cns issue 169

Monitoring central nervous system drug developments worldwide

CNS Drug News

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Lucy VannEditor

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Issue No. 169 6th September 2007

R&D HighlightsPhase III post hoc analysis more positive for safinamide in

PDPage 3

Neurochem reports negative results from North American Alzhemed trial

Page 4

Study suggests cancer drugs may have use for HDPage 9

Lilly’s LY2140023 shows antipsychotic activity in humans4

PRODUCT HighlightsAricept approved for severe AD in Japan

Page 6

Biopartners submits Biferonex in EuropePage 8

Risperdal receives FDA approvals in children and adolescents

Page 16

AGREEMENT HighlightsTeva partners with Compugen for CGEN-54

Page 8

Cephalon acquires rights to AmrixPage 19

EDITORLucy Vann

CONTRIBUTING EDITORSRos Smallman, Fiona Cowie,

Matthew Dennis, Johanna Shiu, Sam Turner

PUBLISHEREric Wigart

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

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

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The continued benefits of statinsStatins have been available for a number of years, however new research suggests that their benefits are not yet fully understood. In separate studies, two research groups have found evidence supporting the use of statins for Alzheimer's disease (AD) and suggesting their continued use after a stroke.

One study, by researchers at the University of Washington and colleagues, has provided evidence of an association between statin use and a lower risk of neuropathologic changes in the brain that are associated with AD. Meanwhile, a second group, which included researchers from the University of Santiago de Compostela in Spain, has found that people who stopped taking their statins while hospitalised after a stroke were more likely to have died or be dependent on others for their care three months after the stroke than people who kept taking the drugs.

This news will be welcomed by those in healthcare due to the relative low cost of statins, however, there have been concerns about the side effects of the drugs' use. Indeed, University of North Carolina (UNC) at Chapel Hill researchers reported at the end of last year that people with low levels of LDL cholesterol are more likely to have Parkinson's disease (PD) than those with high LDL levels, despite the fact that low levels of LDL-C are considered an indicator of good cardiovascular health.

This theory is backed by the fact that people with PD have a lower occurrence of myocardial infarction and stroke than those who do not have the disease. Furthermore, PD patients are also more likely to carry the gene, APOE-2, which is linked with lower LDL-C, and smoking, which increases a person's risk for cardiovascular disease, is also associated with a decreased risk of PD.

Despite the link demonstrated by the UNC research, it was cautioned at the time that people should not change their eating habits, nor their use of statins and other cholesterol-lowering drugs because of the results. Nevertheless, the research did raise concerns among statin users. On the other hand, the new research, particularly the AD study, has been widely reported and may mean an increase in statin use.

In other news, Phase II data have demonstrated the antipsychotic activity of Eli Lilly's LY2140023 in humans. This news has received particular attention, as most currently-approved antipsychotic medications work by affecting dopamine or serotonin, but for LY2140023, the active substance, LY404039, is thought to work by reducing the presynaptic release of glutamate in brain regions where metabotropic glutamate 2/3 (mGlu2/3) receptors are expressed. Indeed, according to Dr Steven Paul, Lilly's Executive Vice President of Science and Technology: "These data provide compelling new evidence that mGlu2/3 receptor agonists have antipsychotic properties and may provide a completely new therapeutic approach for treating schizophrenia and, perhaps, other neuropsychiatric disorders."

©Espicom Business IntelligencePage � 6th September �007

CNS Drug News

The continued benefits of statins..........................................................................................1

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

Phase III post hoc analysis more positive for safinamide in PD ............................................3Ovary removal before menopause linked to decreased neuroprotection..........................3

ALzHEImER'S DISEASE - R&D UPDATE .......................................................4NYU vaccine combats AD tangles ..........................................................................................4Neurochem reports negative results from North American Alzhemed trial ......................4Baxter/ADCS to pursue Phase III study of Gammagard Liquid for AD .................................5Phase I studies completed with ELND-005/AZD-103 ...........................................................6Study supports statin use for AD ...........................................................................................6

PRoDUCT NEwS .......................................................................................6Aricept approved for severe AD in Japan ..............................................................................6Ranbaxy receives tentative FDA approval for galantamine tablets ....................................6

mULTIPLE SCLERoSIS - R&D UPDATE .........................................................7Tysabri demonstrates significant HRQoL improvements for MS patients ..........................7PDL to focus on Ab discovery and development ..................................................................7Recruitment completed for Sativex Phase III trial in MS neuropathic pain ........................8

PRoDUCT NEwS .......................................................................................8Biopartners submits Biferonex in Europe .............................................................................8NICE recommends Tysabri for use in highly-active RRMS ...................................................8New Rebif formulation approved in Europe .........................................................................8Questcor approves new strategy for HP Acthar Gel .............................................................8

AGREEmENT NEwS ..................................................................................8Teva partners with Compugen for CGEN-54 .........................................................................8

oTHER NEURoDEGENERATIvE DISoRDERS - R&D UPDATE ..........................9McMaster study suggests kinase inhibitor use for HD .........................................................9Protox acquires HUMxin research programme from Medicenna........................................9Study suggests cancer drugs may have use for HD ..............................................................9Allergan/ExonHit compound to begin clinical trials ............................................................10FSMA/Tikvah establish collaboration to develop TIK-�01 for SMA .....................................10Ketasyn improves memory in AAMI study ...........................................................................10Study suggests new targets for neurodegenerative diseases ............................................10Neuralstem forms collaboration to advance SCs into ALS patients ....................................11

AGREEmENT NEwS ..................................................................................11Option to IPL455,903 not exercised by Inflazyme ................................................................11

CEREBROVASCULAR DISORDERS .........................11R&D UPDATE ............................................................................................11

Data confirm NXY-059's inefficacy for AIS ............................................................................11Sinobiomed completes evaluation of preclinical studies on first rhK .................................11Study suggests continued use of statins after stroke ..........................................................1�ReGen provides results of small-scale zolpidem study ........................................................1�ImaRx proceeds with Phase I/II trial of SonoLysis+tPA therapy in AIS ...............................1�

ANXIOLyTICS/SLEEP DISORDERS .........................13PRoDUCT NEwS .......................................................................................13

FDA sets PDUFA action date for indiplon capsules ...............................................................13AGREEmENT NEwS ..................................................................................13

Tikvah signs licensing deal with P�D for LY156735 ..............................................................13

ANTIDEPRESSANTS ............................................13R&D UPDATE ............................................................................................13

TCA discovery may lead to more effective drugs..................................................................13AGREEmENT NEwS ..................................................................................14

Tikvah signs licensing deal with P�D for LY156735 ..............................................................14

PSyCHOTIC DISORDERS ......................................14R&D UPDATE ............................................................................................14

Lilly's LY�1400�3 shows antipsychotic activity in humans .................................................14Duke study uncovers clues about possible OCD mechanism ...............................................14Corcept raises funds to advance Corlux.................................................................................15AstraZeneca initiates Phase IIb trial of AZD3480 for cognitive deficits in schizophrenia ..15

PRoDUCT NEwS .......................................................................................15AstraZeneca's Seroquel XR approved in the Netherlands....................................................15Risperdal receives FDA approvals in children and adolescents ...........................................16

ANALGESICS/ANAESTHETICS ...............................16R&D UPDATE ............................................................................................16

Cymbalta reduces pain in fibromyalgia patients; sNDA submitted to FDA.........................16Acura secures funds for Phase III trial of OxyADF Tablets.....................................................16Meda completes acquisition of MedPointe ..........................................................................17Neuromed raises funds to accelerate development of pain treatments ............................17Cannasat to commence Phase I study of CAT 310 ................................................................17Icagen raises funds via Pfizer investment ............................................................................17TorreyPines initiates multiple-dose tezampanel trial .........................................................18Zolmitriptan nasal spray effective for cluster headache .....................................................18Anesiva completes enrolment for Phase III Zingo trial in adults .........................................18Cadence completes enrolment in Phase III trial of iv acetaminophen ................................18Recruitment completed for Sativex Phase III trial in MS neuropathic pain ........................19Allergan/ExonHit compound to begin clinical trials ............................................................19

PRoDUCT NEwS .......................................................................................19Daiichi Sankyo obtains additional indication for fentanyl injection in Japan ....................19FDA approves Watson and Actavis' generic Duragesic products.........................................19

AGREEmENT NEwS ..................................................................................19Cephalon acquires rights to Amrix ........................................................................................19

ANTI-EPILEPTICS ...............................................19R&D UPDATE ............................................................................................19

Study provides clues to origin of Lafora disease ..................................................................19PRoDUCT NEwS .......................................................................................19

Questcor approves new strategy for HP Acthar Gel .............................................................19

EATING DISORDERS ............................................20R&D UPDATE ............................................................................................20

Data support Histalean's use in obese women under 50 years of age ................................�0PRoDUCT NEwS .......................................................................................20

FDA approves Caraco's generic Adipex-P ..............................................................................�0

GENERAL DEVELOPmENT NEwS ..........................20R&D UPDATE ............................................................................................20

Memory commences Phase I programme for R4996/MEM 63908 .....................................�0ImaRx receives grant to study BBB permeability .................................................................�1

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

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PARkINSON'S DISEASE - R&D UPDATEPhase III post hoc analysis more positive for safinamide in PD

Merck Serono (Merck KGaA) and Newron Pharmaceuticals have released the preliminary results from a 12-month extension study of a six-month, Phase III trial of safinamide as an add-on treatment to dopamine agonist therapy in patients with early-stage Parkinson's disease (PD). Merck Serono has exclusive worldwide rights to develop, manufacture and commercialise safinamide in PD, Alzheimer's disease and other therapeutic applications, under an agreement signed with Newron.

Results from the initial six-month trial were presented at the 59th Annual Meeting of the American Academy of Neurology in May (see CNS 162). The objective of the study was to assess the long-term safety and efficacy of safinamide as an add-on treatment to dopamine agonist therapy. In this study, the primary efficacy endpoint, time to intervention, did not reach statistical significance when data from both safinamide dose groups (50-100mg and 150-200mg) were pooled, although a delay of 93 days in median time-to-intervention was observed; it was thought that the lack of a significant effect might be explained by the lack of response with the high-dose group. A post hoc analysis, however, showed that the addition of safinamide 50-100mg once daily to dopamine agonist therapy significantly reduced the number of patients who experienced an intervention, maintained improvement in motor symptoms and improved quality of life (QoL) compared with dopamine agonist monotherapy (MT). Additional Phase III studies are planned to further assess the efficacy of this dose of safinamide.

The 18-month, double-blind, placebo-controlled, international, Phase III trial enrolled patients with early-stage PD (less than five years of disease), treated with a stable dose of a single dopamine agonist. Patients were randomised to receive safinamide 50-100mg/day, safinamide 150-200mg/day or placebo, as an add-on treatment to dopamine agonist therapy. Of the 270 patients originally enrolled in the trial, 227 entered the 12-month extension period and 187 patients completed it, with the main reasons for discontinuation including side effects, lack of efficacy and withdrawal of consent.

The primary efficacy endpoint of the 18-month trial was time from baseline to intervention (defined by the onset of one of the following events: increase in dose of dopamine agonist; addition of another dopamine agonist, levodopa or another PD therapy; or discontinuation due to lack of efficacy). The post hoc analysis of events beyond the initial phase (>240 days) indicated that patients receiving safinamide 50-100mg/day experienced a significantly lower rate of events compared with patients receiving dopamine agonist MT (25 vs 51 per cent; p=0.049).

A post hoc analysis of the mean change in motor symptoms, as measured by the UPDRS III Motor Score, the secondary efficacy endpoint, demonstrated that the addition of safinamide 50-100mg/day resulted in a statistically significant improvement in motor symptoms over the 18-month treatment period (-4.7+/-9.34 vs -1.95+/-7.41; p=0.019) and this improvement was accompanied by a statistically significant improvement in QoL, as measured by the EuroQoL scale (tertiary endpoint), both in the pooled dose group (safinamide: 0+/-1.85, placebo: 0.42+/-1.69; p=0.0046) and in the individual dose groups

versus dopamine agonist MT (safinamide 50-100mg: 0.03+/-1.95; safinamide 150-200mg: -0.03+/-1.73; placebo: 0.42+/-1.69 [low dose vs placebo, p=0.017; high dose vs placebo, p=0.011]). As observed in the initial six-month trial, the higher safinamide dose range of 150-200mg/day did not offer any incremental advantage over placebo over an 18-month period.

Side effects, ECG changes and vital sign abnormalities were reported with similar frequency in patients receiving safinamide and in those receiving dopamine agonist MT, with the most frequent adverse events including back pain, peripheral oedema, cataract, scotoma and dizziness.

A Phase III trial evaluating safinamide 50-100mg/day as an add-on to levodopa therapy is ongoing in patients with mid- to late-stage PD, and additional Phase III trials evaluating this dose range either as an add-on to dopamine agonist or as an add-on to levodopa therapy are expected to be initiated in 2007, in early- and mid- to late-stage PD, respectively.

