aloxi Injection is approved by the FDA for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately- and highly-emetogenic cancer chemotherapy (CT), and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately-emetogenic cancer CT. The submission, which was made in October, has a PDUFA date of 22nd August 2008 and if approved, will provide a more convenient dosage of Aloxi (see CNS 174).

The sNDA includes results from a trial in which patients were stratified by gender and history of CT, and randomly assigned to receive one of three doses of oral Aloxi (0.25, 0.5 or 0.75mg) or a single intravenous (iv) 0.25mg dose. The primary objective of the study was to determine an oral dose that was non-inferior to the iv 0.25mg dose. Overall, results of the study indicate that the oral 0.5mg dose of Aloxi was non-inferior to the iv 0.25mg dose at inducing a complete response (CR; no emesis, no rescue therapy) during both the early (0-24 hours) and delayed phases (0-48, 0-72 and 0-120 hours) following administration of moderately-emetogenic cancer CT. Specifically, CR rates for the 0.5mg dose of oral Aloxi were 76.3 and 58.8 per cent for the 0-24 and 0-120 hour time periods, versus 70.4 and 59.3 per cent for the iv 0.25mg dose, respectively.

GENERAL DEVELOPmENT NEwS

DRUGS USED IN NAUSEA & VERTIGO / GENERAL DEVELOPmENT NEwS


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receives the other treatment in the second treatment segment. The primary outcome measure in this study is the Ashworth Scale assessment of muscle tone.

XP21279 Phase I trial

XP21279 is a new chemical entity that is a transported prodrug of levodopa. It is designed to engage natural nutrient transport mechanisms located throughout the length of the gastrointestinal (GI) tract and then be rapidly converted to levodopa by the body's endogenous enzymes. In addition to levodopa, the metabolic breakdown products of XP21279 are substances with favourable safety characteristics. Because XP21279 is designed to be well absorbed from the lower GI tract, XenoPort believes that it can be formulated for SR, thus reducing fluctuations of levodopa levels in the bloodstream.

XenoPort's randomised, double-blind, placebo-controlled, single-dose, Phase I trial is designed to assess the safety and pharmacokinetics (PK) of a prototype SR formulation of XP21279 administered with carbidopa and to compare its PK profile to that of Sinemet (levodopa+carbidopa). Twelve healthy subjects will participate in a three-period study. Each subject receives two 250mg tablets of XP21279 (216mg equivalent of levodopa) or placebo under fasted and fed conditions during the first two periods, followed by Sinemet (two levodopa 100mg+carbidopa 25mg tablets) administered in an open-label manner in the same subjects in the third period. Subjects dosed with XP21279 receive two Lodosyn (carbidopa) 25mg tablets every 12 hours on the day prior to, and on the day of, each treatment (except on the morning of Sinemet dosing). Blood and urine will be collected to determine the PK profile of XP21279, levodopa, levodopa metabolites and carbidopa, with preliminary PK results expected in the first quarter of 2008.

Lundbeck moves compound into clinical development but discontinues other

Lundbeck has initiated Phase I studies with Lu AA37096 to investigate the drug's safety, tolerability and pharmacokinetic profile. At the same time, the company has decided to discontinue the further development of Lu AA44608, which was in Phase I for the potential treatment of mood disorders.

Lu AA37096 has been discovered based on findings with the unique mechanism of action of Cipralex/Lexapro (escitalopram), but incorporates effects on a number of additional targets in the brain. Lu AA37096 has shown convincing effects in animal models of mood disorders, as well as in pain models.

Researchers elucidate mechanisms behind fragile X syndrome

Researchers at the University of Texas Southwestern Medical Center (UT Southwestern) have reported progress in uncovering how brain cells are affected in fragile X syndrome. Indeed, according to senior author, Dr Kimberly Huber, the team may have discovered a core mechanism underlying the syndrome.

