cns issue 168

Monitoring central nervous system drug developments worldwide

CNS Drug News

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IN FOCUSThe current mood of the schizophrenia market

Page 3

R&D Highlights

Bayhill’s DNA vaccine against MS appears safe and potentially efficacious

0

Researchers identify active genes in ALSPage 11

CCK finding offers potential for mood disorder and epilepsy therapies

Page 28

PRODUCT HighlightsEMEA accepts MAA filing for SNT-MC17

Page 14

Solvay submits complete responses to Luvox FDA approvable letters; bifeprunox not approvable

Page 20

Anesiva receives FDA approval for ZingoPage 24

AGREEMENT HighlightsIcagen/Pfizer enter pact for pain and related disorders

Page 25

Par granted North American rights to ZensanaPage 27

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.

•

•Lucy Vann

[email protected]

Issue No. 168 23rd August 2007

Drugs denied to mild AD patients in UKA court in the UK has upheld the National Institute for Health and Clinical Excellence's (NICE) decision that drugs for Alzheimer's disease (AD) should only be prescribed to those in the moderate stage of the disease, denying their access to people with AD of mild severity.

In 2006, NICE recommended to the NHS that donepezil, galantamine and rivastigmine should only be considered as options in the treatment of people with moderate AD, while memantine was only recommended as part of clinical studies for people with moderately-severe to severe disease. This meant that patients newly diagnosed with mild AD were denied access to these medicines on the NHS. At the time it was announced, Eisai, the licence holder of donepezil, and Pfizer condemned the decision and called it ''perverse.''

Donepezil, marketed as Aricept by Eisai and co-promoted in the US with Pfizer, is a specific and reversible inhibitor of acetylcholinesterase (AChE). Galantamine, marketed as Reminyl in the UK and Republic of Ireland by Shire and as Razadyne in the US by Janssen Pharmaceutica (Johnson & Johnson), is a selective, competitive and reversible inhibitor of AChE. Rivastigmine, marketed as Exelon by Novartis, is an AChE and butyrylcholinesterase inhibitor. Forest Laboratories markets memantine as Namenda in the US, whilst Lundbeck markets the product as Ebixa, both under licence from Merz, which markets it as Axura/Akatinol in a number of markets worldwide. The drug is a voltage-dependent, moderate-affinity, uncompetitive NMDA-receptor antagonist that blocks the effects of pathologically-elevated tonic levels of glutamate that may lead to neuronal dysfunction.

The court's decision will certainly be a blow to the hopes of the pharmaceutical companies involved, patients and their families. Indeed, Neil Hunt, Chief Executive of the Alzheimer's Society (www.alzheimers.org.uk) has described the result as ''deeply disappointing for everyone in the early stages of Alzheimer's and their carers'' and suggested that people will be forced to deteriorate before they get the treatment they need. Hunt believes that NICE failed to listen to the views of thousands of carers who told them drug treatments make a huge difference to their lives.

From a financial point of view, this decision will impact the drug companies' revenues. For instance, Aricept is a hugely significant product for Eisai, with sales showing impressive growth year-on-year since its launch in 1997. In Europe, the treatment of AD is dominated by the use of AChE inhibitors such as Aricept, Exelon and Razadyne, while use of Ebixa has been slowly growing (source: CNS Drug Discoveries - What The Future Holds).

Furthermore, the decision certainly adds more fuel to the ongoing debate over the cost of newly-developed/on-patent drugs and the rights/needs of patients. Although the NHS in the UK has to manage its funds and evaluate drugs in relation to their effectiveness and cost, those patients with mild AD are left asking why they are not worth £2.50 a day.

©Espicom Business IntelligencePage � �3rd August �007

CNS Drug News

Drugs denied to mild AD patients in UK ................................................................................1IN FOCUS ............................................................3

The current mood of the schizophrenia market ...................................................................3NEURODEGENERATIVE DISORDERS ......................5PARKINSoN'S DISEASE - R&D UPDATE .......................................................5

Loss of two neuron types may trigger PD symptoms ..........................................................5BrainStorm moves closer to clinical testing of SC product for PD........................................6

PRoDUCT NEwS .......................................................................................6Higher dosage strength for Stalevo approved in the US ......................................................6

ALZhEIMER'S DISEASE - R&D UPDATE .......................................................6Multi-national study confirms Aricept's positive effects in severe AD ...............................6UCF research links APP, SCs and potential AD treatment .....................................................6Rochester team outlines method to reduce Abeta in the brain ..........................................7AD diagnostic patent issued in Europe .................................................................................8Study confirms role of metal ions in AD; DSMB clears continuation of Phase IIa PBT� trial ....8Effectiveness of AD-mimicking mouse breeds questioned.................................................8APNS/Lilly AD collaboration progresses ...............................................................................9

PRoDUCT NEwS .......................................................................................9Judicial review upholds NICE recommendation of drugs for moderate AD only ................9

AgREEMENT NEwS ..................................................................................10MRCT to humanise Intellect's Abeta-specific Abs for AD .....................................................10EPIX achieves discovery milestone in collaboration with GSK .............................................10

MULTIPLE SCLERoSIS - R&D UPDATE .........................................................10Bayhill's DNA vaccine against MS appears safe and potentially efficacious .......................10Eden Biodesign to develop vOX�:Fc ......................................................................................10Accentia files pre-IND application for Revimmune in refractory MS ..................................11Cytokine demonstrates oral efficacy of small-molecule MIF inhibitors .............................11Opexa receives European patent notification for T-cell vaccine ..........................................11

oThER NEURoDEgENERATIvE DISoRDERS - R&D UPDATE ..........................11Researchers identify active genes in ALS .............................................................................11SIRT1 activation shows potential for neurodegenerative diseases ....................................1�Study demonstrates relevance of HD models ......................................................................1�Motor neurons rescued by SC therapy in ALS model ...........................................................1�Study uncovers differences in neurons from ESC lines ........................................................1�KineMed raises funds to advance development of KM-801 for ALS ...................................13Tikvah granted ODS for sodium phenylbutyrate's use in SMA ............................................13

PRoDUCT NEwS .......................................................................................13Xenazina approved in Italy ....................................................................................................13EMEA accepts MAA filing for SNT-MC17 ...............................................................................14

AgREEMENT NEwS ..................................................................................14Medtronic/Alnylam advance drug-device combinations collaboration.............................14University of Alabama enters collaborative research pact with QRxPharma .....................14Tikvah licenses Navinta technology ......................................................................................14Paladin expands Canadian Elaprase distribution deal with Shire .......................................15

CEREBROVASCULAR DISORDERS .........................15R&D UPDATE ............................................................................................15

EC grants Chelsea two OMP designations for droxidopa .....................................................15Phase Ib trial of SRT501 in MELAS initiated ..........................................................................15

ANXIOLyTICS/SLEEP DISORDERS .........................15R&D UPDATE ............................................................................................15

Research identifies low expression of immune system gene in WBCs of narcolepsy patients ...15DSP discontinues AC-5�16......................................................................................................15

PRoDUCT NEwS .......................................................................................16Valeant begins distribution of Xyrem in Canada ..................................................................16Solvay submits complete responses to Luvox FDA approvable letters; bifeprunox not approvable .............................................................................................................................16

AgREEMENT NEwS ..................................................................................16sanofi-aventis/Chugai terminate Japanese marketing collaboration ................................16

ANTIDEPRESSANTS ............................................16R&D UPDATE ............................................................................................16

Gene variation increases chance of successful citalopram response ..................................16DOV �1,947 safe and well tolerated in Phase Ib study .........................................................16DSP discontinues AC-5�16......................................................................................................17