Ovary removal before menopause linked to decreased neuroprotection

A study by Mayo Clinic researchers has indicated that women who have one or both ovaries removed before menopause face an increased long-term risk of Parkinson's disease (PD) and parkinsonism compared to women who retain their ovaries. The research, which was published in the 29th August online edition of Neurology (10.1212/01.wnl.0000280573.30975.6a), suggests that to protect against these conditions, oestrogen-replacement therapy (ORT) may be warranted for women who have their ovaries removed before menopause.

This study involved reviews of medical records and follow-up interviews with approximately 4,600 women. The Mayo team identified all of the women in Olmsted County, MN, who had one or both ovaries removed (approximately 2,300) from 1950 through 1987, and these women were matched by age with an approximately equal number of women who did not have ovarian surgery. Researchers then interviewed women in both groups (or their relatives if the women had died), examined those women who were suspected of having PD and reviewed their medical records to compare the risk of PD or parkinsonism between the two groups, throughout their full life spans.

Prior to this report, there was either limited or conflicting clinical and epidemiological evidence about oestrogen's ability to protect brain functioning in women. The Mayo research shows that not only did women who had one or both ovaries removed before menopause have an increased risk for PD or parkinsonism compared to other women, but that the risk increased the younger the woman was at ovary removal.

While further studies are needed to validate these findings and clarify their clinical implications, this research is among the first to suggest that there is an age-related therapeutic window of opportunity for ORT. Before the age of 50 years, ORT may in fact be beneficial for the brain function of women who have their ovaries removed. The findings support the concept that there is a window of therapeutic opportunity before the approximate age of naturally-occurring menopause (50 to 55 years), when the benefits of neuroprotection outweigh the risks of side effects of oestrogen therapy.

NEURODEGENERATIVE DISORDERSNEURODEGENERATIVE DISORDERS

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However, based on the results of other studies, the Mayo researchers have stated that after the age of 55 or 60 years, the balance of advantages and disadvantages from starting oestrogen treatment is still somewhat uncertain, and the risk of side effects, such as increased cancers or strokes, from oestrogen therapy may increase progressively with age.

In addition...

Mayo researchers have also found that women who had one or both ovaries removed before menopause were nearly two-times more likely to develop cognitive problems or dementia compared to women who did not have the surgery. Furthermore, those women who were younger when their ovaries were removed were more likely to develop dementia than women who were older when this procedure took place.

The study, which was also published in the 29th August issue of Neurology (10.1212/01.wnl.0000276984.19542.e6), involved approximately 1,500 women who underwent the removal of one or both ovaries for non-cancer-related reasons, such as ovarian cysts, endometriosis, or for the prevention of ovarian cancer. The women were compared to an equal number of women who still had both ovaries at the beginning of the study. All participants were followed for a median of 27 years and were interviewed about their memory. If the women could not be interviewed directly, the investigators interviewed a family member.

The results indicate that there may be a critical age window for the protective effect of oestrogen on the brain in women. It was found that women who had both ovaries removed before the age of 49 years, but were given oestrogen treatment until at least 50 years of age, did not have an increased risk of developing memory problems, which suggests that oestrogen is protective for these women in this age window. By contrast, past studies from the Women's Health Initiative have shown that oestrogen use started at the age of 65 years or later may have a negative effect on memory and could increase the risk of developing dementia.

According to study author, Dr Walter A Rocca, it is possible that oestrogen has a protective effect on the brain and that a lack of the hormone due to ovary removal may increase a woman's risk of developing memory problems. Furthermore, Rocca believes that these findings have important clinical implications and should prompt physicians to re-assess removing ovaries before menopause and the use of oestrogen treatment following such surgery.

ALzHEImER'S DISEASE - R&D UPDATENYU vaccine combats AD tangles

A new study by New York University (NYU) Medical Center researchers has shown for the first time that the immune system can combat the pathological form of tau protein, which is implicated in Alzheimer's disease (AD).

The researchers, led by Dr Einar Sigurdsson, have created a vaccine in mice that suppresses aggregates of tau. According to the study, which was published in the 22nd August issue of the Journal of Neuroscience (2007;27:9115-9129), the vaccine successfully slowed the deterioration of motor abilities produced by excessive amounts of tau in the CNS of mice. Sigurdsson plans to conduct follow-up studies using mice that slowly develop tangles and cognitive impairments without movement problems.

The study used mice that were genetically engineered to produce abnormal tau proteins early in life, which became entangled in several regions of the CNS. The resulting loss of motor co-ordination was significantly reduced in those immunised with a specific piece of the detrimental tau protein. By producing antibodies (Abs) that could enter the brain and bind to irregular tau, the immune system prevented their harmful aggregation and associated behavioural impairments. Sigurdsson believes that this approach may have extensive therapeutic implications because the problematic protein can be specifically targeted. Tau aggregates are confined inside brain cells, making it especially difficult to develop a therapy to target and clear them from the cell.

The therapeutic approach is based on using fragments of abnormal tau protein as a vaccine. These fragments are studded with phosphate groups, which are thought to promote the aggregation of tau. The Abs generated by the vaccine are therefore likely to bind to abnormal tau and promote its breakdown. Meanwhile, normal tau, which has important biological functions, would be far less affected.

The transgenic mice in the study were predisposed to forming tau tangles early in life. Although a decline in motor abilities had progressed by eight months, the mice still remained healthy enough to walk, feed and attempt simple behavioural tasks. However, the mice did not undergo thorough cognitive testing, which requires intact mobility to navigate various mazes.

The battery of behavioural tests at five and eight months of age showed that immunised mice performed better. These mice were also found to have less tau protein tangles in the brain. An object-recognition test showed that immunised mice and their controls remained cognitively normal, although mental deficits were expected to appear after the maximum eight-month period allowed in the study. The mice in the study also had tau aggregates in the hippocampus. The vaccine cleared tangles in this region, suggesting that the immunotherapy could improve cognition.

The Abs raised by the vaccine must reach the brain by traversing the blood-brain barrier. In this animal model (and also in AD), there is a breakdown of this barrier. In addition, it is well established that neurons have receptors that can bind to and promote the uptake of Abs, and the team's studies indicate that ''sick'' neurons that are accumulating tau aggregates take up more Abs than healthy neurons. The Abs then end up at the site where they can interact with pathological tau protein in the neuron and promote its clearance.

Neurochem reports negative results from North American Alzhemed trial

Neurochem has reported top-line results from the North American Phase III trial that was designed to assess the safety, efficacy and disease-modification effect of Alzhemed (tramiprosate) for the treatment of Alzheimer's disease (AD).

Following a recent meeting with the FDA and subsequent statistical analyses, this trial, despite the descriptive data showing numerical differences, did not demonstrate a statistically significant difference in favour of tramiprosate with respect to the primary endpoints over 18 months of treatment. However, a substantial difference observed in hippocampal volume did approach statistical significance.

Due to significant interference from high between-site variations that complicated the statistical analyses beyond expectations, the company believes that it is not possible to draw definitive conclusions with respect to the treatment effect of tramiprosate.

NEURODEGENERATIVE DISORDERS


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This was a multi-centre, double-blind, placebo-controlled, three-arm, parallel-designed, 18-month trial that included 1,052 patients with mild-to-moderate AD, who were recruited across 67 sites in Canada and the US, and randomised to receive either placebo or tramiprosate 100 or 150mg twice daily. All patients were required to be treated with conventional symptomatic AD therapies during the trial and to be on a stable dose of such therapies for at least four months prior to the initial screening visit of the study.

In the trial, tramiprosate was generally safe and well tolerated. The incidence of serious adverse events reported in patients treated with tramiprosate was comparable to that for patients in the placebo group. The most common adverse events (>10 per cent) reported more frequently for tramiprosate than placebo were nausea, falling, diarrhoea, dizziness, body weight decrease and vomiting.

Tramiprosate has received fast track designation from the FDA for the treatment of mild-to-moderate AD and is a small, orally-administered amyloid beta (Abeta) antagonist, which crosses the blood-brain barrier, binds to soluble Abeta peptide and interferes with the amyloid cascade that is associated with amyloid deposition and the toxic effects of Abeta peptide in the brain.

At the recent FDA meeting, Neurochem sought feedback on appropriate next steps, especially with respect to the statistical models and detailed analysis of potential confounding factors. The Agency recognised the difficult issues surrounding a trial of this magnitude, with its significant site effect and the large number of covariates identified during the modelling process, but advised that neither the proposed adjusted models nor any further adjustments could be used for this trial to provide results in support of a claim of clinical efficacy. However, the Agency recognised that it might be possible to utilise the findings of the North American study to potentially revise the statistical analysis plan and/or modify the study design of the ongoing European Phase III trial of tramiprosate for the treatment of AD.

In the European trial, to date, 966 mild-to-moderate AD patients are enrolled at 69 clinical centres in ten countries. The European Data Safety Monitoring Board has met three times and recommended on each occasion that the study should continue. In August, Neurochem stopped patient screening activities as it had met its recruitment target and the company is presently considering potential modifications to the European study to take best advantage of the experience gained from the recently-completed North American trial.

Neurochem will continue to evaluate the treatment effect of tramiprosate with post hoc evaluations to facilitate its understanding of the data and assess any treatment effect from the North American trial. The company has established a Special Advisory Board to assist it over the coming months in reviewing and analysing the data from this trial. The Board's mandate will also be to provide advice to Neurochem as it considers its options for the future direction of the tramiprosate programme.

Baxter/ADCS to pursue Phase III study of Gammagard Liquid for AD

Baxter International and the Alzheimer's Disease Cooperative Study (ADCS) group have decided to pursue a multi-centre, US Phase III study evaluating the role of Gammagard Liquid, an intravenous immunoglobulin (IVIg) preparation, for the treatment of patients with mild-to-moderate Alzheimer's disease (AD).

IVIg has been used for almost three decades to treat primary immunodeficiency. The rationale for testing it as a possible treatment for AD is based on the presence of natural antibodies that are

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directed against several forms of amyloid beta (Abeta). Treatment with naturally-occurring antibodies against Abeta contained in IVIg may result in the clearance of Abeta from the brain, as well as the dissolution of plaques.

The decision to pursue the study is based on the results of two completed open-label clinical studies, plus the preliminary analysis of interim data from a double-blind, placebo-controlled, Phase II study by a team at Weill Cornell Medical College. In this study, 24 patients with mild-to-moderate AD were randomly assigned to receive Gammagard Liquid (n=8), Gammagard S/D (n=8) or placebo (n=8) for six months. Cognitive, behavioural and functional measures were collected at baseline, and at three and six months of treatment. The primary endpoints of the trial were cognitive function (as measured by ADAS-Cog score) and global function (as assessed by ADCS-CGIC rating). The prespecified criterion for going forward with Phase III was a favourable outcome in IVIg-treated patients relative to those given placebo. Final results of the analysis of the study are expected later this year.

This Phase II study follows earlier Phase I results in eight patients that were reported at the International Conference on Alzheimer's Disease in July 2006. Although these findings are promising, both studies were small and results must therefore be confirmed in a larger, sufficiently-powered study.

The study protocol will be submitted to the FDA for review in the coming months, with the intention of initiating patient recruitment early in 2008. The trial is jointly sponsored by the National Institutes of Health and Baxter, and will include approximately 35 academic centres in the US that are members of ADCS.

Phase I studies completed with ELND-005/AZD-103

Transition Therapeutics has reported the completion of Phase I studies with the Alzheimer's disease (AD) drug candidate, ELND-005/AZD-103.

Transition and its development partner, Elan, have performed multiple Phase I studies evaluating the safety, tolerability and pharmacokinetic profile of ELND-005/AZD-103 in healthy volunteers. Orally-administered ELND-005/AZD-103 may act through the unique mechanism of preventing and reversing the fibrilisation of amyloid beta.

Approximately 110 subjects have been exposed to ELND-005/AZD-103 in multiple Phase I studies, including single and multiple ascending dosing, pharmacokinetic evaluation of levels in the brain, and cerebrospinal fluid (CSF) and plasma studies. ELND-005/AZD-103 was safe and well tolerated at all doses and dosing regimens examined, with no severe or serious adverse events observed. The compound was also shown to be orally bioavailable, cross the blood-brain barrier and achieve levels in the human brain and CSF that were shown to be effective in animal models of AD. The pharmacokinetic and safety data obtained in the Phase I studies will be used to select the appropriate doses for Phase II trials.

The next steps in the development of ELND-005/AZD-103 will be the submission of data supporting Phase II studies to the FDA. Transition and Elan anticipate starting Phase II by the end of 2007 or early 2008.

Study supports statin use for AD

Scientists have found evidence showing an association between statin use and a lower risk of neuropathologic changes in the brain that are associated with Alzheimer's disease (AD).