Huber's research with mice focuses on how fragile X syndrome affects communication between cells in the hippocampus. Her findings show that two different chemical signals go awry in fragile X syndrome, indicating that drugs that interact with these signals might be a pathway to help treat the syndrome. Huber previously co-discovered that mice genetically engineered to lack the Fmr1 gene have a defective signalling system in the brain that controls learning in the hippocampus. This system relies on glutamate, which under normal circumstances, causes nerve cells to make proteins and change their

electrical firing patterns in response to learning situations. Without a properly-working Fmr1 gene, the glutamate signalling system malfunctions. In 2007, she and colleagues at UT Southwestern found that acetylcholine affects the same protein-making factory as glutamate.

In the current study, which was published in the 9th January issue of the Journal of Neuroscience (2008;28:543-547), Huber and post-doctoral researcher, Dr Jennifer Ronesi, investigated a protein called Homer, which serves as a kind of structural support for the glutamate system. In fragile X syndrome, the Homer-glutamate support system is disconnected. Huber's group discovered that this disconnection results in an inability of brain cells to make the new proteins important for learning and memory. These results show that Homer plays a vital role making proteins and learning, which may also indicate where drugs could be targeted.

AGREEmENT NEwS£4 million consortium investment to accelerate research into mental illness

P1vital has entered into a consortium agreement with AstraZeneca Pharmaceuticals, GlaxoSmithKline, Lundbeck, Organon (Schering-Plough) and Wyeth, under which the consortium partners will fund a series of studies over a period of three years to establish the sensitivity of healthy volunteer CNS experimental medicine models and validate their ability to detect the efficacy of novel compounds.The studies will be carried out by P1vital in collaboration with clinical psychopharmacology groups in the UK, based at the University of Bristol, Cardiff University, the Institute of Psychiatry, the University of Manchester and the University of Oxford. The objective of the studies is to validate existing healthy volunteer models and to develop novel models in the areas of anxiety, cognitive disorders, depression and schizophrenia.

The initial studies will validate new surrogate biomarkers for positive, negative and cognitive deficits in schizophrenia. In depression, the consortium will validate an "at risk" group (dysphoric volunteers) using a recently-established emotional test battery as a surrogate population. In cognitive disorders, studies will focus on two recently-developed virtual reality models and examine their utility for the early detection of cognitive deficits in mild cognitive impairment and schizophrenia. Studies will also investigate the potential efficacy of antidepressant drugs in treating anxiety disorders using an experimental model of anxiety.

Medistem modifies licence agreement with ICM

Medistem Laboratories has modified its licence agreement with the Institute for Cellular Medicine (ICM), with the effect of: (i) revising the royalty rate from 85 per cent of ICM's pre-tax income to 20 per cent of its gross revenues; (ii) extending the term of the agreement from expiring in 2010 to perpetuity; and (iii) removing Medistem's obligation to fund ICM pursuant to the agreement. According to Medistem, these events will allow the company's management to focus on its biotech endeavours, while retaining cash flows related to the ICM licence.

In May 2006, Medistem executed a technology licensing and royalty agreement that enables ICM to culture stem cells (SCs) and work with physicians to develop and deliver Medistem's SC technologies and therapies. Initially, Medistem planned to focus on the development of SC-based therapeutics for a number of currently-incurable neurological conditions, such as Parkinson's and Alzheimer's diseases.