PRoDUCT NEwS .......................................................................................17FDA approves first escitalopram capsules ............................................................................17

PSyCHOTIC DISORDERS ......................................17R&D UPDATE ............................................................................................17

Johns Hopkins team develops mouse model of schizophrenia ...........................................17AstraZeneca releases R&D pipeline update ..........................................................................17

Gene polymorphism predicts better ADHD outcome in teens ............................................18Medistem proposes SC therapy for autism ...........................................................................18Modafinil shows potential for BPD .......................................................................................18Risperdal Consta compares favourably to oral Zyprexa .......................................................19Scientists describe genetic variation linked to predisposition to schizophrenia................�0

PRoDUCT NEwS .......................................................................................20Solvay submits complete responses to Luvox FDA approvable letters; bifeprunox not approvable .............................................................................................................................�0

AgREEMENT NEwS ..................................................................................20Noven to receive Daytrana sales milestone ..........................................................................�0Avanir completes sale of FazaClo to Azur .............................................................................�0

ANALGESICS/ANAESTHETICS ...............................21R&D UPDATE ............................................................................................21

Javelin initiates Phase III trial of intranasal ketamine ..........................................................�1FDA accepts Acrux' IND for Fentanyl MDTS ...........................................................................�1Encore reports positive preclinical data for ER ropivacaine gel ...........................................�1TorreyPines completes enrolment in Phase IIb tezampanel trial .......................................�1Hydra data reveal role of ion channel in pain receptor activation ......................................�1Merck/Neuromed discontinue development of pain drug candidate ................................��ReceptoPharm pain study produces positive results ...........................................................��Avigen initiates clinical development of AV411 in the US ....................................................��Verapamil for cluster headaches linked to heart problems .................................................��NeurAxon's NXN-188 safe and well tolerated; raises funds to advance pain therapeutics .....�3Cephalon to file Fentora sNDA following positive Phase III data .........................................�3AstraZeneca releases R&D pipeline update ..........................................................................�3

PRoDUCT NEwS .......................................................................................23FDA issues second approvable letter for Trexima .................................................................�3Sativex approved in Canada for cancer pain .........................................................................�4FDA requests more time to review Frova sNDA ....................................................................�4Eslax receives Japanese approval ..........................................................................................�4Anesiva receives FDA approval for Zingo ..............................................................................�4Vimpat MAA submitted for DNP ...........................................................................................�4Ranbaxy receives FDA approval for generic Norco/Vicodin/Lortab ....................................�4

AgREEMENT NEwS ..................................................................................24Ono obtains Japanese rights to CNS 7056 ............................................................................�4Paladin signs licensing agreement for Glide Pharma's Glide SDI ........................................�5Icagen/Pfizer enter pact for pain and related disorders ......................................................�5EKR acquires US rights to Pacira's DepoDur ..........................................................................�5ProStrakan enters agreements with Orexo and LG ..............................................................�5

ANTI-EPILEPTICS ...............................................25R&D UPDATE ............................................................................................25

Valeant completes enrolment in first retigabine Phase III epilepsy study .........................�5Ovation initiates clinical trial of iv carbamazepine ..............................................................�6

PRoDUCT NEwS .......................................................................................26FDA approves Cerebyx generics ............................................................................................�6

EATING DISORDERS ............................................26R&D UPDATE ............................................................................................26

Interim Phase I trodusquemine data presented ..................................................................�6DRUGS USED IN NAUSEA & VERTIGO ....................26AgREEMENT NEwS ..................................................................................26

ProStrakan enters agreements with Orexo and LG ..............................................................�6Par granted North American rights to Zensana ...................................................................�7

GENERAL DEVELOPmENT NEwS ..........................27R&D UPDATE ............................................................................................27

Lexicon's LX-6171 completes Phase I trials ...........................................................................�7Eisai updates clinical progress ...............................................................................................�7Neuren sets out plans for Hamilton acquisition ...................................................................�7CCK finding offers potential for mood disorder and epilepsy therapies .............................�8Pfizer set to triple its Phase III portfolio by �009 .................................................................�8Research offers hope for new antisense drug class .............................................................�8Noven completes JDS acquisition..........................................................................................�9

PRoDUCT NEwS .......................................................................................29FDA approves first generic Dantrium injection ....................................................................�9

AgREEMENT NEwS ..................................................................................29Neurocrine in-licenses valnoctamide isomers from Yissum ...............................................�9BrainStorm restructures agreement with Ramot ................................................................�9Valeant's candidate selection triggers payment to Ardea ..................................................�9

COmPANy INDEX ................................................30COmPOUND INDEX .............................................31

TABLE OF CONTENTSTABLE OF CONTENTS

©Espicom Business Intelligence�3rd August �007

CNS Drug News IN FOCUS

Schizophrenia is a psychiatric disorder that is characterised by a wide variety of symptoms, making the causes of the disease difficult to determine. Positive symptoms include behaviours such as hallucinations (visual and/or auditory), depression, abnormal thinking and delusions, while negative behaviours include social detachment, poor personal hygiene and an impaired ability to express emotion. Patients with the disorder tend to feel a mixture of these symptoms, with most not experiencing the full extent of the disease.

The World Health Organization estimates that approximately 1 per cent of the global population is affected by schizophrenia at some point in their lives. Prevalence rates tend to be higher in poorer urban communities, although there is some controversy as to whether this is because patients with untreated schizophrenia tend not to be able to remain in employment.

Because of its variety of symptoms, scientists have found it difficult to pin down a definitive cause of the disease, if it exists at all. Researchers in the field have found several genes that are associated with the disease, along with some anatomical brain differences compared to healthy controls. Many scientists have also noted structural differences in the brains of patients with schizophrenia compared to healthy controls, including the density of grey matter within the frontal and temporal lobes. It could be that in addition to a genetic susceptibilty, the disease requires several external events to occur before it develops.

Schizophrenia is typically associated with increased dopaminergic activity in the mesolimbic pathway, known as the dopamine hypothesis. Phenothiazines, a class of drugs that block dopamine function, have been found to reduce psychotic symptoms, lending support to the dopamine theory of the condition. Conversely, drugs such as amphetamines and cocaine, which increase dopamine levels in the brain, have been found to cause psychosis. Indeed, some medications for Parkinson's disease that act on these pathways have been known to induce psychosis when given at a dose higher than needed. Advances in imaging techniques have allowed scientists to demonstrate that in some cases, many dopamine receptors can be blocked with only a slight decrease in psychotic symptoms. However, it was noted that in such cases, psychosis had been present for between ten and 30 years. On a similar note, drugs that act to repress dopamine typically exert their action in minutes, yet the decrease in symptoms can take days or weeks to become evident, although it can be argued that it takes longer for changes in thought processes to occur.

A study conducted by researchers at Duke University has revealed that antipsychotics leave chemicals behind in the bloodstream of patients and that these trails are different depending upon the antipsychotic medication used (see CNS 163). The team speculates that some of these trails are responsible for metabolic side effects of the drugs, while others may provide clues as to the beneficial workings of the drug. The group hopes that such experiments may be useful in personalising treatments for the disorder.

Genetic link

Although many researchers speculate a genetic basis for schizophrenia, this has become notoriously difficult to support. Twin studies and other heritability studies in humans have shown an increased prevalence of the condition in those with first-degree relatives who also have it. However, such experiments do not eliminate environmental contributions to the disorder.

The role of the disrupted in schizophrenia 1 (DISC1) gene in the disorder is unknown. A team from the University of Edinburgh, Merck Sharp & Dohme (Merck & Co) and the University of Glasgow found that the gene encoding phosphodiesterase 4B (PDE4B) was disrupted in a patient with schizophrenia and a relative with the disease. cAMP, which is rendered inactive by PDEs, is a second messenger that is implicated in learning, memory and mood. The team demonstrated that DISC1 interacts with the UCR2 domain of PDE4B, leading to a dissociation of PDE4B from DISC1 because of the elevation in cellular cAMP.