In the study, which was published in the 28th August issue of Neurology (2007;69:878-885), researchers at the University of Washington, the Veterans Affairs Puget Sound Health Care System and the Group Health Cooperative of Puget Sound reviewed autopsies on 110 patients aged 65 to 79 years, who had died in the course of a long-term, community-based study on cognitive changes in the elderly.

After controlling for age and other factors, they found that the brains of statin users showed significantly reduced risk of having the typical signs of AD than non-users, including a more than two-fold reduction in the risk of having neurofibrillary tangles.

Nymox Pharmaceutical holds US and global patent rights for the use of statin drugs for the prevention and treatment of AD, including for patients at risk of AD because of vascular-related risk factors or disease. These findings demonstrate an association between antecedent statin use and neurofibrillary tangle burden at autopsy, however, it has been cautioned that additional study is needed to examine whether statin use may be causally related to decreased development of AD-related neuropathologic changes.

For details of a study suggesting the continued use of statins after a stroke, see Cerebrovascular Disorders, R&D Update.

PRODUCT NEwSAricept approved for severe AD in Japan

Aricept (donepezil) has been approved to treat severe Alzheimer's disease (AD) in Japan, meaning it is now approved there to treat all stages of the disease. An acetylcholinesterase inhibitor developed by Eisai, Aricept is the only approved prescription medicine for the treatment of AD in Japan and was approved for this new indication in the US in October 2006, where it is co-promoted with Pfizer.

The approval was based on the results of clinical trials conducted both in Japan and abroad. The trial in Japan, involving approximately 300 patients with severe AD, compared the efficacy of Aricept 5 and 10mg/day versus placebo. In this six-month, multi-centre, randomised, double-blind, placebo-controlled study, the patients treated with both doses of Aricept showed a statistically significant improvement in cognitive function compared to those taking placebo. In addition, those patients treated with 10mg/day showed a statistically significant improvement in global function compared to the placebo group. No statistically significant difference was observed between the 5mg/day dose group and the placebo group in the rate of adverse events (AEs), while in the 10mg/day dose group, patients experienced a statistically higher incidence of AEs compared to the placebo group, with the most commonly observed being gastrointestinal in nature and mild-to-moderate in severity.

The recommended initial dose for adult patients is Aricept 3mg administered orally once daily, increasing to 5mg once daily after one to two weeks. For patients with severe AD, administration should be started with Aricept 5mg once daily and the daily dose increased to 10mg after four weeks.

Ranbaxy receives tentative FDA approval for galantamine tablets

On 28th August, Ranbaxy Laboratories received tentative FDA approval to manufacture and market galantamine tablets 4, 8 and 12mg on an exclusive basis. Galantamine, which is marketed by Janssen Pharmaceutica (Johnson & Johnson) as Razadyne, is indicated



CNS Drug News

for the treatment of mild-to-moderate dementia of the Alzheimer's disease type and Ranbaxy will benefit from the 180-day shared exclusivity on the product. Final approval is anticipated on 14th December 2008.

mULTIPLE SCLEROSIS - R&D UPDATETysabri demonstrates significant HRQoL improvements for MS patients

According to data published in the 14th August online edition of the Annals of Neurology (10.1002/ana.21163), multiple sclerosis (MS) patients treated with Tysabri (natalizumab) showed a significant improvement in health-related quality-of-life (HRQoL) measures when compared to those receiving placebo. These results are from the first Phase III MS studies to have demonstrated improvement on HRQoL measures in patients with relapsing forms of MS.

Tysabri is a therapy approved for relapsing forms of MS in the US and relapsing-remitting MS (RRMS) in the EU. Discovered by Elan and co-developed with Biogen Idec, the product is also approved in Switzerland, Canada, Australia and Israel.

The two-year, randomised, double-blind, placebo-controlled, multi-centre trials, AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) and SENTINEL (Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis), were conducted in 2,113 patients with relapsing forms of MS. In AFFIRM, patients received natalizumab 300mg (n=627) or placebo (n=315), while in SENTINEL, participants received Avonex (interferon [IFN] beta-1a) plus natalizumab 300mg (n=589), or IFN beta-1a plus placebo (n=582). The SF-36 and a Subject Global Assessment Visual Analogue Scale (VAS) were administered at baseline, as well as at weeks 24, 52 and 104. Odds ratios for clinically-meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) were also calculated.

In the AFFIRM trial, natalizumab-treated patients showed: a statistically significant improvement in the SF-36 PCS beginning at week 24 and all subsequent time points, compared with a decline in the placebo-treated group; a statistically significant improvement in the SF-36 MCS at week 104, compared with a decline in the placebo-treated group; and statistically significant benefits using the VAS when compared with placebo at weeks 52 and 104. Natalizumab-treated patients showed sustained improvement from baseline QoL measures, not just a slowing down of QoL deterioration, while HRQoL measures correlated with common measures of MS severity, including the EDSS, sustained disability progression, relapse number, MSFC and volume of T2-hyperintense and T1-hypointense lesions. Improvements on QoL measures were also observed in the SENTINEL study.

For details of Tysabri being recommended in the UK for use in highly-active RRMS, see Product News.

PDL to focus on Ab discovery and development

PDL BioPharma is to undertake a significant strategic change to focus on the discovery and development of novel antibodies (Abs) in select immunological diseases and oncology, following a months-long business and portfolio review.

PDL has revised its corporate strategy to take advantage of its clinical and preclinical portfolio, and leverage its ability to innovate in the science and development of monoclonal Abs. PDL will focus its

SMi present their 6th Annual Conference on…

Clinical Trials in CNS 26th & 27th November 2007, Copthorne Tara Hotel,

London PLUS AN ASSOCIATED HALF-DAY POST-

CONFERENCE WORKSHOP

Combination compounds in CNS and efficacy boosting

28th November 2007, Copthorne Tara Hotel, London

In association with: PharmaNeuroBoost

This year the SMi Group has set to explore the latest advancements in CNS clinical trials design and conduction, and is offering the chance to gain

unique insights into the field.

Building on the success of the previous events, the conference offers a packed and varied agenda

covering recent results, case study presentations and analysis methods. In addition, a networking

drinks reception has also been set at the end of the first day, enabling attendees to exchange thoughts

and ideas in a relaxed social setting.

To download a brochure visit our website at: www.smi-online.co.uk/2007cnstrials13.asp

The excellent speaker line up includes:

- Dr Gail Farfel, NovartisVice President and CNS Therapeutic Area Head - Dr Menelas N Pangalos, WyethVice President, Neuroscience Research, - Dr Tanya Ramey, Pfizer,Clinical Lead, Neurosciences - Dr Stig Johan Wiklund, AstraZeneca,Director Statistical Science, Technical and Scientific Development, - Dr Michel Dib, Sanofi-Aventis, Medical Director, CNS - Dr Paul Thompson, GlaxoSmithKline,CPDM-Neurology Biomarker Group- Dr James V Cassella, Alexza Pharmaceuticals, Senior Vice President, Research and Development

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www.smi-online.co.uk/2007cnstrials13.aspOR

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CNS Drug News

research and development initiatives and strengthen its expertise in two therapeutic areas, select immunological diseases and oncology. The company's immunological programmes include daclizumab in multiple sclerosis and other indications, Nuvion (visilizumab) in various potential indications and several preclinical candidates. The company is planning an R&D update in mid-November to detail the status of its initiatives.

Recruitment completed for Sativex Phase III trial in MS neuropathic pain

Patient recruitment has been completed in GW Pharmaceuticals' double-blind, randomised, placebo-controlled, pivotal Phase III trial of Sativex, a buccal spray composed primarily of tetrahydrocannabinol and cannabidiol, in patients with central neuropathic pain due to multiple sclerosis (MS), who have achieved inadequate pain relief with existing therapies.

The study has recruited 339 patients in the UK, Canada, France, Spain and the Czech Republic, and is GW's largest clinical trial, to date. The duration of treatment in the trial is 14 weeks and the last patient will exit the study at the end of 2007, with headline results expected in the first half of 2008.

GW previously carried out a similar pivotal Phase III trial with positive results. This study showed that Sativex was significantly superior to placebo in reducing pain (p=0.005) and sleep disturbance (p=0.003). This second pivotal Phase III study in MS neuropathic pain has two potential roles in the regulatory strategy for Sativex, as follows:

in Europe, this study may provide a clinical data package to support a regulatory submission for Sativex in the indication of MS neuropathic pain; and in Canada, this study is intended to meet the condition associated with the approval of Sativex in order to obtain a full Notice of Compliance.

Sativex is already approved in Canada, where it is exclusively marketed by Bayer, as adjunctive treatment for the symptomatic relief of neuropathic pain in MS and in cancer pain. Health Canada approved Sativex under the Notice of Compliance with conditions policy.

PRODUCT NEwSBiopartners submits Biferonex in Europe

Biopartners Holdings, which was acquired by Bioton in March, has submitted an MAA to the EMEA for Biferonex (interferon beta-1a [IFN beta-1a]), a pH-neutral and human serum albumin-free formulation of IFN beta for patients with relapsing-remitting multiple sclerosis (RRMS).

IFN beta has been extensively studied in MS, exhibiting beneficial effects in both the RR and progressive forms of the disease by inhibiting inflammatory activity and thereby reducing nerve cell damage. It is also thought to inhibit damage to the myelin sheath by both preventing a T-cell-mediated autoimmune response to myelin and reducing the effect of other naturally-occurring compounds that can enhance the autoimmune response.

This formulation boasts a low incidence of neutralising antibodies and is therefore expected to optimise drug treatment effectiveness, plus the product's neutral pH minimises the risk of injection site reactions, which is anticipated to enhance tolerability.

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NICE recommends Tysabri for use in highly-active RRMS

Final guidance by the UK's National Institute for Health and Clinical Excellence (NICE) has recommended the NHS' use of Biogen Idec/Elan's Tysabri (natalizumab) in people with highly-active relapsing-remitting multiple sclerosis (RRMS).

Tysabri is the first treatment for MS to be recommended for use by NICE and the first to be specifically licensed for highly-active RRMS. Data indicate that over two years, treatment with the product for highly-active RRMS, defined as those with two or more relapses and MRI activity, leads to a 64 per cent reduction in the risk of disability progression and an 81 per cent reduction in annualised relapse rate compared with placebo.

For details of Tysabri demonstrating significant health-related quality-of-life improvements for MS patients, see R&D Update.

New Rebif formulation approved in Europe

The EC has granted marketing authorisation for a new formulation of Merck Serono's (Merck KGaA) Rebif (interferon beta-1a) for the treatment of relapsing multiple sclerosis. The formulation has been developed to increase treatment benefit by improving injection tolerability, while targeting an improved immunogenicity profile.

The decision applies to all 27 countries in the EU, as well as Iceland, Liechtenstein and Norway, with launches in the various EU countries starting in September. The new formulation will be available in the same strengths and pharmaceutical forms as currently registered, ie, 8.8, 22 and 44mcg, as a solution for injection in prefilled syringes.

Questcor approves new strategy for HP Acthar Gel

For details, see Anti-Epileptics, Product News.

AGREEmENT NEwSTeva partners with Compugen for CGEN-54

Teva Pharmaceutical Industries has signed an agreement covering Compugen's CGEN-54, a novel splice variant of monocyte chemoattractant protein 1 (MCP1). The agreement covers both an initial research collaboration and an option to Teva for a worldwide exclusive development and commercialisation licence.

CGEN-54, a drug candidate for chronic inflammatory diseases, is one of a large number of novel splice variants predicted in silico using a Compugen discovery engine and then experimentally validated.

Under the terms agreed, Compugen will provide Teva with research quantities of CGEN-54. Teva will then conduct further in vivo validation experiments and has received from Compugen an option to enter into an exclusive worldwide milestone and royalty-bearing licence agreement for the development and commercialisation of any resulting products.

CGEN-54 is an antagonistic variant of MCP1, which is induced in response to various inflammatory stimuli. Binding of this protein to its cognate receptor, CCR2, leads to the recruitment of specialised immune cells into the site of inflammation, often leading to chronic inflammation. CGEN-54 has been shown to inhibit MCP1-related



CNS Drug News

activity. The inhibition of the MCP1-CCR2 pathway represents a promising target to effectively modulate disease progression in a number of chronic inflammatory diseases, such as multiple sclerosis.

OTHER NEURODEGENERATIVE DISORDERS - R&D UPDATE

McMaster study suggests kinase inhibitor use for HD

According to research published in the 18th August online edition of Human Molecular Genetics (10.1093/hmg/ddm217), a team at McMaster University has made an insight into how Huntington's disease (HD) is triggered.

Dr Ray Truant has been studying the biological role of the huntingtin protein and the sequences in the protein that tell it where to go within a brain cell. The researchers have discovered a small protein sequence in huntingtin that allows it to locate to the part of the cell that is critical for protein quality control. Similar findings have been seen to be important for other neurodegenerative diseases, such as Parkinson's and Alzheimer's.