GENERAL DEVELOPmENT NEwS


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Addex Pharmaceuticals .............................................................................................7, 10Akela Pharma .......................................................................................................................12Albert Einstein College of Medicine .......................................................................... 3Alkermes ................................................................................................................................13Alnylam Pharmaceuticals ................................................................................................ 3Alseres Pharmaceuticals .................................................................................................. 6Amarin................................................................................................................................ 5, 13Amgen ......................................................................................................................................1Arcion Therapeutics .........................................................................................................11AstraZeneca ..................................................................................................................10, 17Barr Laboratories .................................................................................................................4Baylor College of Medicine ............................................................................................. 5Bial .............................................................................................................................................14BioDelivery Sciences International ...........................................................................12Biogen Idec .............................................................................................................................4Biovail ......................................................................................................................................12BrainStorm Cell Therapeutics ........................................................................................ 7Breckenridge Pharmaceutical .....................................................................................13Brookhaven National Laboratory .............................................................................15Cephalon ...............................................................................................................................13Chiba University ................................................................................................................... 9Cilag ..........................................................................................................................................13Clalit Health Services ......................................................................................................... 5Cobalt Pharmaceuticals ................................................................................................... 4CoMentis ..............................................................................................................................3, 4deCODE genetics................................................................................................................. 9Eisai .............................................................................................................................................4Elan ................................................................................................................................4, 11, 13Eucalyptus ............................................................................................................................... 5Evotec ...............................................................................................................................12, 13FASgen ....................................................................................................................................14Forest Laboratories ............................................................................................................. 4Georgetown University ....................................................................................................9GlaxoSmithKline .........................................................................................................16, 17Hebrew University of Jerusalem .................................................................................. 5Helsinn Healthcare ...........................................................................................................16Hemispherx Biopharma ................................................................................................... 8Immunex .................................................................................................................................1Innocoll ...................................................................................................................................11Institute for Cellular Medicine .....................................................................................17Janssen Pharmaceutica ..................................................................................................12Jazz Pharmaceuticals .......................................................................................................13Johns Hopkins University ......................................................................................... 9, 14Johnson & Johnson ...................................................................................................12, 13Lundbeck ..........................................................................................................................4, 17Lupin ..........................................................................................................................................4Massachusetts General Hospital ................................................................................. 9Mayo Clinic ..............................................................................................................................3

Meda AB .................................................................................................................................12Medistem Laboratories ..................................................................................................17Merck & Co ............................................................................................................................10Merz ............................................................................................................................................4MGI Pharma ..........................................................................................................................16Mor Research Applications ............................................................................................. 5Neurogen ..............................................................................................................................14Novartis ......................................................................................................................3, 13, 14Orchid Chemicals & Pharmaceuticals ....................................................................... 4Orexigen Therapeutics ...................................................................................................14Organon .......................................................................................................................... 11, 17Orion ..........................................................................................................................................3Ortho-McNeil ......................................................................................................................12Ovation Pharmaceuticals ..............................................................................................13P1vital ......................................................................................................................................17Parkinson’s Institute and Clinical Center.................................................................. 3Pfizer ............................................................................................................................4, 10, 11Pipex Pharmaceuticals ......................................................................................................4Prana Biotechnology ......................................................................................................... 4Ramot ........................................................................................................................................5ReNeuron ................................................................................................................................ 6Rexahn Pharmaceuticals .................................................................................................8Roche ................................................................................................................................12, 16Rutgers, The State University of New Jersey ......................................................... 7sanofi-aventis ........................................................................................................................7Schering-Plough ......................................................................................................... 11, 17Sepracor .................................................................................................................................14Shire ..........................................................................................................................................10Somaxon Pharmaceuticals ............................................................................................. 8Southwestern Medical Center ....................................................................................17Sun Pharmaceutical ...........................................................................................................3Taisho Pharmaceutical ....................................................................................................10Taro Pharmaceutical Industries ..................................................................................13Tel Aviv University ...............................................................................................................5Teva Pharmaceutical Industries ................................................................................... 4University of Arkansas .......................................................................................................1University of California .................................................................................................6, 9University of Heidelberg .................................................................................................. 7University of Texas ............................................................................................................17Upsher-Smith Laboratories ............................................................................................ 4US Department of Energy .............................................................................................15Wockhardt............................................................................................................................... 4Wyeth ..................................................................................................................................1, 17XenoPort .........................................................................................................................16, 17Yale University .......................................................................................................................9Yeshiva University ...............................................................................................................3Yissum .......................................................................................................................................5Zogenix ...................................................................................................................................11