Research conducted by Clinical Data's PGxHealth Division and published in Molecular Psychiatry (2007;12:572–580) found a link between schizophrenia and a cytokine receptor gene. A whole-genome scan revealed an effect of a novel region near to the CSF2RA gene, with sequencing identifying specific variants in the CSF2RA and IL3RA genes, both of which are associated with schizophrenia.

A group led by scientists from Shanghai Jiao Tong University identified the chitinase 3-like 1 (CHI31) gene as a potential schizophrenia susceptibility gene (see CNS 156). The team, whose research was published in the American Journal of Human Genetics (2007;80:12-18), suggests that genes involved in the body’s biological responses to adverse environmental stimuli are likely to be related to schizophrenia. The gene is located on the 1q32.1 chromosome, which has previously been demonstrated to have a weak correlation with schizophrenia.

Recently, a team from the University of Oxford in the UK isolated genetic variations in a DNA sequence close to a gene that produces the Neuregulin 1 (NRG1) protein. The researchers found that the genetic variation causes a gene to be overexpressed in the brain, but have stated that how the NRG1 gene, which is associated with schizophrenia, is affected remains unknown (for details, see Psychotic Disorders, R&D Update). Separately, researchers at the University College London have indicated that the pericentriolar material 1 (PCM1) gene has a role in schizophrenia. The team has linked the gene with orbitofrontal grey matter volumetric deficits.

IN FOCUSThe current mood of the schizophrenia market

Affecting approximately 1 per cent of the global population, schizophrenia is a psychiatric disorder with a number of speculated causes. This issue's In Focus investigates the possible genetic links with the disorder and describes the current market leaders, as well

as the more promising candidates in development for treating the condition.

©Espicom Business Intelligence �3rd August �007

CNS Drug News

Finally, scientists based at the University of North Carolina (UNC), at Chapel Hill, believe that they have identified a molecular mechanism that could be involved in the development of schizophrenia. The research, which was published in Genome Biology (2007;8:R27), suggests that the disease could be associated with altered microRNA (miRNA) profiles. The group found that 16 miRNAs were differentially expressed in the prefrontal cortex of subjects, compared to psychiatrically-unaffected individuals. It has previously been shown that miRNAs participate in regulating brain development and an increasing amount of research suggests that schizophrenia may be related to problems with synaptic plasticity.

Treatments

Many of the available drugs to treat schizophrenia have debilitating side effects that prevent patients from regularly taking their medication. There are two main types of antipsychotic medicine: typical antipsychotics, which were developed in the 1950s, and atypical antipsychotics, which generally cause fewer side effects. Typical antipsychotics are mostly effective in treating the positive symptoms of the disease, while atypical antipsychotics tend to be better at targeting the negative symptoms.

Research presented at the International Congress on Schizophrenia Research, held from 28th March to 1st April, in Colorado Springs, CO, suggested that as early as two weeks into antipsychotic treatment, clues can be obtained as to the efficacy of the medication. The team found that early non-response to antipsychotic medication was a strong predictor of later non-response to the medication. Early non-responders were less likely to achieve symptom remission, tended to view medication adherence as less beneficial and had a lower level of functioning, compared to early responders.

On 17th May, the FDA approved AstraZeneca's 5-HT2/D

2 antagonist, Seroquel XR, a once-daily formulation of quetiapine (previously known as

Seroquel SR). The approval was based on clinical data demonstrating that Seroquel 400, 600 and 800mg doses were effective and well tolerated in patients with acute schizophrenia. For details of AstraZeneca's progress with Seroquel, see Psychotic Disorders, R&D Update.

Johnson & Johnson's paliperidone is a full 5-HT2 antagonist and partial D

2 antagonist. The drug is available in two formulations: paliperidone ER

uses ALZA's (J&J) patented OROS extended-release delivery technology that releases drug into blood steadily over 24 hours, while paliperidone IM is a long-acting injectable version that uses nanocrystal technology to improve bioavailability. Janssen-Cilag's (J&J) Invega (paliperidone prolonged-release tablets), a once-daily medication, has been licensed in the UK.

First-generation typical antipsychotics include: Schering AG's (now Bayer Schering Pharma) Trilafon (perphenazine), J&J's Haldol (haloperidol), GlaxoSmithKline's Thorazine (chlorpromazine) and Abbott's 5-HT antagonist, Nipolet (zotepine). First-generation atypical antipsychotics include: Lundbeck/Novartis’ Clozaril (clozapine) and sanofi-aventis’ Solian (amisulpride).

The main side effects of second-generation atypical antipsychotics include:

increased risk of diabetes and hyperglycaemia;increased prolactin levels/heightened risk of hyperprolactinaemia;heightened risk of cardiac arrhythmias; andheightened risk of mortality in the elderly population.

Risperdal (risperidone), J&J's 5-HT2/D

2 antagonist, comes off patent in the US and Europe this year, while Abilify, Bristol-Myers Squibb/Otsuka's

5-HT1A

/D2 partial agonist/5-HT

2A antagonist, comes off patent in 2009. Seroquel, Eli Lilly's 5-HT

2/D

1/D

2/D

3 antagonist, Zyprexa (olanzapine), and

Pfizer's 5-HT1A

/2A

/2C

/D2/D

3/D

4 antagonist, Geodon/Zeldox (ziprasidone), all come off patent from 2011 onwards.

According to Espicom’s CNS Drug Discoveries – What The Future Holds report, Lilly dominated the market in 2005 for antipsychotics, with 28 per cent of all sales. J&J held 23 per cent and AstraZeneca held 18 per cent of all sales in this market. Pfizer and BMS were each responsible for 4 per cent of market sales. In 2000, Zyprexa was responsible for 55 per cent of all sales made in this market, but this figure had declined to 19 per cent in 2005, which is likely due largely to the medicine's side effects, along with the introduction of better-tolerated drugs. The report estimates that sales of Abilify will increase to US$2.1 billion by 2012, assuming that generics are launched in Europe in 2010 and in the US in late 2012.

Geodon has been shown in clinical studies to target both positive and negative symptoms of the disease, giving it an advantage over some other medications that act with more specificity. Espicom’s report forecasts that global sales of Geodon will reach approximately US$1 billion by 2012. For an update on Geodon's continued development, see General Development News, R&D Update.

A study published in the British Journal of Psychiatry (2007;191:131-139) demonstrated that Janssen-Cilag's Risperdal Consta (risperidone long-acting injection) compares favourably to oral Zyprexa (for details, see Psychotic Disorders, R&D Update). Risperdal is a more potent inhibitor of the negative symptoms of schizophrenia, however Espicom’s report anticipates that a generic risperidone will be launched by early 2008 and expects that sales will decline from US$4.1 billion in 2006 to less than US$1 billion by 2012. Furthermore, the report anticipates that global sales of Zyprexa will decline to US$1.6 billion by 2012 due to generic competition.

Drugs in development

Being co-developed by Pfizer and Organon (Akzo Nobel), asenapine is a Phase III compound that is expected to be launched in 2008. Espicom’s report anticipates that the drug, which is a 5-HT

15/5-HT

2/D

2 antagonist, has approximately a 70 per cent chance of reaching the market by 2008

and estimates that the drug could reach sales figures of approximately US$1.1 billion by 2012.