Huntingtin protein is essential for normal development in mammals and is found in all cells, yet its function was unknown. Now, it appears that huntingtin is crucial for a brain cell's response to stress and moves from the endoplasmic reticulum into the nucleus. However, when mutant huntingtin is expressed, it enters the nucleus as it should in response to stress, but cannot exit properly, piling up in the nucleus and leading to brain cell death in HD. The researchers also found that huntingtin can be sent to the nucleus by kinases and determined the 3D shape of this sequence. The team's work indicates that if mutant huntingtin is prevented from entering the nucleus, it cannot kill a brain cell, which suggests that a kinase inhibitor drug may be effective for HD.

Protox acquires HUMxin research programme from Medicenna

Protox Therapeutics has entered into an asset purchase agreement for the acquisition of Medicenna Ventures' HUMxin Program, a research programme to develop fully-humanised fusion proteins based upon the Bcl-2 family, which are key components of apoptosis. HUMxin represents a third technology platform for the company and may have application for the treatment of neurodegenerative diseases.

Prior to joining Protox as President and Chief Executive Officer, Dr Fahar Merchant founded Medicenna and had worked with the National Institutes of Health (NIH) to develop the HUMxin Program. Medicenna entered into a CRADA with the NIH related to the HUMxin Program. Pursuant to the terms agreed, Medicenna has transferred the HUMxin CRADA and all its rights and interests to Protox, and the company has agreed to pay Medicenna C$209,680 for its audited out-of-pocket HUMxin CRADA and related expenses incurred, to date. Half of this amount will be paid to Medicenna in cash and the other half in the form of 127,854 common shares of the company, which will be subject to a four-month hold period.

Study suggests cancer drugs may have use for HD

Scientists at the University of Leeds have made what is thought to be a major breakthrough in the understanding and potential treatment of Huntington's disease (HD). They have discovered that one of the body's naturally-occurring proteins is preventing 57 genes from

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CNS Drug News

operating normally in the brains of patients with HD. In addition, the destructive nature of this protein could potentially be halted using drugs that are already being used to help cancer patients.

According to Dr Lezanne Ooi, the research could lead to radical changes in treatment for HD patients and the fact that these cancer drugs have already been through the clinical trials process should accelerate the time it takes for this research to impact directly on patients.

Ooi's research, which was carried out in collaboration with the University of Milan and King's College, London, and published in the 27th June issue of the Journal of Neuroscience (2007;27:6972-6983), has identified the effects of one of the body's proteins on the neurons of HD patients. Neurons are usually protected by brain-derived neurotrophic factor (BDNF), whose many functions also include encouraging the growth and differentiation of new neurons and synapses. However, in HD patients, the repressor protein known as repressor element 1-silencing transcription factor (REST), which is usually found only in certain regions of the brain, enters the nucleus of the neuron and decreases the expression of BDNF.

Ooi has also been studying some of the enzymes that assist the function of this protein. It is these enzymes that provide the mechanism for the protein to cause disruption in the brains of HD patients and that are already being targeted by certain cancer drugs.

Allergan/ExonHit compound to begin clinical trials

Clinical testing is to be initiated with the first new chemical entity (NCE) to emerge from Allergan and ExonHit Therapeutics' strategic collaboration to identify, develop and commercialise drugs targeted at the treatment of neurodegenerative diseases, pain and ophthalmology. The NCE, designated EHT/AGN001, has a novel mechanism of action and will enter a Phase I study later in 2007.

Under terms previously agreed, Allergan will assume responsibility for the ongoing clinical development and commercialisation of EHT/AGN001, while contingent upon progress, ExonHit will receive milestone payments and royalties upon commercialisation.

FSMA/Tikvah establish collaboration to develop TIK-201 for SMA

Families of Spinal Muscular Atrophy (FSMA) and Tikvah Therapeutics have established a collaboration to help advance and accelerate the clinical development of TIK-201, the latter's new formulation of sodium phenylbutyrate, for the treatment of spinal muscular atrophy (SMA). This collaboration is focused on utilising the existing Project Cure SMA clinical network and protocols to clinically test Tikvah's non-viscous, concentrated solution formulation.

SMA results from the loss of both copies of the survival motor neuron (SMN1) gene. Early ex vivo and other clinical results suggest that sodium phenylbutyrate, amongst other histone deacetylase inhibitors, may be effective in the treatment of SMA by increasing production of the remaining SMN2 protein. However, such trials have been complicated by difficulties in administering currently-available tablet and powder preparations of sodium phenylbutyrate due to its unpleasant taste and smell, plus other properties. Tikvah's proprietary formulation overcomes these limitations and is optimised for the delivery of drugs to infants, toddlers and others with swallowing difficulties by conventional routes of administration. Specific details on the trial design and dates will be available later this year, with the goal of beginning enrolment in the first half of 2008.

Ketasyn improves memory in AAMI study

Data from a Phase II study in age-associated memory impairment (AAMI) have shown that Accera's lead compound, Ketasyn (AC-1202), has a positive and clinically-meaningful effect on memory in older adults.

The randomised, double-blind, placebo-controlled, parallel trial was conducted at six centres in the US. A total of 159 subjects (mean age, 65 years) diagnosed with AAMI received either Ketasyn or placebo for 90 days, followed by a two-week washout period. Subjects underwent genomic testing for variations in the coding regions of genes that are known to influence memory and cognition, including the apolipoprotein E gene (APOE), a known genetic risk factor for Alzheimer's disease (AD). On days zero, 30, 60, 90 and 104, subjects were evaluated through a battery of neuropsychometric tests that measure various aspects of memory and cognition.

Ketasyn showed significant efficacy in tests of memory. On average, subjects taking the compound performed significantly better on the First-Last Name Association test (FLN) than those taking placebo (p=0.042). In another memory test, known as Name-Face Recognition (NFA), Ketasyn-treated subjects under the age of 59 years improved significantly more than placebo subjects at day 90 (p=0.0217).

Consistent with the findings of Accera's Phase IIa and IIb AD studies, subjects who did not have the APOE4 genotype (E4[-]) responded particularly well to treatment: E4(-) subjects showed a further significant treatment effect of Ketasyn in the FLN at day 90 (p=0.012). In contrast, and consistent with the AD trial results, APOE4(+) subjects showed no difference between Ketasyn and placebo for FLN scores at day 90 (p=0.4639).

The safety profile of Ketasyn was positive, as shown in the previous AD trials. The incidence of adverse events was low and similar between Ketasyn and placebo groups.

AAMI symptoms may be related to declines in glucose metabolism in the brain that are also associated with ageing. Ketasyn is an orally-available compound that is metabolised into ketone bodies, which the brain can use for energy even when its ability to process glucose is impaired.

Accera recently completed a Phase IIb trial in AD patients that confirmed Ketasyn's safety and efficacy, as measured by improvement in ADAS-Cog scores, and the company plans to initiate a pivotal, multi-centre, Phase III trial in early 2008 in mild-to-moderate AD patients. This study will focus on several measures of efficacy, including the ADAS-Cog, safety and the role of insulin regulation in AD.

Study suggests new targets for neurodegenerative diseases

Researchers have provided new information about how communication among neurons may be prevented from deteriorating in conditions such as Alzheimer's disease (AD). The results, which were published in the August issue of Molecular & Cellular Proteomics (2007;6:1318-1330), may lead to new therapies for the treatment of not only AD, but also motor neuron and prion diseases.

Most current research efforts to find a treatment for AD and similar conditions focus on what happens to the main part of a neuron, but recent studies have examined how neuronal communication is impaired in human diseases such as AD. The deterioration of synapses and axons can be delayed via a protein created by the slow Wallerian



CNS Drug News

degeneration (Wlds) gene, although how this protein works is still a mystery. In the study, researchers from the University of Edinburgh and colleagues identified 16 proteins that are affected by the Wlds gene.

Although details are still missing, Wlds probably prevents these proteins from deteriorating synapses and axons. The team found that some of the proteins had previously been shown to deteriorate synapses and axons, but, unexpectedly, eight proteins regulated the function of mitochondria. These results reveal for the first time that mitochondria are involved in the protection of neurons provided by the Wlds gene and suggest that targeting some of the proteins identified in this study may lead to novel therapies for the treatment of AD, as well as motor neuron and prion diseases.

Neuralstem forms collaboration to advance SCs into ALS patients

Neuralstem has entered into a collaborative agreement with the ALS Clinic at University of Michigan Health System, the goal of which is to provide further proof-of-principle data to move the company's spinal cord stem cells (SCs) into patients with amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease).

Neuralstem's patent-protected technology enables, for the first time, the ability to produce neural SCs of the human brain and spinal cord in commercial quantities, and the ability to control the differentiation of these cells into mature, physiologically-relevant human neurons

and glia. The company expects that its first IND application will be for the treatment of ischaemic paraplegia, and hopes to submit its initial application to the FDA and begin its first clinical trial during 2007.

AGREEmENT NEwSOption to IPL455,903 not exercised by Inflazyme

Inflazyme Pharmaceuticals has confirmed that it will not exercise its option to IPL455,903, a PDE-IV inhibitor discovered and patented by the company. Under the limited licence granted to Helicon Therapeutics in January 2003, Inflazyme had 90 days to exercise its option after receiving certain information that included the results of the first Phase IIa study.

Helicon recently completed a Phase IIa study with IPL455,903 in elderly subjects with age-associated memory impairment. Inflazyme commented on the results of this study in June and stated that the data may support further clinical studies with the compound, as well as the development of the company's other PDE-IV inhibitors (see CNS 165). However, Inflazyme has insufficient cash to exercise the option, which is estimated to be in the range of C$3 million to C$4 million based on limited information provided by Helicon. By not proceeding with the option, Inflazyme will receive certain royalties on any product commercialised. Helicon only has rights in the field of learning and memory disorders, while Inflazyme has retained rights to this compound for all other uses.

CEREBROVASCULAR DISORDERSR&D UPDATE

Data confirm NXY-059's inefficacy for AIS

Data published in the 9th August issue of the NEJM (2007;357:562-571) have confirmed that NXY-059 is ineffective for the treatment of acute ischaemic stroke (AIS) within six hours after the onset of symptoms.

NXY-059, a free radical–trapping agent, showed promise as a neuroprotectant in the SAINT I (Stroke–Acute Ischemic NXY Treatment I) trial, reducing disability when given to patients who had AIS, therefore confirmation of efficacy was sought in a second, larger trial, named SAINT II.

A total of 3,306 patients with AIS were enrolled in the randomised, double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within six hours after the onset of stroke symptoms.

The primary endpoint was the distribution of disability scores on the modified Rankin Scale (mRS) at 90 days, with scores on neurologic and activities of daily living scales examined as secondary endpoints. The researchers also tested the hypothesis that NXY-059 would reduce alteplase-related intracranial haemorrhages.

The efficacy analysis was based on 3,195 patients. The results indicate that prognostic factors were well balanced between the treatment groups, plus mortality was equal in the two groups and adverse event rates were similar. However, the distribution of scores on the mRS did not differ between the NXY-059-treated group (n=1,588) and the placebo group (n=1,607; p=0.33 by the Cochran–Mantel–Haenszel test; odds ratio for limiting disability, 0.94; 95% CI, 0.83 to 1.06).

Furthermore, analysis of categorised scores on the mRS confirmed the lack of benefit: the odds ratio for trichotomisation into mRS scores of 0 to 1 versus 2 to 3 versus 4 to 6 was 0.92 (95% CI, 0.80 to 1.06). There was no evidence of efficacy for any of the secondary endpoints and among patients treated with alteplase, there was no difference between the NXY-059 and placebo groups in the frequency of symptomatic or asymptomatic haemorrhage.

These data confirm the SAINT II results that were reported in October 2006, which indicated that NXY-059 had shown no efficacy in AIS. At that time, AstraZeneca revealed that it planned no further development of NXY-059 in AIS, but would analyse the pooled data from the SAINT I and II trials in close co-operation with the SAINT Steering Committee and Renovis, to ensure that learnings for further stroke research were identified and communicated.

Sinobiomed completes evaluation of preclinical studies on first rhK

Sinobiomed has provided an update on preclinical trial progress for the recombinant human kallikrein (rhK1) being developed by its 82 per cent-owned subsidiary, Shanghai Wanxing Bio-pharmaceuticals. Shanghai Wanxing researchers are developing rhK1, the world's first rhK, with purity levels as high as 98 per cent and low production costs, to treat stroke and peripheral vascular disorders, plus to prevent blood clots and thrombosis.