COmPANy INDEXCOmPANy INDEX

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ADX10059 ................................................................................................................................ 7ADX63365 ..............................................................................................................................10Akatinol ....................................................................................................................................4Aloxi ..........................................................................................................................................16Ambien .....................................................................................................................................7Ampligen .................................................................................................................................8AMR-101 ...................................................................................................................................5ARC-4558 ...............................................................................................................................11Aricept .......................................................................................................................................4Axura ..........................................................................................................................................4BEMA Fentanyl ....................................................................................................................12BIA 2-093 ................................................................................................................................14bupivacaine ..........................................................................................................................11bupropion ......................................................................................................................14, 15carbidopa ......................................................................................................................... 3, 17Cethrin ...................................................................................................................................... 6clobazam ...............................................................................................................................13clonazepam ..........................................................................................................................13clonidine ................................................................................................................................11Coprexa ....................................................................................................................................4CTS-21166 ............................................................................................................................3, 4donepezil .................................................................................................................................4doxepin..................................................................................................................................... 8Ebixa ........................................................................................................................................... 4Empatic ............................................................................................................................14, 15Enbrel......................................................................................................................................... 1entacapone ............................................................................................................................3eslicarbazepine acetate..................................................................................................14etanercept ............................................................................................................................... 1ethyl-eicosapentanoic acid ............................................................................................ 5EVT 302 ............................................................................................................................12, 13FAS89B ....................................................................................................................................14fentanyl ...................................................................................................................................12Fentanyl TAIFUN .................................................................................................................12granisetron ...........................................................................................................................16JZP-8 .........................................................................................................................................13Kytril..........................................................................................................................................16levodopa ........................................................................................................................... 3, 17

lisdexamfetamine dimesylate ....................................................................................10lorazepam .............................................................................................................................13Lu AA37096 ..........................................................................................................................17Lu AA44608 ..........................................................................................................................17memantine .............................................................................................................................4N-acetylcysteine amide ................................................................................................... 5naltrexone .............................................................................................................................13Namenda .................................................................................................................................4natalizumab ...........................................................................................................................4NGD-4715 ..............................................................................................................................14oxcarbazepine .............................................................................................................13, 14palonosetron .......................................................................................................................16PBT2 ............................................................................................................................................ 4Poly I. Poly C12U ...................................................................................................................8quetiapine .............................................................................................................................10Ralivia.......................................................................................................................................12ReN001 .....................................................................................................................................6Serdaxin ...................................................................................................................................8Seroquel .................................................................................................................................10Silenor ....................................................................................................................................... 8SSR180711 ................................................................................................................................9Stalevo .......................................................................................................................................3sugammadex.......................................................................................................................11sumatriptan ..........................................................................................................................11sumatriptan DosePro ......................................................................................................11tetrathiomolybdate ............................................................................................................ 4tramadol.................................................................................................................................12Trileptal ............................................................................................................................13, 14TS-032 ...............................................................................................................................10, 11Tysabri ...................................................................................................................................4, 5Ultram......................................................................................................................................12Vivitrol .....................................................................................................................................13Vyvanse ..................................................................................................................................10XP13512 ...................................................................................................................................16XP19986 ..................................................................................................................................16XP21279 ...........................................................................................................................16, 17zolpidem ..............................................................................................................................7, 8zonisamide ....................................................................................................................14, 15

COmPOUND INDEXCOmPOUND INDEX

The report answers key questions...Who’s developing what, and with whom?What are the prospects for Gardasil achieving US$1.6 billion sales by 2011?Which products are likely to launch in 2009 and 2010?Why do some cancer vaccines fail?Which company is leading the race to develop a breast cancer vaccine?What cancer vaccines are there in Phase II/III for lung, breast, prostate and colorectal cancer?

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Who are the players and

products in the race to launch?

This report critically assesses the candidates in their wider market context, providing a complete review of the market and its likely development to 2013.

Cancers coveredBrainBreastGastrointestinalGenito-urinaryGynaecologicalHaematologicalLungMelanoma/Sarcoma

••••••••

Types of cancer vaccine

Antigen/adjuvant vaccinesWhole-cell tumour vaccinesDendritic cell vaccinesViral vectors and DNA vaccinesIdiotype vaccines

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