••••

IN FOCUS


CNS Drug News

Bifeprunox, a D2 partial agonist with 5-HT

1A agonist activity that is being developed by Wyeth/Solvay and Lundbeck, is a Phase III compound that

is expected to be launched in 2009. Espicom’s report predicts that the drug has a 69 per cent chance of reaching the market by 2009 and could reach sales of approximately US$871 million by 2012. For details of an FDA action letter for bifeprunox, see Psychotic Disorders, Product News.

The report anticipates that Dainippon Sumitomo Pharma's Phase III compound, blonanserin, has a 75 per cent chance of reaching the market and predicts that the product could achieve sales of approximately US$155 million by 2012, with 75 per cent of this revenue generated in Japan.

ACADIA Pharmaceuticals' ACP-103, a 5-HT2A

inverse agonist, D2/D

3 partial agonist, acetylcholine M

1 receptor agonist, is in Phase II development

for the treatment of schizophrenia. Also in Phase II is ACADIA's ACP-104 (N-desmethylclozapine), a metabolite of clozapine that combines M1

muscarinic agonism, 5-HT2A

inverse agonism and D2/D

3 partial agonism. The company initiated a Phase IIb trial with ACP-104 in June.

Memory Pharmaceuticals and Roche have an ongoing agreement for the development of nicotinic alpha-7 receptor agonist drugs for the treatment of numerous CNS disorders, including cognitive impairment associated with schizophrenia (CIAS). In June, the companies expanded their agreement to support plans to initiate a proof-of-concept Phase IIa study with MEM 3454 for the treatment of CIAS (see CNS 165).

BioLineRx initiated a Phase II trial with BL-1020 in July, in 60 patients with schizophrenia or schizoaffective disorder. The drug is a first-in-class, orally-bioavailable, GABA-enhanced antipsychotic that is being developed under a licence from Ramot and Bar-Ilan Research & Development, the technology transfer arms of Tel Aviv University and Bar-Ilan University, respectively. Data gathered with the compound, to date, demonstrate that it could offer an enhanced safety profile compared to currently-available antipsychotics, without compromising on efficacy. Phase IIa results are expected during the fourth quarter of this year.

In May, Lundbeck initiated Phase II trials with Lu 31-130 in patients with schizophrenia (see CNS 162). Positive preclinical results, along with the conclusion of a Phase I trial in healthy volunteers, contributed to this decision. Also in May, Lundbeck initiated Phase I trials with Lu AA39959 to investigate the compound's tolerability and pharmacokinetic profile. The product modulates ion channels in the brain via a novel mechanism of action and has demonstrated antipsychotic potential in preclinical models of schizophrenia.

Lexicon Pharmaceuticals has completed Phase I trials with LX-6171, its candidate for cognitive disorders that may be efficacious in treating CIAS (for details, see General Development News, R&D Update). Meanwhile, in June, Intra-Cellular Therapies initiated Phase I trials with ITI-007, a first-in-class dual 5-HT

2A antagonist and dopamine phosphoprotein modulator that is being developed for the treatment of schizophrenia (see CNS 165).

Finally, VistaGen Therapeutics has reported preclinical data for AV-101, a prodrug analogue of kynurenic acid that regulates NMDA receptors in the brain. The studies indicate that the product could be efficacious in treating schizophrenia and Parkinson's disease, with results suggesting that the drug is able to stimulate the firing of and activate dopamine neurons.

Conclusion

In light of the number of proposed aetiologies for schizophrenia, it makes sense that there should be a range of therapeutics that target different mechanisms. However, due to the debilitating side effects that most antipsychotics induce, better methods for diagnosing subtypes of the condition would be of great benefit. In May, Curidium Medica reported developing a blood diagnostic test that was able to identify subgroups of patients with schizophrenia and bipolar disorder. Personalised treatments that are able to identify the precise cause of the condition and detect a person's likelihood of experiencing serious side effects with specific medications would appear to be the way forward for this therapeutic area.

NEURODEGENERATIVE DISORDERSPARkINSON'S DISEASE - R&D UPDATE

Loss of two neuron types may trigger PD symptoms

Scientists from Emory University and the University of Georgia have suggested that the loss of two types of brain cells rather than just one may trigger the onset of symptoms associated with Parkinson's disease (PD).

The evidence, based on mouse models, shows a link between the loss of both norepinephrine and dopamine neurons and the delayed onset of symptoms associated with PD. It was originally thought that the loss of only dopamine neurons triggered symptoms. In light of this study, which was published in the 16th August online edition of PNAS (10.1073/pnas.0702753104), it has been suggested that simultaneously treating both the dopamine and norepinephrine loss could further ameliorate the symptoms of PD. People do not start showing symptoms of the disease until approximately 80 per cent of their

dopamine neurons are gone, which is when some sort of threshold is crossed. The study looked at what happens while the dopamine neurons are dying and people still appear to be healthy. The lack of symptoms until the death of most of the dopamine neurons suggested the existence of a system that can temporarily compensate for the loss of the dopamine.

It is known that norepinephrine is important for regulating the activity of dopamine neurons, therefore the researchers suspected that the dopamine and norepinephrine neurons function in concert. As the dopamine neurons start dying, the norepinephrine neurons compensate by signalling the surviving dopamine cells to dramatically increase their activity and the output of dopamine. Eventually, the norepinephrine neurons die, the surviving dopamine neurons lose their ability to release extra dopamine and symptoms start to appear.

To test their hypothesis, the researchers gave healthy, one-year-old mice the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine, at a dose that kills approximately 80 per cent of the dopamine cells,

NEURODEGENERATIVE DISORDERS


CNS Drug News

but observed no motor impairments in the mice. Surprisingly, when they tested mice that were unable to synthesise norepinephrine and have trouble releasing dopamine properly, they observed symptoms of PD, including resting tremor, hunched posture and deficits in co-ordinated movement. These results indicate that having a normal complement of dopamine neurons is not enough for normal motor function; norepinephrine also needs to be present to ensure proper dopamine release.

BrainStorm moves closer to clinical testing of SC product for PD

BrainStorm Cell Therapeutics has reported preliminary results from its first safety-supporting experiment, in which the company's human bone marrow-derived mesenchymal stem cells (SCs) were transplanted into a healthy monkey. The SCs had been induced to differentiate into neurotrophic factor-producing cells, according to the protocol developed by BrainStorm.

The monkey was treated daily with ciclosporin to prevent immune system rejection of the human-derived cells and was monitored for a variety of parameters for a period of three months. Throughout this phase, the monkey appeared well and in good health, with a normal appetite and no apparent change in physical or behavioural parameters. Blood tests, an MRI of the animal's brain and autopsy examination of the internal organs were also found to be normal.

Additionally, several human-originating cells were detected in sections of the monkey's brain by staining the sections with an antibody. The human transplanted cells were surrounded by macrophages, which may indicate a reaction of the monkey's immune system to the transplanted human cells and their initial rejection. BrainStorm's actual approach would involve autologous transplantation. With this strategy, no rejection is expected and there will be no need to use immunosuppressant drugs.

Two additional healthy monkeys recently underwent transplantation with BrainStorm's human SCs. The monkeys will also be monitored for a period of three months for collection of additional data; so far, the monkeys are in good health. Financing that BrainStorm received in July will help to move forward the preparations necessary for carrying out Phase I/II trials in patients with Parkinson's disease (PD), as well as providing the funding and support needed to conduct additional safety pharmacology studies.

For details of BrainStorm restructuring an agreement relating to the differentiation of bone marrow-derived SCs, see General Development News, Agreement News.

PRODUCT NEwSHigher dosage strength for Stalevo approved in the US

On 2nd August, the FDA approved a new higher dose strength of Stalevo (carbidopa+levodopa+entacapone), which is indicated for Parkinson's disease patients with signs and symptoms of end-of-dose "wearing off".