The preliminary results of the preclinical research show that dogs can be safely injected with 400-times the normal human dose. Trial results in dogs and rabbits further demonstrated that rhK1 could significantly reduce the nerve function barrier caused by ischaemic brain infarction, decrease the infarction scope and attenuate cerebral oedema. The

CEREBROVASCULAR DISORDERS

©Espicom Business IntelligencePage 1� 6th September �007

CNS Drug News

animal study also showed that the efficacy of rhK1 is better than that of the kallikrein treatments extracted from human fluids and organs. Once the preclinical study data have undergone final analysis, Shanghai Wanxing intends to apply for approval to undertake clinical research. The clinical study of rhK1 is expected to begin with ischaemic brain infarction and extend to other conditions.

Shanghai Wanxing has applied for a Chinese patent for rhK1 and is applying to the Patent Control Treaty for an international patent.

Study suggests continued use of statins after stroke

The results of a study published in the 28th August issue of Neurology (2007;69:904-910) have suggested that people who stopped taking their statins while hospitalised after a stroke were 4.7-times more likely to have died or be dependent on others for their care three months after the stroke than people who kept taking the drugs. According to study author, Dr José Castillo, of the University of Santiago de Compostela in Spain, the results strongly support the recommendation to physicians to continue statin drugs during the acute phase of an ischaemic stroke.

The study involved 89 people who were already taking the cholesterol-lowering drugs at the time when they had a stroke. For the first three days after being admitted to the hospital, 46 of the patients received no statin drugs, while 43 received the drugs. After three months, 27 people (60 per cent) in the group that received no statins had either died or were disabled to the point that they could not complete their daily activities independently, compared to 16 people (39 per cent) in the group that kept taking statins.

For details of a further study demonstrating the positive effects of statin use, see Neurodegenerative Disorders, Alzheimer's Disease - R&D Update.

ReGen provides results of small-scale zolpidem study

ReGen Therapeutics has reported the results of a small-scale study that is part of its clinical programme designed to explore the antidormancy effect of zolpidem.

This was a double-blind, Phase IIa study in 20 conscious, fully-perceptive ambulant patients having various debilities as a consequence of brain damage. It was performed in collaboration with ReGen's subsidiary, Guildford Clinical Pharmacology Unit, and investigators at the Walko Medical Centre in Springs, South Africa, where the antidormancy effect of zolpidem was first discovered.

The study compared various single doses of a novel sublingual spray formulation (2.5, 5 and 10mg) with an existing tablet formulation (10mg) in terms of the onset and degree of sedation. It also looked for preliminary signs of efficacy, although the study was small and only single doses of drug were given. The results indicate that:

the 2.5mg spray regimen was no more sedative than placebo;the 5 and 10mg spray regimen induced sedation in a dose-responsive manner;the spray showed a faster onset of action (sedative effect) than the tablet; andthe 5mg spray induced the same peak level of sedation as the 10mg tablet (15 vs 90 minutes, respectively).

According to ReGen, the fact that a spray is absorbed faster and more completely than tablets will enable patients to control the effect more accurately. Furthermore, as a dose of 2.5mg caused no more sedation than placebo, it may be possible that repeated 2.5mg spray doses will show efficacy without undue sedation.

Based on these results, the company now has the confidence to continue the development of novel zolpidem formulations for the treatment of brain dormancy and is reviewing options to achieve this.

ImaRx proceeds with Phase I/II trial of SonoLysis+tPA therapy in AIS

ImaRx Therapeutics has received approval from a Data and Safety Monitoring Board (DSMB) to proceed with the second dose cohort in its TUCSON (Transcranial Ultrasound in Clinical SONoLysis) study evaluating SonoLysis plus tissue plasminogen activator (tPA) therapy in patients with acute ischaemic stroke (AIS).

ImaRx' SonoLysis programme is focused on the development of product candidates that involve the administration of its proprietary MRX-801 microbubbles and ultrasound to break up blood clots and restore blood flow to oxygen-deprived tissues with or without a thrombolytic drug.

Initiated in January, the dose-escalation, Phase I/II trial is expected to enrol a total of 72 patients in four successive cohorts, each receiving an increasing dose of MRX-801 microbubbles, ultrasound and the standard dose of tPA. The DSMB reviews the data from each cohort before granting approval to enrol patients in the next successive cohort utilising a higher dose of MRX-801 microbubbles. ImaRx expects to complete enrolment in this trial in the first half of 2008.

For details of ImaRx receiving a grant to study changes in the permeability of the blood-brain barrier with targeted microbubbles and ultrasound, see General Development News, R&D Update.

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CEREBROVASCULAR DISORDERS


CNS Drug News

PRODUCT NEwSFDA sets PDUFA action date for indiplon capsules

The FDA has accepted Neurocrine Biosciences' resubmission of its NDA for indiplon 5 and 10mg capsules for the treatment of insomnia and has set a PDUFA action date of 12th December.

Editor's note: in June, Neurocrine resubmitted its NDA for indiplon 5 and 10mg capsules for the treatment of insomnia in both adult and elderly patients to the FDA (see CNS 164). Indiplon, which was licensed from DOV Pharmaceutical in 1998, is a non-narcotic, non-benzodiazapine agent that acts on a specific site of the GABA-A receptor and potentiates the action of GABA. While other drugs also act on this receptor, indiplon's mechanism is unique in that it has been shown to bind more selectively to the specific subtype of GABA-A receptors within the brain that are believed to be responsible for promoting sleep.

AGREEmENT NEwSTikvah signs licensing deal with P2D for LY156735

Tikvah Therapeutics has signed a licensing agreement with Phase 2 Discovery (P2D), a drug-development company affiliated with researchers at the University of Cincinnati School of Medicine, Department of Psychiatry, for worldwide rights to develop and

commercialise LY156735 for the treatment of circadian rhythm, sleep disorders and depression. Tikvah will also explore additional indications for LY156735 through its own research and development efforts in special subpopulations, and other general conditions of sleep deprivation and/or insomnia, among others.

P2D acquired LY156735 from Eli Lilly in 2001. Under its own IND application, P2D has generated substantial Phase II data demonstrating statistically significant improvement in both objective and subjective sleep measures. Pilot clinical studies, which were conducted by P2D in response to the unique receptor binding profile of LY156735, suggest that improved efficacy in standard measures of sleep may be possible compared to another melatonin agonist. Further, in patients with severe insomnia, LY156735 significantly decreased latency to persistent sleep compared to placebo. Efficacious results were also obtained in pilot clinical studies where jet lag was induced by a time shift in an aerospace temporal isolation clinical laboratory unit.

In receptor binding studies, LY156735 has equal or better affinity for 5-HT

2c receptors as agomelatine, a molecule that acts as an

antidepressant, in part, through interaction with melatonin receptors and 5-HT

2 receptors. The potential antidepressant actions of LY156735

have been shown in a preclinical rodent model of antidepressant activity.

P2D will be transferring its open IND application for LY156735 to Tikvah, which will then assume responsibility for the further clinical development and commercialisation of the compound, which will be known as TIK-301.

ANXIOLyTICS/SLEEP DISORDERS

ANTIDEPRESSANTSR&D UPDATE

TCA discovery may lead to more effective drugs

Researchers at Oregon Health & Science University (OHSU) have identified a new mechanism by which tricyclic antidepressants (TCAs) inhibit neurotransmitter transporters. Reported in the 23rd August issue of Nature (2007;448:952-956), the discovery may improve the design of new antidepressants that are more effective than currently-marketed TCAs, which have been prescribed for decades, but have been largely supplanted by selective serotonin reuptake inhibitors because of their lack of specificity.

The researchers began their studies with the goal of understanding how TCAs interact with their clinical target, sodium-coupled neurotransmitter transporters. Disorders such as depression, epilepsy, autism or obsessive-compulsive disorder can result from impaired function of sodium-coupled neurotransmitter transporters, therefore these molecules are the target of a variety of drugs, including TCAs. However, it has been difficult to understand precisely how these molecules function and interact with drugs, as the transporters found in humans are not amenable to study. Instead, the researchers focused on a sturdier transporter in bacteria that functions similarly. That molecule, called LeuT, is used by the bacterium, Aquifex aeolicus, which thrives in superheated deep-sea vents. LeuT transports leucine across the bacterial membrane.

The team explored how the TCA, clomipramine, which had been found to be a potent inhibitor of LeuT, attached to the bacterial transporter. X-ray crystallography was used to develop a detailed structure of clomipramine attached to LeuT. Furthermore, how two other TCAs, desipramine and imipramine, attached to LeuT was also analysed.

One plausible way for a drug to interfere with a transporter's function is by physically blocking the part of the molecule that binds to the molecule to be transported. The steady-state kinetic data and crystallographic studies revealed, however, that clomipramine and the other TCAs do not attach to the same site on the transporter as leucine.

Rather, they plug into a cleft in a different part of the transporter and lock it into a conformation that traps leucine, preventing it both from passing through and being released. This cleft is on the region of the transporter that juts outside the cell. Similar findings were reported in an article published in the 9th August online edition of Science (10.1126/science.1147614) by researchers at New York University (NYU).

They found that desipramine binds LeuT in the same cleft, but the two groups diverge in their conclusions about the relevance of the TCA site in LeuT to the antidepressant site in the human neurotransmitter transporters. The NYU team argues that it is identical, whereas the OHSU researchers are more cautious, suggesting that the TCA site is different and probably located 'deeper' in the human transporter, close to or overlapping the substrate site. Nevertheless, the concept

ANXIOLyTICS/SLEEP DISORDERS / ANTIDEPRESSANTS


CNS Drug News

that a molecule binding to an allosteric site may inhibit a transporter by stabilising an occluded or locked state is one that has not previously been described.

The OHSU team hypothesised that the TCA molecules slowed the release of leucine from the transporter. Indeed, it was found that the transporter released leucine approximately 700-times slower when clomipramine was attached. This study is thought to define a new principle for the inhibition of this class of sodium-coupled transporters and the discovery of the new mechanism may spur the development

of improved inhibitors. In future studies, the OHSU researchers will seek to isolate and crystallise the delicate human transporter for structural studies to establish if the basic same inhibitory mechanism is at work.

AGREEmENT NEwSTikvah signs licensing deal with P2D for LY156735

For details, see Anxiolytics/Sleep Disorders, Agreement News.

PSyCHOTIC DISORDERSR&D UPDATE

Lilly's LY2140023 shows antipsychotic activity in humans

The results of an investigational, Phase II study have demonstrated that Eli Lilly's LY2140023, a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors, has antipsychotic activity.

In this double-blind, placebo-controlled, proof-of-concept trial, which was published in the 2nd September online edition of Nature Medicine (10.1038/nm1632), a total of 196 patients with schizophrenia were randomly assigned to four weeks of treatment with either LY2140023 (40mg twice daily), Zyprexa (olanzapine; 15mg daily) as an active control, or placebo. All participants were hospitalised to ensure patient safety and tapered off from any pretrial antipsychotic medications (no therapeutically-stable patients were included in the trial). In all, 118 patients completed four weeks of the planned study treatment.

It was found that treatment with LY2140023 or olanzapine resulted in a statistically significant improvement in PANSS total score (primary outcome) compared to placebo (-20.8, p<0.001; -26.7, p<0.001; respectively). Both groups showed a rapid response, within one week. After four weeks of treatment, both the LY2140023 (32 per cent, p<0.001) and olanzapine (41.2 per cent, p<0.001) groups demonstrated significantly greater response rates compared to the placebo group (3.2 per cent). Additionally, a mean 0.51kg weight reduction from baseline was observed in the LY2140023 group. A moderate, but statistically significant weight gain was observed in the olanzapine group (0.74kg, p=0.017) relative to the placebo group.

Results showed that the placebo arm experienced the highest rate of study discontinuation due to lack of efficacy, however, discontinuation due to adverse events (AEs) was not significantly different across the three treatment groups (p=0.66).

Overall, LY2140023 40mg twice daily was found to be safe and well tolerated, with most AEs being mild-to-moderate in severity and not treatment limiting. The most common treatment-emergent AEs in the LY2140023 group were insomnia, affect lability (p=0.038), nausea, headache, somnolence and blood creatine phosphokinase increase. The AE profile of LY2140023 did not include prolactin increase or worsening of extrapyramidal symptoms. Although mood lability seems to represent the most important potential AE, this outcome was observed primarily at one clinical site. In the olanzapine group, treatment-emergent AEs included elevation in blood triglyceride levels (p=0.005), insomnia, weight gain (p=0.034), somnolence, akathisia, agitation and periodontitis (p=0.03).

LY2140023 is an investigational compound that is being developed as a new treatment option for schizophrenia. It is an oral prodrug that once administered, is metabolised to provide the active mGlu2/3 receptor agonist called LY404039. Most currently-approved antipsychotic medications work by affecting dopamine or serotonin, but for LY2140023, the active substance, LY404039, is thought to work by reducing the presynaptic release of glutamate in brain regions where mGlu2/3 receptors are expressed.