Stalevo, originated and manufactured by Orion, was approved by the FDA in June 2003 and is marketed in the US by Novartis Pharmaceuticals. The product is already available in 50, 100 and 150mg strengths, and the new dose is expected to be available in October.

The approval of the Stalevo 200mg dose (carbidopa 50mg+levodopa 200mg+entacapone 200mg) was based on a bioequivalence study with two tablets of Sinemet (levodopa+carbidopa) 100/25mg taken concomitantly with Comtan (entacapone 200mg), implicating the same safety and efficacy of the comparator.

ALzHEImER'S DISEASE - R&D UPDATEMulti-national study confirms Aricept's positive effects in severe AD

The results of a multi-national study have indicated that patients entering the severe stage of Alzheimer's disease (AD) can show improvement in cognition and global function when treated with Aricept (donepezil). The findings, which were published in the 31st July issue of Neurology (2007;69:459-469), further affirm those from a study published in The Lancet (2006;367:1057-65) indicating positive outcomes for nursing home patients who received treatment with donezepil during the severe stage of the disease.

The 24-week study included 343 men and women; 176 were given donezepil (10mg/day), while the rest received placebo. The study was conducted at 98 sites in Canada, the US, the UK, France and Australia in 2006, with patients living in the community and/or assisted-living settings.

Two well-established diagnostic tools were used to assess baseline capacities and to monitor progress at eight, 16 and 24 weeks. Patients on donezepil showed significant improvement in their total scores on the Severe Impairment Battery, and in the CIBIC-Plus, significantly more patients taking the drug remained stable or improved compared to those on placebo. Cognitive function stabilised or improved in 63 per cent of people taking donepezil, compared to 39 per cent of those taking placebo. Compared to the placebo group, those taking donepezil showed improvement in memory, language, attention and recognising their own name. The donepezil group also showed less of a decline in social interaction, skills needed to complete a jigsaw puzzle and arranging sentences compared to the placebo group.

Donezepil was generally well tolerated by patients. The most common adverse effects occurring more frequently in the treatment group were diarrhoea, insomnia, nausea, infection, urinary incontinence and pain.

Discovered by Eisai, donepezil is marketed as Aricept with Pfizer. In Canada, Aricept is marketed by Pfizer and was approved there for the symptomatic treatment of severe AD on 28th June, meaning that it is now approved for the symptomatic treatment of all stages of the disease (mild, moderate and severe).

For details of a judicial review on the use of drugs, such as Aricept, in the UK for AD of mild severity, see Product News, while for an update on Eisai's clinical progress, including a Phase III Aricept trial, see General Development News, R&D Update.

UCF research links APP, SCs and potential AD treatment

As reported in the 24th July issue of PNAS (2007;104:12506-12511), scientists at the University of Central Florida (UCF), Karolinska Institutet and the National Institutes of Health may have found a new way to treat Alzheimer's disease (AD). The researchers combined a technique for transplanting stem cells (SCs) into rats along with the recently-developed cholinesterase inhibitor, phenserine, which reduces the



CNS Drug News

amount of an AD-related plaque. The combination triggered the regeneration of neurons that are destroyed by AD and are necessary for healthy brain function.

Previous research showed that human neural SCs (hNSCs) exposed to high concentrations of secreted amyloid precursor protein (APP) in vitro differentiated mainly into astrocytes, suggesting that pathological alterations in APP processing associated with neurodegenerative conditions such as AD may prevent neuronal differentiation of hNSCs. Thus, the scientists hypothesised that successful neuroplacement therapy for AD may require regulating APP expression to favourable levels to enhance neuronal differentiation of hNSCs.

The researchers treated AD model mice producing human APP with phenserine, which is known to reduce the amount of APP in the brain. The APP level in the brains of treated mice was reduced by up to 50 per cent, which would provide optimal conditions for the hNSCs to become neurons. Under this environment, the research team found that SCs transplanted into the brain successfully produced neurons.

The scientists are now investigating whether a combination of phenserine and NBI-18, a compound that is being developed by lead UCF researcher, Professor Kiminobu Sugaya, which increases brain SCs by 600 per cent, could become another way to treat AD.

Rochester team outlines method to reduce Abeta in the brain

Scientists at the University of Rochester Medical Center are trying to rid the brain of the amyloid build-up in patients with Alzheimer's disease (AD) by draining the toxic protein away.

The method is outlined in a paper published in the 12th August online edition of Nature Medicine (10.1038/nm1635). The scientists show how the body's natural way of ridding the body of the substance is flawed in people with AD and demonstrate an experimental method in mice to repair the process, dramatically reducing the levels of the toxic protein in the brain and halting symptoms. The team is now working on developing a version of the protein that could be tested in people with the disease.

The approach does not take direct aim at the pathology that is ubiquitous in the AD patients' brains, where amyloid beta (Abeta) forms a toxic plaque. Instead, researchers take an indirect approach, focusing not on the brain, but rather on a protein that absorbs Abeta in the body, where it is regarded as harmless. The scientists found that if they increase the body's ability to soak up amyloid, the brain responds, causing levels of the substance in the brain to decrease.

The team concentrated its efforts around a protein known as sLRP (soluble low-density lipoprotein receptor-related protein). It was discovered that in healthy people, the protein binds to and neutralises anywhere from 70 to 90 per cent of the Abeta that is circulating in the body. The team also found that sLRP is doing only a fraction of the job in AD patients that it does in healthy people. Levels of sLRP in people with AD were approximately 30 per cent lower than in healthy people and the sLRP that was present was almost three-times as likely to be damaged compared to the same protein in healthy people. As a result, the AD patients had, on average, three- to four-times as much loose, unbound Abeta in their bloodstreams, high levels that would likely also be reflected in the brain.

The group decided to try to reduce Abeta levels in the body by synthesising an altered, super-potent form of sLRP that binds Abeta more efficiently than natural sLRP. In blood samples from patients

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CNS Drug News

with AD, the modified version of sLRP, known as LRP-IV, soaked up and virtually eliminated Abeta. The compound had an even more dramatic effect in mice with features of AD: LRP-IV lowered the levels of Abeta in their brains by 85 to 90 per cent. The mice that received the compound also had improved learning and memory compared to those that did not receive LRP-IV, and they had 65 per cent more blood flow in their brains in response to brain stimulation.

The team is now working with Socratech to create a form of LRP-IV that could be tested in people and it is hoped that such a product will be ready for trials within two years.

AD diagnostic patent issued in Europe

A patent application, entitled: "Neurosteroids as Markers for Alzheimer's disease," has been granted by the European Patent Office. Patent No. 1254251, which took effect on 15th August, protects the invention of a quick and simple blood test that is capable of predicting and leading to an early diagnosis of Alzheimer's disease (AD). The novel innovation presents dehydroepiandrosterone as the biological marker to detect AD and other neurodegenerative diseases. The patent has been exclusively licensed to Samaritan Pharmaceuticals by Georgetown University.

Samaritan is planning to take the appropriate steps to fulfil patent registration requirements in the following European countries: Austria, Belgium, Switzerland, Liechtenstein, Germany, Spain, France, the UK, Ireland, Italy, the Netherlands and Sweden.

Study confirms role of metal ions in AD; DSMB clears continuation of Phase IIa PBT2 trial

Research published in the 14th August edition of PNAS (2007;104:13313-13318) by Emory University and University of Georgia scientists has confirmed the pivotal pathological role of metal ions in Alzheimer's disease (AD) and potentially other major neurodegenerative disorders.

The multi-institutional team has shown how interactions between amyloid beta (Abeta) and the biological metals, copper and zinc, can induce conformational alterations to the Abeta protein, causing it to adopt a multitude of toxic forms.

The investigators noted that subtle variations in the chemical environment of the brain can radically influence the binding of copper to a specific sequence of Abeta to generate both fibrillar and non-fibrillar (oligomeric) forms of the protein. The oligomeric forms of Abeta, in particular, are currently the subject of great interest in AD research as the best validated therapeutic target in the disease. The team also emphasised that the findings have relevance to other neurodegenerative conditions, including Parkinson's disease, where metal binding is believed to modulate or induce the pathological aggregation of proteins.

Previously, scientists at Prana Biotechnology have promoted the concept that changes in brain chemistry associated with the ageing process cause subtle fluctuations in the regulation of copper, zinc and iron, permitting toxic interactions with the Abeta protein. According to Prana, the PNAS study lends further endorsement to the company's therapeutic approach in neurodegeneration, which is to intercede in the metal-dependent process of target protein aggregation. Prana's therapeutic approach uses MPAC (metal protein attenuating compound) technology, comprising orally-bioavailable small molecules that specifically target such pathological interactions. PBT2, the company's lead compound, was designed to inhibit the formation of toxic Abeta oligomers resulting from interactions with copper

and zinc. PBT2 is currently in a Phase IIa AD trial, meanwhile, further leads from the MPAC library are currently being validated for clinical development in other neurodegenerative disorders.

In addition...

An independent Data Safety Monitoring Board (DSMB) has reviewed blinded data from over 50 patients and confirmed that Prana's Phase IIa trial of PBT2 in patients with early AD is safe to continue as per the original protocol. A total of 55 patients (or approximately 70 per cent of the planned 80 patients) have been randomised and 30 patients have completed dosing, with no treatment-related serious adverse events or withdrawals. As planned, patient dosing is expected to be completed by the end of 2007.

This is a double-blind, placebo-controlled, safety and tolerability study of PBT2 in patients with mild forms of AD. In addition, the trial is investigating the effect of PBT2 on multiple cerebrospinal fluid (CSF) and blood biomarkers that have been directly associated with the aetiology of AD. Outcomes will include measures of CSF Abeta and tau levels, as well as neurocognitive and behavioural changes.

Effectiveness of AD-mimicking mouse breeds questioned

A research team, including scientists from Heinrich-Heine University and the University of Mainz, has indicated that recently-developed mouse breeds that mimic the symptoms of Alzheimer's disease (AD) may not be as effective as previously assumed. According to the results, which were published in the 24th August issue of the Journal of Biological Chemistry (2007;282:24504-24513), in some mouse breeds, drugs that had been shown to reduce levels of amyloid beta (Abeta) had only minor or no effect on these mice.

Most compounds being developed for AD try to prevent Abeta peptides from aggregating and forming plaques. To reduce the amount of Abeta, the compounds are tested for their ability to block gamma secretase or reduce its activity. The compounds are tested on mice that carry mutations in the gene that produces amyloid precursor protein (APP) proteins, leading to an excess of APP, which, when cleaved, generate too many Abeta peptides. New mouse breeds have recently been created to also carry mutant genes for the protein, presenilin, which is part of gamma secretase. These mutations cause gamma secretase to cut APP in a slightly different way than in normal mice, which also leads to an accumulation of Abeta peptides. Mouse breeds that carry both APP and presenilin mutations develop symptoms earlier and the disease has a more aggressive course.

In the new study, the researchers noticed that chemical compounds that had been shown to reduce Abeta deposits did not affect some of these new mouse breeds. The findings indicate that these mouse breeds may not reflect what may really happen in the brains of patients with AD if they were treated with such compounds in future clinical studies. Indeed, these compounds may seem to be ineffective on these mice, while it is actually the mouse breed that is to blame.

The researchers suggest using mouse breeds that carry only APP mutations for further studies of compounds that block or reduce the activity of gamma secretase. These breeds are probably more reliable than the ones that carry both APP and presenilin mutations, because they cause less aggressive symptoms.

The scientists also propose creating a mouse breed in which the presenilin mutation does not affect both members of the pair of chromosomes that carry the gene (as is the case in current transgenic mice), but only one of the chromosomes. Such a breed,



CNS Drug News

called a “knock-in” mouse, would reflect the genetic condition of approximately 5 per cent of patients with AD. In these patients, the origin of early-onset familiar AD is mostly genetic and mutations, including the presenilin one, are carried by only one chromosome in a pair. So far, scientists have created only a few mouse breeds with a mutation on one chromosome; it is thought that such breeds would probably better reflect what actually happens in the brains of patients with AD.

The researchers are now planning to investigate how presenilin mutations cause Abeta peptides to be overproduced and to understand how promising chemical compounds block gamma secretase or reduce its function.

APNS/Lilly AD collaboration progresses

Applied NeuroSolutions (APNS) has provided an update on the progress of its collaboration with Eli Lilly to develop drugs that will halt the progression of Alzheimer's disease (AD) by interfering with the early stages of tau pathology.

The collaboration management, working teams and external resources are up and running, with all key assets and proprietary tools having been transferred to support ongoing work by Lilly, Dr Peter Davies (a Founding Scientist at APNS) and APNS. Lilly is providing substantial resources to the collaboration.

Progress on a proprietary APNS target, the first tau-related target to be advanced by the collaboration, has been described as 'rapid' by Lilly management. High-throughput in vitro and cell-based screens have been established, as has a correlation between the in vitro and cell-based potency of active compounds. Additionally, multiple compounds that have been selected from the hits successfully cross the blood-brain barrier.

The APNS proprietary target successfully passed its first internal milestone in the second quarter of 2007 and is on schedule for the next key internal milestone by the end of the year. APNS anticipates achieving its first paid milestone in late 2008/early 2009.

PRODUCT NEwSJudicial review upholds NICE recommendation of drugs for moderate AD only

A legal challenge to the recommendation of the UK's National Institute for Health and Clinical Excellence (NICE) that drugs for Alzheimer's disease (AD) should only be prescribed to those in the moderate stage of the disease has failed.

In April, the High Court granted Eisai, the licence holder of Aricept (donepezil), and Pfizer, its co-promotion partner, permission to proceed to a Judicial Review in order to challenge NICE's decision to refuse NHS support of drugs for new patients in the UK with AD of mild severity (see CNS 159).

The judge ruled in favour of NICE on five out of the six grounds bought in court, including finding that:

NICE did appropriately take into account the benefits these drugs bring to carers;NICE appropriately reflected the costs of long-term care in its calculations;NICE did not breach principles of procedural fairness by providing a "read-only" version of the economic model;

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

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

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

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

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CNS Drug News

NICE was not irrational in concluding that there is no cumulative benefit to patients after six months of treatment with these drugs; andNICE's assessment and consideration of the AD 2000 study was not irrational.

The judge ruled against NICE on one of the six grounds bought in court: that NICE had breached its duties under the Disability Discrimination Act and the Race Relations Act, by not offering specific advice regarding people with learning disabilities and those for whom English is not their first language in its technology appraisal guidance.

As a result of the decision, NICE's guidance stands and the drugs continue to be recommended only for people with moderate AD. With regard to the one ruling against it, NICE stated that it was always the organisation's intention that people with learning disabilities or whose first language is not English should have equal access to the drugs in the moderate stage of AD. NICE will re-issue its guidance to the NHS to make this clear.

For details of Aricept studies, see R&D Update and General Development News, R&D Update.

AGREEmENT NEwSMRCT to humanise Intellect's Abeta-specific Abs for AD

Medical Research Council Technology (MRCT) has entered into an agreement under which it will use its proprietary technology and advanced know-how to humanise Intellect Neurosciences' amyloid beta (Abeta)-specific monoclonal antibodies (Abs) for the treatment of Alzheimer's disease (AD). The Abs are intended to be used as a form of passive immunisation to promote clearance from the brain of the endogenous soluble AD toxin, Abeta.