According to Lilly, these data provide compelling new evidence that mGlu2/3 receptor agonists have antipsychotic properties and may provide a completely new therapeutic approach for treating schizophrenia and, perhaps, other neuropsychiatric disorders. Further studies are either planned or ongoing to learn more about the safety and effectiveness, including determining an optimal therapeutic dose for LY2140023.

Duke study uncovers clues about possible OCD mechanism

Duke University Medical Center investigators have discovered that mice with a genetic mutation that prevents their brain cells from producing one key protein exhibited obsessive-compulsive disorder (OCD)-like behaviour and when given a replacement dose of the protein in a specific region of the brain or drugs used to treat humans with the disorder, many of these mice seemed to get better. This research, which was published in the 23rd August issue of Nature (2007;448:894-900), may have uncovered important clues about a possible mechanism for OCD.

In their experiments, the researchers focused on the striatum, an area that controls the planning and execution of movement, as well as other cognitive functions. In normal brains, a protein known as SAPAP3 is crucial for nerve signals to travel from one nerve cell to another across the synapse. This protein is produced at high levels in the cells that make up the striatum. When the researchers looked closely at the brain cells of the mutant mice, they found that there were defects in the synapses. When they returned the protein into the striatum of the mutant mice, the synaptic defects were repaired and their OCD-like behaviours subsided. This is thought to be the first direct evidence that a synaptic defect in the striatum caused these OCD-like behaviours.

The researchers also found that selective serotonin reuptake inhibitors (SSRIs) reduced anxiety levels and suppressed the over-grooming in the mutant mice, further suggesting that what they observed in mice may also be analogous to human OCD. While SSRIs are the most commonly-prescribed drug for humans with OCD, they are only effective for approximately half of the patients, suggesting that many pathways involving different neurotransmitters are likely to be

PSyCHOTIC DISORDERS


CNS Drug News

involved. Duke researchers are currently looking for additional gene variations that may affect how nerve signals cross synapses, as well as beginning studies to determine if the gene mutant they discovered in mice plays a role in humans with OCD.

Corcept raises funds to advance Corlux

Corcept Therapeutics has reported a US$10.1 million private equity financing, the proceeds from which are to be used to conduct the next Phase III trial evaluating Corlux (mifepristone) for the treatment of the psychotic features of psychotic depression. The funds will also be used to conduct studies to extend and confirm the results of its recent study of Corlux for the prevention of antipsychotic-induced weight gain, to continue development of its new chemical entities and for general corporate purposes, including working capital.

AstraZeneca initiates Phase IIb trial of AZD3480 for cognitive deficits in schizophrenia

AstraZeneca has initiated a Phase IIb trial of AZD3480 (TC-1734) for cognitive deficits in schizophrenia, for which there is no product currently approved. The company entered into an exclusive global licence and research collaboration agreement for this Targacept compound in December 2005.

In the double-blind, placebo-controlled study, which is being conducted in the US and Canada, approximately 400 patients taking atypical antipsychotics will be randomly assigned to one of three dose groups of AZD3480 or placebo over a 12-week period. The primary outcome measure is the MATRICS cognitive test battery, which includes assessments of cognitive functions across nine different domains; secondary measures include life functioning, such as performance in day-to-day tasks and social skills. The trial is expected to complete by the end of 2008.

AZD3480 was designed to target select neuronal nicotinic receptors and has been evaluated in 12 clinical trials, to date, in approximately 540 subjects. In a previous Phase IIb trial conducted by Targacept in age-associated memory impairment, AZD3480 achieved statistically significant results on all of the primary endpoints, reflecting improved cognitive performance by memory-impaired older adults. A Phase IIb trial in Alzheimer's disease is also ongoing.

PRODUCT NEwSAstraZeneca's Seroquel XR approved in the Netherlands

The Netherlands' regulatory authority, MEB (Medicines Evaluation Board), has approved AstraZeneca's Seroquel XR (quetiapine) Extended-Release Tablets, a once-daily medicine for the treatment of schizophrenia in adult patients. With Seroquel XR, which was approved for the treatment of schizophrenia in the US in May (see CNS 163), patients can achieve a dose within the recommended range from the second day of treatment, plus the MEB approval also includes relapse prevention in the long-term treatment of schizophrenia. AstraZeneca will proceed with the mutual recognition procedure, seeking similar approvals across Europe.

The approval was based on clinical trials evaluating effectiveness and safety at doses of 400, 600, and 800mg/day, in acute treatment, relapse prevention, and in a non-inferiority study of acute efficacy and safety when switching from the original formulation to Seroquel

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PSyCHOTIC DISORDERS


CNS Drug News

XR. In the studies, Seroquel XR showed its potential as a once-daily treatment for both acute and clinically-stable schizophrenia patients, with the effective dose range reached within two days of starting treatment; the data demonstrated that this range is between 400 and 800mg/day.

Beyond schizophrenia, ongoing clinical studies of Seroquel XR cover bipolar disorder, major depressive disorder and generalised anxiety disorder.

Risperdal receives FDA approvals in children and adolescents

On 22nd August, the FDA approved Risperdal (risperidone) for the treatment of schizophrenia in adolescents aged 13 to 17 years, as well as for the short-term treatment of manic or mixed episodes of bipolar I disorder in children and adolescents aged ten to 17 years.

This is the first FDA approval of an atypical antipsychotic drug to treat either disorder in these age groups. Until now, there has been no approved drug for the treatment of schizophrenia available for paediatric use and only lithium has been approved for the treatment of bipolar disorder in adolescents aged 12 years and over. The FDA first approved Risperdal in 1993, for the treatment of schizophrenia

in adults. The drug was later approved for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder in adults, and the treatment of irritability associated with autistic disorder in children and adolescents aged five to 16 years. Risperdal is marketed in the US by Janssen Pharmaceutica and promoted by McNeil Pediatrics (both Johnson & Johnson).

The efficacy of Risperdal in the treatment of schizophrenia in adolescents was demonstrated in two short-term (six to eight weeks), double-blind, controlled trials involving more than 430 adolescents. All patients were experiencing an acute episode of schizophrenia at the time of enrolment. Treated patients generally had fewer symptoms, including a decrease in hallucinations, delusional thinking and other symptoms of their illness.

The efficacy of Risperdal in the treatment of manic or mixed episodes in children or adolescents with bipolar I disorder was demonstrated in a three-week, randomised, double-blind, placebo-controlled, multi-centre trial involving 160 children and adolescents who were experiencing a manic or mixed episode. Treated patients generally had fewer symptoms, including a decrease in their elevated mood and hyperactivity, and other symptoms of their illness. Drowsiness, fatigue, increase in appetite, anxiety, nausea, dizziness, dry mouth, tremor and rash were among the most common side effects reported.

ANALGESICS/ANAESTHETICSR&D UPDATE

Cymbalta reduces pain in fibromyalgia patients; sNDA submitted to FDA

New data presented at MYOPAIN 2007, the Seventh World Congress On Myofascial Pain Syndrome and Fibromyalgia Syndrome, held from 19th to 23rd August, in Washington DC, suggest that patients with fibromyalgia treated with Eli Lilly's Cymbalta (duloxetine) 60 or 120mg experienced a greater reduction in pain severity beginning one week after starting duloxetine than those taking placebo, as measured by the Brief Pain Inventory Average Pain Score (BPI). Furthermore, Lilly has submitted an sNDA to the FDA for Cymbalta, for the management of fibromyalgia. The submission is based on data from approximately 1,400 patients in five clinical trials.

The study, which included patients with and without depression, also showed greater improvements in patients taking duloxetine than in those taking placebo in scores on the PGI-I. At three months, patients treated with duloxetine 60 or 120mg/day showed a significantly greater reduction in pain and improvement in PGI-I scores compared with those taking placebo. At three months, more patients treated with either duloxetine 60 or 120mg showed a significantly greater reduction in pain, as measured by a 30 per cent improvement in baseline BPI scores (50.7 and 52.1 per cent, respectively) compared with patients taking placebo (36 per cent).

At six months, patients taking duloxetine 60 or 120mg maintained reduced BPI scores and patients taking 120mg had improved PGI-I scores compared with those taking placebo. Furthermore, at the end of the six-month trial, more patients treated with duloxetine 60 or 120mg showed a response to treatment, defined as a 50 per cent reduction of baseline BPI scores (32.6 and 35.9 per cent of patients, respectively), compared with patients taking placebo (21.6 per cent).

Discontinuation rates over six months were similar among the groups (45.3 and 46.3 per cent for duloxetine 60 and 120mg vs 50 per cent for placebo). Adverse event (AE)-related discontinuation was significantly higher in patients taking 120mg (26.5 per cent), but not in the 60mg (15.3 per cent) group, as compared with placebo (13.2 per cent). Discontinuations due to lack of efficacy were not statistically different among treatment groups.

AEs were similar to those seen in prior duloxetine studies. In this study, the most common AEs (occurred at a rate of >=5 per cent and at least twice the rate of placebo) included nausea, dry mouth, constipation, somnolence, fatigue, insomnia, decreased appetite, hyperhydrosis, cough, tremor, rash and weight increase.

Acura secures funds for Phase III trial of OxyADF Tablets

Acura Pharmaceuticals has entered into a securities purchase agreement with an investor group that is expected to raise net cash proceeds to the company, after expenses relating to closing the transaction, of approximately US$14.5 million.

The company plans to utilise a portion of the net proceeds to fund Study 105, a pivotal Phase III trial of OxyADF (oxycodone+niacin) Tablets, its lead product candidate utilising Aversion Technology. This is a randomised, double-blind, placebo-controlled, multi-centre, repeat-dose study of the safety and efficacy of OxyADF Tablets for the treatment of acute, moderate-to-severe postoperative pain following bunionectomy surgery in adult patients.

It is a three-arm trial comparing two dose levels of OxyADF Tablets to placebo, with study medication administered to patients every six hours for 48 hours following the onset of moderate-to-severe pain following bunionectomy surgery. Study 105 is targeted to enrol 135 patients per arm (approximately 405 patients in total).

ANALGESICS/ANAESTHETICS


CNS Drug News

As previously reported, Acura has executed a clinical trial development agreement with a contract research organisation and commenced preliminary Study 105 start-up activities. Now that new funding has been secured, the company intends to proceed with enrolment in the study. Acura believes that the completion of Study 105 is critical to a 505(b)(2) NDA submission for OxyADF Tablets.

Meda completes acquisition of MedPointe

Meda AB has completed its acquisition of MedPointe for a final purchase price of SKr 5,229 million, with consolidation of the company starting immediately (see CNS 167). New shareholders in Meda include the Carlyle Group, the Cypress Group and other US investors, which will have a combined shareholding in Meda of approximately 7 per cent. With the acquisition, Meda will have full marketing coverage in both the US and Europe, with revenues of approximately SKr 9 billion.

Neuromed raises funds to accelerate development of pain treatments

Neuromed Pharmaceuticals has completed a series E financing of US$53.3 million, which will allow the company to accelerate the development of its drugs to treat pain, including NMED-1077 (OROS Hydromorphone), a product for chronic pain that is in Phase III development.

Neuromed recently acquired the US marketing rights to NMED-1077, an extended-release formulation of hydromorphone, from ALZA (Johnson & Johnson). Current formulations of hydromorphone marketed in the US are immediate release, requiring dosing several times per day. NMED-1077 employs the OROS PUSH-PULL osmotic delivery system to release hydromorphone at a controlled rate over an extended period.

Neuromed is also evaluating two pathways for the development of new classes of oral pain drugs. In collaboration with Merck & Co, the company is researching compounds that are designed to block the N-type calcium channel, a target linked to pain signal transmission. Separately, Neuromed is also developing T-type calcium channel blockers for the treatment of acute and chronic pain, as well as other potential disorders such as epilepsy and hypertension.

Cannasat to commence Phase I study of CAT 310

Health Canada has approved Cannasat Therapeutics' clinical trial application for a Phase I study of CAT 310, its cannabinoid-based product that is designed to help manage neuropathic pain and other disorders.

This is a randomised, single-dose, crossover study comparing two different formulations of the drug in normal healthy male volunteers. The primary objectives of the trial are to evaluate the safety, tolerability and pharmacokinetics of the CAT 310 prototypes, with enrolment in Canada expected to begin in early October.

Icagen raises funds via Pfizer investment

Icagen has completed the previously-reported sale of 2,688,172 shares of common stock to Pfizer at a price of US$1.86 per share, resulting in gross proceeds to the former of approximately US$5 million. Icagen has an option to sell up to an additional US$10 million of common stock to Pfizer at the time of exercise, subject to certain terms and conditions, at any time during the 18 months following the execution of the purchase agreement.