Under the terms agreed, Intellect will pay MRCT milestone payments related to the development and commercialisation of the humanised Abs and a royalty based on sales of the resulting drug products. Intellect is the holder of patents in Japan and other countries related to Abs, and methods of treatment for AD. Intellect believes that free-end-specific Abs, such as those it is developing, reduce the risk of triggering adverse reactions because of their specificity.

EPIX achieves discovery milestone in collaboration with GSK

EPIX Pharmaceuticals has achieved an initial milestone under its collaboration with GlaxoSmithKline related to the first of three discovery-stage programmes. Using its proprietary, integrated computational-medicinal chemistry approach to drug discovery, EPIX has identified three lead candidates that will move forward into lead optimisation in this first collaborative G-protein coupled receptor (GPCR) discovery programme. Under the collaboration, EPIX is entitled to receive a US$3 million milestone payment from GSK in the next 30 days. The companies have agreed upon the three discovery programme targets and are making significant progress on each programme.

EPIX and GSK entered into the worldwide, multi-target strategic collaboration in December 2006, to discover, develop and market novel medicines targeting four GPCRs for the treatment of a variety of diseases, including EPIX' novel 5-HT

4 partial agonist programme, PRX-

03140, which is in early-stage clinical development for the treatment

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of Alzheimer's disease. As part of the collaboration, EPIX received total initial payments of US$35 million, including US$17.5 million through the purchase of its common stock at a premium, and may be eligible to earn up to US$1.2 billion in milestones across the four GPCR programmes. Under the terms agreed, EPIX is also entitled to receive tiered double-digit royalties of sales by GSK on all collaboration-developed product sales.

mULTIPLE SCLEROSIS - R&D UPDATEBayhill's DNA vaccine against MS appears safe and potentially efficacious

According to research published in the 13th August online issue of the Archives of Neurology (10.1001/archneur.64.10.nct70002), a newly-developed DNA vaccine, BHT-3009, appears to be safe and may produce beneficial changes in the brains and immune systems of individuals with multiple sclerosis (MS).

Researchers at the Montréal Neurological Institute and colleagues tested Bayhill Therapeutics' experimental vaccine, which encodes a full-length human myelin basic protein. Between 2004 and 2006, the researchers administered the vaccine to 30 patients with relapsing-remitting or secondary-progressive MS who were not taking any other disease-modifying drugs.

For enrolment, the patients were also required to have either one to five gadolinium-enhancing lesions on screening brain MRI, a relapse in the previous two years, or disease worsening in the previous two years. After one, three, five and nine weeks, participants received intramuscular injections of placebo or BHT-3009 (0.5, 1.5 or 3mg), with or without atorvastatin 80mg. After 13 weeks, participants who initially received placebo received four injections of BHT-3009.

There were no increases in clinical relapses, disability, drug-associated laboratory abnormalities, adverse events, or the number and volume of contrast-enhancing lesions on brain MRI with BHT-3009 compared to placebo treatment. In fact, there was a trend toward a decrease in the number and volume of contrast-enhancing lesions in the brains of patients treated with BHT-3009 compared to placebo.

The vaccine also produced beneficial antigen-specific immune changes, consisting of a marked decrease in the proliferation of interferon gamma–producing, myelin-reactive CD4+ T-cells from peripheral blood and a reduction in titres of myelin-specific auto-antibodies from cerebral spinal fluid, as assessed by protein microarrays. Interestingly, the researchers did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone. Based on these results, a randomised, Phase IIb trial with BHT-3009 in approximately 290 patients is under way.

Eden Biodesign to develop vOX2:Fc

Eden Biodesign has been selected by the University of Birmingham in the UK to develop and produce vOX2:Fc, a novel therapeutic candidate for the treatment of autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis.

This novel drug candidate is being investigated by Dr David Blackbourn and his research team, and has attracted interest from a number of biotech and pharmaceutical companies. According to Blackbourn, clinical applications for this novel therapy could range from autoimmune diseases, such as rheumatoid arthritis, to asthma and allergy.



CNS Drug News

Accentia files pre-IND application for Revimmune in refractory MS

Accentia Biopharmaceuticals has filed a preliminary IND (pre-IND) application with the FDA for Revimmune (high-dose cyclophosphamide) in the treatment of refractory multiple sclerosis (MS). The company has requested a meeting with the Agency within the next 60 days to discuss a proposed pivotal Phase III trial involving approximately 270 patients with relapsing-remitting MS, with a primary endpoint of improvement in function (reversal of disability). According to Accentia, its proposal to use the restoration of neurologic function as the endpoint will be the first filed with the FDA.

Based on a clinical study at the Johns Hopkins University School of Medicine, which showed a 42 per cent average improvement in function, the company believes that Revimmune holds the potential to restore function in many patients who have acute deficits due to MS. In addition, it believes that the long-term follow-up with patients in the proposed 48-week trial will demonstrate that Revimmune induces not only a reduction of the risk of exacerbations, but potentially, also long-lasting remissions and/or cures in patients with MS.

Developed by a team at Johns Hopkins, Revimmune temporarily eliminates peripheral immune cells, including the immune cells causing the autoimmunity, while selectively sparing haematopoeitic stem cells (SCs) in the bone marrow. Investigators at Johns Hopkins discovered that SCs uniquely have high levels of a particular protective enzyme that can be measured in advance of therapy, which makes them impervious to Revimmune, and allows the surviving SCs to give rise to a new immune system over two to three weeks. The newly-reconstituted peripheral immune system typically lacks the misdirected immunity to self-antigens.

Revimmune can be administered as an in- or out-patient infusion for four hours per day for four consecutive days. The treatment is intended to allow patients to recover at home while their immune system reconstitutes itself over a two- to three-week period. Revimmune includes a risk-management programme to enhance patient safety by ensuring appropriate patient selection, supportive care and tracking of outcomes data.

Cytokine demonstrates oral efficacy of small-molecule MIF inhibitors

Cytokine PharmaSciences has reported that recent experiments with its small-molecule macrophage migration inhibitory factor (MIF) inhibitors demonstrated oral efficacy in animal models of multiple sclerosis (MS) and arthritis. Based on these results, the company is advancing one of these compounds into preclinical development.

MIF is linked to many conditions, including arthritis, inflammatory bowel disease, asthma, cancer and sepsis, as well as other infections and autoimmune disorders. Neutralisation of MIF biological activity has been shown to have a protective effect against these diseases. Cytokine has an extensive patent portfolio focused on MIF, covering various methods for neutralisation, including small molecules.

These compounds were shown to be effective in animal models of MS and arthritis when administered orally. The MS animal experiments were conducted in the laboratories of Drs Abhay Satoskar and Caroline C Whitacre, both of Ohio State University. According to Satoskar, the therapeutic efficacy of these compounds was positive, with no outward signs of toxicity, and these findings indicate that small-molecule MIF inhibitors are viable drug candidates for treating

other autoimmune and inflammatory diseases in which MIF has been identified as a pathogenic factor. The inhibitors were especially effective in treating disease that had already started.

Opexa receives European patent notification for T-cell vaccine

Opexa Therapeutics has received notification that the European Patent Office intends to issue a patent for "Autologous T Cell Vaccine Materials and Method." This patent application is related to a unique method-specific approach for generating a T-cell vaccine that attacks what is believed to be the underlying cause of multiple sclerosis (MS). It is expected that the patent will be granted within the next six months.