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ANTICANCER PRODUCTSAbegrin

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Bristol-Myers SquibbKW-2871

Kyowa Pharmaceuticalmatuzumab

EMD Pharma/Merck/TakedaMDX-060

Medarexofatumumab

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UnitherRencarex

Wilex CentocorSGN-30

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Pfizer/Amgenvolociximab

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belimumabHuman Genome Sciences/GSK

certolizumab pegolUCB

golimumabCentocor/Schering Plough

HuMax CD-20 Genmab

tocilizumabChugai/Roche

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CNS Drug News

The purchase agreement was completed in conjunction with the formation of a collaboration between Icagen and Pfizer for pain and related disorders. After deducting transaction expenses payable by the company, Icagen intends to use the net proceeds from this private placement to fund its research and development programmes and otherwise for general corporate purposes.

TorreyPines initiates multiple-dose tezampanel trial

TorreyPines Therapeutics has initiated a multiple-dose, Phase I trial to evaluate the safety, tolerability and pharmacokinetics of tezampanel.

Tezampanel, an AMPA/kainate (AK) receptor antagonist that selectively binds to certain AK receptors to potentially block the transmission of pain signals, has been administered in single doses to more than 300 patients and healthy adults. Data from this trial will support the continued development of tezampanel for the treatment of migraine, as well as allow TorreyPines to consider expanding the compound's development into additional chronic pain conditions.

The double-blind, placebo-controlled trial will be conducted at one centre in the US. Approximately 30 healthy male and female volunteers, between the ages of 21 and 55 years, will be enrolled in sequential, dose-escalating cohorts and receive once-daily subcutaneous (sc) doses of placebo or tezampanel 40, 70 or 100mg for four consecutive days.

These same dose strengths, given as a single-dose sc injection, are currently being evaluated by TorreyPines in a Phase IIb trial of tezampanel for acute migraine that has completed enrolment; the company is on track to report top-line results in the fourth quarter of this year.

In five placebo-controlled, Phase IIa trials, tezampanel demonstrated proof-of-concept in multiple pain models. In a placebo- and active-controlled trial in patients with acute migraine, the compound, administered intravenously, achieved statistical significance on all primary and secondary endpoints traditionally required for regulatory approval. These endpoints included pain relief at two hours, pain-free at two hours, and relief of nausea, photophobia and phonophobia.

Zolmitriptan nasal spray effective for cluster headache

The results of a study published in the 28th August issue of Neurology (2007;69:821-826) have indicated that zolmitriptan nasal spray is safe and effective at rapidly treating cluster headaches.

The double-blind trial involved 52 people with cluster headache who used zolmitriptan nasal spray 5 or 10mg, or placebo to treat 151 separate cluster headache attacks. It was found that 63 per cent of people treated with the drug at the higher dose reported headache relief at 30 minutes, compared to 50 per cent of those taking the lower dose of zolmitriptan nasal spray and 30 per cent in the placebo group. Furthermore, the 10mg dose worked as quickly as ten minutes in some patients. Side effects were mild and no serious adverse events were reported during the study.

Zolmitriptan is currently marketed as Zomig by AstraZeneca, which sponsored this research. According to study author, Dr Alan M Rapoport, from the David Geffen School of Medicine at the University of California, Los Angeles, while the FDA has not approved zolmitriptan nasal spray for use in cluster headaches, it may someday be considered a first-line therapy.

Anesiva completes enrolment for Phase III Zingo trial in adults

Anesiva has completed enrolment in a Phase III study of Zingo (lidocaine) powder intradermal injection system to reduce the pain associated with peripheral venous access procedures in adults.

The study has enrolled 699 patients undergoing intravenous cannulation or venipuncture procedures at multiple centres in the US. Patients have been randomised to receive treatment with either Zingo or placebo approximately one to three minutes prior to the peripheral venous access procedure.

Zingo, a fast-acting topical, needlefree system for local analgesia, was approved by the FDA on 16th August, to reduce the pain associated with venous access procedures, such as intravenous insertions or blood draws, in children aged three to 18 years (see CNS 168). Anesiva expects to report results from the adult trial in October, with the goal of utilising the data to file an sNDA for the use of Zingo in adults.

Cadence completes enrolment in Phase III trial of iv acetaminophen

Cadence Pharmaceuticals has completed patient enrolment in a pivotal Phase III trial to evaluate its investigational product candidate, intravenous (iv) acetaminophen, for the treatment of acute pain following gynaecologic surgery.

Referred to as the IV APAP 301 Study, this randomised, double-blind, placebo-controlled trial has enrolled a total of 331 subjects at 27 sites throughout the US. Patients were treated with either iv acetaminophen or placebo in the 48-hour period following gynaecologic surgery.

The primary endpoint of the trial is analgesic efficacy, measured by reduction in pain intensity, compared to placebo. According to Cadence, with enrolment completed two months ahead of schedule, the company is on track to report top-line results of this study in early 2008.

Furthermore, Cadence has provided an update on its clinical development programme for iv acetaminophen, which consists of three pivotal Phase III efficacy trials, two safety studies and two pharmacokinetic (PK) studies, as follows:

Pivotal Phase III efficacy trials Enrolment statusTreatment of pain following gynaecologic surgery (IV APAP 301 Study)

Completed

Treatment of fever in adults OngoingTreatment of fever in adults comparing iv and oral administration

Ongoing

Other trials Enrolment statusAdult PKs CompletedAdult safety Initiation in fourth quarter of 2007Paediatric PKs OngoingPaediatric safety Initiation in fourth quarter of 2007

The company anticipates completing enrolment in the two remaining planned Phase III efficacy trials of iv acetaminophen by the end of 2007. Additionally, Cadence's licensor for iv acetaminophen, Bristol-Myers Squibb, is conducting a randomised trial of the product for marketing purposes in Europe in patients undergoing total hip replacement surgery. Cadence expects that data from this trial may



CNS Drug News

be available in 2008, however, it does not plan to rely on this trial as a pivotal efficacy study for its NDA submission. Assuming successful completion of the planned clinical trials, Cadence expects to submit a 505(b)(2) NDA to the FDA in the second half of 2008, requesting marketing approval of iv acetaminophen for acute pain and fever in adults and children.

Recruitment completed for Sativex Phase III trial in MS neuropathic pain

For details, see Neurodegenerative Disorders, Multiple Sclerosis - R&D Update.

Allergan/ExonHit compound to begin clinical trials

For details, see Neurodegenerative Disorders, Other Neurodegenerative Disorders - R&D Update.

PRODUCT NEwSDaiichi Sankyo obtains additional indication for fentanyl injection in Japan

As of 23rd August, Daiichi Sankyo Propharma has obtained approval in Japan for an additional paediatric indication for fentanyl injection 0.1 and 0.25mg.

Fentanyl injection is used in analgesia and sedation, as well as in anaesthesia and as an anaesthetic adjunct, but its use was contraindicated in Japan for paediatric patients aged two years and under because its safety in this group had not been established. However, because of the urgent clinical needs in this area, a physician-led Phase III trial was conducted in paediatric patients. On the basis of the results, the additional indication in paediatric patients, including infants aged two years and under, was filed for approval in September 2006.

FDA approves Watson and Actavis' generic Duragesic products

On 20th August, Watson Pharmaceuticals received final FDA approval of its ANDA for fentanyl transdermal system in 25, 50, 75 and 100mcg/hour strengths. The system is a generic equivalent to ALZA's (Johnson

& Johnson) Duragesic, which is indicated for the management of persistent, moderate-to-severe chronic pain that requires continuous, around-the-clock opioid administration for an extended period of time and cannot be managed by other means such as non-steroidal analgesics, opioid combination products or immediate-release opioids. Watson's product was launched immediately.

Actavis (via its acquisition of Abrika Pharmaceuticals) also received US clearance for its therapeutic equivalents of Duragesic in these strengths on the same date, with Lavipharm Group and Mylan Technologies having previously received approval of their versions. Mylan and ALZA are currently the only companies listed for an approved 12.5mcg/hour product. Actavis began distribution immediately.

AGREEmENT NEwSCephalon acquires rights to Amrix

Cephalon has signed an agreement to acquire North American rights to Amrix (cyclobenzaprine hydrochloride extended-release capsules) from ECR Pharmaceuticals.

Under the terms agreed, Cephalon will acquire the rights to Amrix for US$100 million cash and could also make future cash payments to ECR upon the achievement of certain cumulative net sales milestones. The transaction is expected to be accretive in 2008 and thereafter. Amrix was developed by Eurand for ECR using its proprietary Diffucaps technology. Eurand, as the licensor and exclusive manufacturer of the product, will now work with Cephalon to support the commercialisation of the product in the US. Eurand will receive royalty payments from Cephalon on Amrix sales.

Amrix is a once-daily, extended-release version of cyclobenzaprine, the active ingredient in Johnson & Johnson's Flexeril. Two dosage strengths of Amrix (15 and 30mg) were approved by the FDA in February, for short-term use as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Amrix provides relief from muscle spasm comparable to that with cyclobenzaprine taken three-times daily and currently has market exclusivity until the first quarter of 2010. There is also a pending US patent application that contains claims directed to the formulation of the product. Cephalon expects to launch the product early in the fourth quarter.

ANTI-EPILEPTICSR&D UPDATE

Study provides clues to origin of Lafora disease

For a century, scientists have known that Lafora disease is a progressive and deadly form of epilepsy caused by a build-up of carbohydrates in the brain. Although this type of epilepsy has been well described in patients, researchers have been at a loss to explain precisely why, on a molecular level, neurons begin to accumulate toxic amounts of carbohydrate.

However, research published in the 30th July issue of the Journal of Cellular Biology (2007;178:477-488) has offered a hint about the nature of this malfunction. A team at the University of California, San Diego

has shown that humans, plants and protozoa all seem to rely on the same basic cellular machinery to solve the problem of carbohydrate build-up. The paper outlines the common mechanism that humans and other organisms use to purge excess carbohydrates, as well as how this information could help to develop a treatment for Lafora disease.

PRODUCT NEwSQuestcor approves new strategy for HP Acthar Gel

Questcor Pharmaceuticals' Board of Directors has approved a new strategy and business model for HP Acthar Gel, a natural form of adrenocorticotropic hormone, which may affect its use in the

ANTI-EPILEPTICS

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CNS Drug News

treatment of certain diseases, including infantile spasms (IS) and multiple sclerosis (MS). Specifically, Questcor will initiate a new pricing model, create an expanded safety net for patients using Acthar and provide a group of medical science liaisons to work with healthcare providers who are administering the product.

Acthar is currently approved in the US for the treatment of MS exacerbations and other conditions. No drug is approved in the US for the treatment of IS, however, pursuant to guidelines published by the American Academy of Neurology and the Child Neurology Society, many child neurologists use Acthar to treat infants afflicted with this condition. In June 2006, Questcor submitted an sNDA to the FDA and is currently pursuing formal Agency approval for Acthar in

the treatment of IS. Previously, the FDA granted orphan designation to HP Acthar Gel for this indication, therefore if Questcor is successful in obtaining FDA approval for the IS indication, the company will also qualify for a seven-year exclusivity period.

Questcor's new strategy is intended to create an economic model that will allow it to support ongoing efforts to manufacture and distribute Acthar, to conduct any FDA-required studies, to continue the development of QSC-001, a unique, orally-disintegrating tablet formulation of hydrocodone and acetaminophen for the treatment of moderate-to-moderately severe pain, and to develop or acquire other drugs or drug candidates for neurological disorders or rare diseases.

EATING DISORDERSR&D UPDATE

Data support Histalean's use in obese women under 50 years of age

Obecure has reported the preliminary results of a Phase II trial designed to evaluate the efficacy and safety of Histalean (betahistine; formerly OBE101) for the treatment of obesity. According to the company, the results suggest a strong gender and age effect, and support the potential of the drug as a breakthrough anti-obesity agent in women aged 50 years or younger.

Histalean is comprised of betahistine, an H1 receptor agonist and

partial H3 receptor antagonist that is approved and marketed

worldwide, except in the US, for the treatment of vertigo. Obecure is repurposing betahistine for the treatment of obese individuals and for other weight management indications. The double-blind, placebo-controlled study included 281 patients (males and females aged 18 to 65 years) with a body mass index ranging from 30 to 40, and was conducted at 19 sites across the US. Subjects were randomised into one of four groups comparing the safety and efficacy of Histalean 16, 32 or 48mg/day versus placebo, over the 12-week treatment period.

Top-line results show that although there was weight loss in many of the patients, there were no statistically significant differences among any of the treatment arms versus placebo. However, a post hoc segmentation analysis revealed an important finding regarding the effect of age and gender on drug response. Analysis of the subpopulation consisting of females, aged 50 years or less, in the per-protocol cohort demonstrated a substantial difference between the

mean weight loss in the high-dose arm (48mg/day) versus the placebo arm; the result showed a trend towards statistical significance (p=0.06 at eight weeks and p=0.146 at 12 weeks). The effect was even more pronounced when the analysis was limited to non-hispanic women, aged 50 years or younger. At the end of week 12, the 25 women on Histalean 48mg had lost an average of 2.61kg (2.91 per cent) of their weight, versus 23 women on placebo, who lost 0.4kg (0.43 per cent) of their weight; this result was statistically significant (p=0.003).

However, the effect of ethnicity on drug responsiveness in the current analysis is still inconclusive, since the number of hispanic women in each study group was very small (four to five). Nevertheless, the trajectory of weight loss in this high-dose group continued over the entire study duration, up to and including the week 12 visit.

There were no drug-related serious adverse events (AEs) observed and the incidence of AEs in the treatment arms was comparable to that for patients in the placebo group. The only AE more common in the treatment group was headache (<10 per cent).

PRODUCT NEwSFDA approves Caraco's generic Adipex-P

On 21st August, the FDA approved Caraco Pharmaceutical Laboratories' ANDA for phentermine tablets 37.5mg, a bioequivalent to Teva Pharmaceutical Industries' Adipex-P. Phentermine is indicated only as short-term monotherapy for the management of exogenous obesity. Caraco plans to market its product to the generic pharmaceutical market immediately.

GENERAL DEVELOPmENT NEwSR&D UPDATE

Memory commences Phase I programme for R4996/MEM 63908

Memory Pharmaceuticals has dosed the first subject in the single ascending-dose study of its Phase I programme for R4996/MEM 63908, a partial agonist of the nicotinic alpha-7 receptor. Compounds acting on this receptor could be beneficial in the treatment of Alzheimer's disease and schizophrenia, as well as other psychiatric

and neurological disorders. The randomised, double-blind, placebo-controlled study will evaluate the safety, tolerability and pharmacokinetics of ascending doses of R4996/MEM 63908 in healthy adult male volunteers. The study will be conducted in Montréal, Canada, under a clinical trial application that Memory filed with Health Canada, and the company expects to complete it in the first quarter of 2008.

Furthermore, as part of the Phase I programme for R4996/MEM 63908, Memory is also planning to conduct a food interaction study in healthy adult male volunteers, plus a randomised, placebo-controlled,

EATING DISORDERS / GENERAL DEVELOPmENT NEwS

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single-dose study in elderly male and female volunteers. R4996/MEM 63908 is being developed as part of Memory's nicotinic alpha-7 receptor collaboration with Roche. Under the terms of the companies' agreement, the initiation of this Phase I trial triggers a US$2 million milestone payment from Roche.

ImaRx receives grant to study BBB permeability

ImaRx Therapeutics has received an approximately US$950,000 Phase I STTR grant from the National Institute of Neurological Disorders and Stroke to study changes in the permeability of the blood-brain barrier (BBB) with targeted microbubbles and ultrasound over a two-year

period. Although vital for normal brain function, BBB impermeability presents a problem when treating degenerative and malignant disorders of the CNS.

Under the terms of this grant, ImaRx will evaluate whether microbubbles and transcranial ultrasound can safely enhance drug delivery across this barrier. ImaRx, in collaboration with Dr Thomas Porter at the University of Nebraska Medical Center, will begin work on the grant in the autumn.

For an update on ImaRx' TUCSON study, see Cerebrovascular Disorders, R&D Update.

CONfERENCE LISTINGSCNS CONFERENCES - DECEMBER 2007

DATE CONFERENCE TITLE CONTACT TEL/FAX/E-MAIL3-6 Molecular Mechanisms of

Neurodegeneration, St Mary's Parish, Antigua & Barbuda

Dr Rhian Hayward Tel:Fax:E-mail:

44 122 369 600044 122 369 [email protected]

7-8 Advances in Clinical Neuroimmunology, Poznan, Poland

Prof Dr Jacek Losy Tel:Fax:E-mail:

48 618 691 58348 618 691 [email protected]

9-13 17th International Congress on Parkinson's Disease and Related Disorders, Amsterdam, the Netherlands

CPO Hanser Service, Paulsborner Strasse 44, 14193 Berlin, Germany

Tel:E-mail:

49 30 300 [email protected]

9-13 2007 Annual Meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, US

American College of Neuropsychopharmacology, 545 Mainstream Drive, Suite 110, Nashville, TN 37228, US

Tel:Fax:E-mail:

1 615 324 23601 615 324 [email protected]

24-31 6th Annual Pulmonary, Infectious Disease and Sleep Disorders Conference, Honolulu, HI, US

Sandra Barnhart Tel:Fax:E-mail:

1 800 422 07111 727 527 [email protected]

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

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CNS Drug News

Abrika Pharmaceuticals..................................................................................................19Accera ......................................................................................................................................10Actavis .....................................................................................................................................19Acura Pharmaceuticals ...................................................................................................16Allergan ...........................................................................................................................10, 19ALZA.................................................................................................................................. 17, 19Alzheimer’s Disease Cooperative Study .................................................................. 5Anesiva ...................................................................................................................................18AstraZeneca ...........................................................................................................11, 15, 18Baxter International ........................................................................................................... 5Bayer ..........................................................................................................................................8Biogen Idec .........................................................................................................................7, 8Biopartners .............................................................................................................................8Bioton ........................................................................................................................................8Bristol-Myers Squibb .......................................................................................................18Cadence Pharmaceuticals .............................................................................................18Cannasat Therapeutics ...................................................................................................17Caraco Pharmaceutical Laboratories ......................................................................20Cephalon ...............................................................................................................................19Compugen ..............................................................................................................................8Corcept Therapeutics ......................................................................................................15Daiichi Sankyo .....................................................................................................................19DOV Pharmaceutical ........................................................................................................13Duke University ..................................................................................................................14ECR Pharmaceuticals .......................................................................................................19Eisai .............................................................................................................................................6Elan .................................................................................................................................... 6, 7, 8Eli Lilly ...................................................................................................................1, 13, 14, 16Eurand .....................................................................................................................................19ExonHit Therapeutics ......................................................................................................10Families of Spinal Muscular Atrophy .......................................................................10Group Health Cooperative of Puget Sound .......................................................... 6Guildford Clinical Pharmacology ..............................................................................12GW Pharmaceuticals ..........................................................................................................8Helicon Therapeutics ......................................................................................................11Icagen ............................................................................................................................... 17, 18ImaRx Therapeutics ..................................................................................................12, 21Inflazyme Pharmaceuticals ..........................................................................................11Janssen Pharmaceutica .............................................................................................6, 16Johnson & Johnson ....................................................................................... 6, 16, 17, 19King’s College ......................................................................................................................10Lavipharm Group ..............................................................................................................19Mayo Clinic ..............................................................................................................................3McMaster University ..........................................................................................................9Meda AB .................................................................................................................................17Medicenna Ventures .......................................................................................................... 9

MedPointe.............................................................................................................................17Memory Pharmaceuticals .............................................................................................20Merck & Co ............................................................................................................................17Merck KGaA ........................................................................................................................3, 8Merck Serono ....................................................................................................................3, 8Mylan Technologies .........................................................................................................19Neuralstem ...........................................................................................................................11Neurochem ........................................................................................................................4, 5Neurocrine Biosciences ..................................................................................................13Neuromed Pharmaceuticals ........................................................................................17New York University ....................................................................................................4, 13Newron Pharmaceuticals ................................................................................................3Nymox Pharmaceutical .................................................................................................... 6Obecure..................................................................................................................................20Oregon Health & Science University .......................................................................13PDL BioPharma ..................................................................................................................... 7Pfizer .............................................................................................................................6, 17, 18Phase 2 Discovery..............................................................................................................13Protox Therapeutics ........................................................................................................... 9Questcor Pharmaceuticals ............................................................................................19Ranbaxy Laboratories ....................................................................................................... 6ReGen Therapeutics ........................................................................................................12Renovis ...................................................................................................................................11Roche .......................................................................................................................................21Shanghai Wanxing Bio-pharmaceuticals ..............................................................11Sinobiomed ..........................................................................................................................11Targacept ...............................................................................................................................15Teva Pharmaceutical Industries ............................................................................8, 20Tikvah Therapeutics..................................................................................................10, 13TorreyPines Therapeutics ..............................................................................................18Transition Therapeutics .................................................................................................... 6University of California ............................................................................................18, 19University of Cincinnati ..................................................................................................13University of Edinburgh .................................................................................................11University of Leeds ............................................................................................................. 9University of Michigan ....................................................................................................11University of Milan ............................................................................................................10University of Nebraska ....................................................................................................21University of North Carolina .......................................................................................... 1University of Santiago de Compostela ...............................................................1, 12University of Washington ............................................................................................1, 6Veterans Affairs Puget Sound Health Care System ............................................ 6Walko Medical Centre .....................................................................................................12Watson Pharmaceuticals ...............................................................................................19Weill Cornell Medical College ....................................................................................... 6

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AC-1202 ...................................................................................................................................10acetaminophen ................................................................................................... 18, 19, 20Adipex-P .................................................................................................................................20Alzhemed ................................................................................................................................4Amrix........................................................................................................................................19Aricept .......................................................................................................................................6AZD-103 ....................................................................................................................................6AZD3480 ................................................................................................................................15betahistine ............................................................................................................................20Biferonex .................................................................................................................................. 8cannabidiol ............................................................................................................................. 8CAT 310 ...................................................................................................................................17CGEN-54 ................................................................................................................................... 8clomipramine ...............................................................................................................13, 14Corlux ......................................................................................................................................15cyclobenzaprine ................................................................................................................19Cymbalta ................................................................................................................................16daclizumab ............................................................................................................................. 8desipramine .........................................................................................................................13donepezil .................................................................................................................................6duloxetine .............................................................................................................................16Duragesic ...............................................................................................................................19EHT/AGN001 .........................................................................................................................10ELND-005 ................................................................................................................................6fentanyl ...................................................................................................................................19galantamine ...........................................................................................................................6Gammagard .......................................................................................................................5, 6Histalean ................................................................................................................................20HP Acthar Gel ..........................................................................................................8, 19, 20hydrocodone .......................................................................................................................20hydromorphone ................................................................................................................17imipramine ...........................................................................................................................13indiplon ..................................................................................................................................13interferon beta-1a ...........................................................................................................7, 8IPL455,903 .............................................................................................................................11Ketasyn ...................................................................................................................................10lidocaine .................................................................................................................................18

LY156735 .........................................................................................................................13, 14LY2140023 ........................................................................................................................ 1, 14MEM 63908 ................................................................................................................... 20, 21mifepristone .........................................................................................................................15natalizumab .......................................................................................................................7, 8niacin .......................................................................................................................................16NMED-1077 ...........................................................................................................................17Nuvion....................................................................................................................................... 8NXY-059 ..................................................................................................................................11OBE101 ....................................................................................................................................20OxyADF............................................................................................................................16, 17oxycodone ............................................................................................................................16phentermine ........................................................................................................................20QSC-001 ..................................................................................................................................20quetiapine .............................................................................................................................15R4996 ............................................................................................................................... 20, 21Razadyne .................................................................................................................................6Rebif ...........................................................................................................................................8recombinant human kallikrein ...................................................................................11Risperdal ................................................................................................................................16risperidone............................................................................................................................16safinamide .............................................................................................................................. 3Sativex ................................................................................................................................8, 19Seroquel ..........................................................................................................................15, 16sodium phenylbutyrate .................................................................................................10TC-1734 ....................................................................................................................................15tetrahydrocannabinol ....................................................................................................... 8tezampanel...........................................................................................................................18TIK-201 .....................................................................................................................................10TIK-301 .....................................................................................................................................13tramiprosate.......................................................................................................................4, 5Tysabri ...................................................................................................................................7, 8visilizumab ..............................................................................................................................8Zingo ........................................................................................................................................18zolmitriptan ..........................................................................................................................18zolpidem ................................................................................................................................12Zomig ......................................................................................................................................18

COmPOUND INDEXCOmPOUND INDEX

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The £2.4 billion UK generics market is one of the world’s largest in terms of both size and generic penetration. In 2005 over 59% of prescriptions were

dispensed as generics, accounting for 26% of the market value. But fierce competition and price pressure are

turning up the heat. How will the market continue to grow?

The report answers key questions such as:What is the estimated value of the UK generic market now and in 2012?What is the current pricing and reimbursement situation for generic drugs and how might it change?The market is set to grow over the next 5 years – what will be the drivers?Which companies have marketing authorisation for amlodipine and how does the generic compare to the brand?Major companies in the UK generics industry are merging – will consolidation mean greater price competition?

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Key areas addressed:

5-year market forecast to 2012 for valueThe generics market in context of the whole pharmaceutical industryPricing issues and reimbursementPolitical, legal and economic assessmentInsightful review of 18 major domestic and foreign players in the marketDetailed listing of 18 leading products including prescription data, price comparisons and marketing authorisationsFocus on developing generic markets for statins and proton pump inhibitors

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www.espicom.com/ukgen

Monitoring central nervous system drug developments worldwide

CNS Drug News

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