Studies have indicated that T-cell vaccination with peripheral blood-derived autologous myelin peptide selected T-cells in MS patients resulted in the in vivo induction of CD8+ cytotoxic T-cells and CD4+CD25+FoxP3 regulatory T-cells (Tregs) specific for T-cell vaccine. The induction of anti-idiotypic cytotoxic CD8+ effector T-cells and anti-ergotypic CD4+CD25+FoxP3-positive Tregs is believed to provide a therapeutically effective dual mechanism of protection to patients treated with Tovaxin, an investigational T-cell vaccine that is currently in a Phase IIb trial.

The observed regulatory immune responses have been shown to collectively correlate with clinical improvement in treated patients. Patients treated in Opexa's open-label, Phase I/II studies have experienced an approximately 90 per cent average reduction in annualised relapse rate, minimal side effects and observed improvement in average EDSS scores.

OTHER NEURODEGENERATIVE DISORDERS - R&D UPDATE

Researchers identify active genes in ALS

A group led by researchers at the Translational Genomics Research Institute has conducted a whole-genome analysis and identified more than 50 genetic abnormalities in people with sporadic amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), a discovery that provides expanded opportunities for developing therapies to treat this disorder.

The researchers, whose work was published in the 1st August online issue of the NEJM (10.1056/NEJMoa070174), conducted the analysis using almost 767,000 SNPs found in 386 white patients with sporadic ALS and 542 neurologically-normal white controls. The associations of SNPs with sporadic ALS were confirmed in two independent replication populations.

The investigators identified ten genetic loci that are significantly associated (p<0.05) with sporadic ALS in three of the independent patient and control series, plus an additional 41 loci that had significant associations in two of the three series.

The team identified genes likely to play a role in cell function that controls nerve adhesion, offering a major new avenue for ALS research. The findings indicate that these genes produce a molecular adhesive that attaches motor neurons to muscle. It appears that in ALS, the nerve is able to peel off the muscle and, when that occurs repeatedly, the nerves die.


©Espicom Business IntelligencePage 1� �3rd August �007

CNS Drug News

SIRT1 activation shows potential for neurodegenerative diseases

The activation of SIRT1, a member of the sirtuin family of enzymes, has been shown to be neuroprotective in an animal model of optic neuritis, one of the first signs of multiple sclerosis. The work is significant because it shows that a SIRT1 activator is neuroprotective and thus has the potential to be therapeutic for a range of neurodegenerative diseases of ageing.

Sirtuins are a recently-discovered class of enzymes that appear to affect the ageing process in mammals, and increase the number and function of mitochondria. According to the findings, which were published in the August issue of Investigative Ophthalmology and Visual Science (2007;48:3602-3609), resveratrol, a SIRT1 activator, reduced the loss of retinal ganglion cells and preserved axonal function in a preclinical model of optic neuritis. A single intravitreal dose of SRT501, Sirtris Pharmaceuticals' proprietary formulation of resveratrol, was sufficient for neuroprotection. Furthermore, this neuroprotective effect was shown to be SIRT1-dependent because it was blocked by sirtinol, a SIRT1 inhibitor. For details of a Phase Ib trial with SRT501, see Cerebrovascular Disorders, R&D Update.

Study demonstrates relevance of HD models

An international team of researchers, led by a scientist from Ecole Polytechnique Fédérale de Lausanne in Switzerland, has published a benchmark study showing that gene expression in several animal models of Huntington's disease (HD) closely resembles that of human HD patients. The results, published in the 1st August issue of Human Molecular Genetics (2007;16:1845-1861), validate the applicability of using animal models to study human disease and may have important consequences for the pertinence of these models in preclinical drug testing.

Motor neurons rescued by SC therapy in ALS model

A team of scientists from the University of Wisconsin-Madison has shown that it is possible to rescue the dying neurons characteristic of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease).

The work, conducted in a rat model of ALS and published in the 1st August online edition of PLoS ONE (10.1371/journal.pone.0000689), shows that stem cells (SCs) engineered to secrete a key growth factor can protect the motor neurons that waste away as a result of the disease. However, while the motor neurons within the spinal cord are protected by the growth factor, their ability to maintain connections with the muscles they control was not observed. At the early stages of disease, the researchers saw almost 100 per cent protection of motor neurons, but when they looked at the function of these animals, they saw no improvement; the muscles were not responding.

In the study, neural progenitor cells derived from human foetal tissue were engineered to secrete glial cell line-derived neurotrophic factor (GDNF), an agent that has been shown to protect neurons, but is very difficult to deliver to specific regions of the brain. The engineered cells were then implanted in the spinal cords of rats afflicted with a form of ALS.

GDNF has a very high affinity for motor neurons in the spinal cord. When implanted, the GDNF-secreting cells survived well and in 80 per cent of the animals, the team saw maturing transplants. In fact, the implanted cells demonstrated an affinity for the areas of the spinal cord where motor neurons were dying.

The Wisconsin team transplanted the cells on one side of the spinal cord and used the untreated side to compare the affects of the transplanted cells and their chemical secretions. The areas where the researchers saw the human cells were the only areas where protection of motor neurons was observed. However, while the motor neurons exposed to GDNF were protected, the team was unable to detect the connections between the neurons and the muscles they govern. Even in animals that had lots of motor neurons surviving, the researchers did not see the muscle connection, which explained why they did not see functional recovery.

Although the obvious next step in the research is to try and determine the reasons why the protected motor neurons are unable to connect with muscles, the work is thought to further support movement toward clinical trials. Indeed, the cells are believed to be safe and do increase the survival of the motor neurons, which may be very important for patients who lose neurons every day. However, it was noted that it is not a trivial intervention, as a hole has to be drilled in the spinal cord to deliver the cells releasing GDNF. Nevertheless, there are few options for these patients and the researchers plan to continue to move forward with this approach.

Study uncovers differences in neurons from ESC lines

In comparing neurons generated from two National Institutes of Health-approved embryonic stem cell (ESC) lines, scientists have uncovered significant differences in the mature, functioning neurons generated from each line. The discovery, which was published in the 10th August online edition of PNAS (10.1073/pnas.0706199104), implies that culture conditions during ESC generation, which have yet to be identified, can influence the developmental properties of human ESCs. Furthermore, the report also describes a new technique for producing functioning neurons from SCs that may be important for creating models of human neurodegenerative diseases.

Yi Sun, an SC biologist at the University of California, Los Angeles, and her colleagues developed procedures to differentiate the two SC lines first into neural progenitor cells and then into mature neurons, and were also able to purify those neurons for study. To investigate how the neurons functioned, the researchers developed a culture technique that induced the newly-produced neurons to establish synapses with one another. Through functional analyses of these neurons, the team found that the two ESC lines differentiated into two distinct types of neurons that are found in different parts of the brain.

The researchers next performed electrophysiological studies of the synaptic connections between the neurons. They found that the neurons derived from the two cell lines have completely different properties in terms of what type of synapses they develop and over what time course this happens during culture. In addition, the studies showed that the neurons derived from the two cell lines used different neurotransmitters to communicate with one another.

Sun and her colleagues also compared the microRNAs (miRNAs) produced by the two types of neurons. Their analysis showed that as the ESCs matured into neural progenitors and neurons, the expression of the miRNA genes specific to ESCs dropped thousands of times and those specific to brain cells increased thousands of times. When the researchers compared the two lines, they found differences in miRNA gene expression that might contribute to this neuronal bias in the lines. It is thought that the differences among ESC lines could have implications for potential treatments using the cells. For example, if a motor neuron disease is to be treated, those types of neurons are needed, whereas if it is a forebrain disease such as Huntington's, ESCs are needed that differentiate into that type of neuron. The differences



CNS Drug News

in neurons produced by cell lines may offer both advantages and disadvantages for treatment. On the one hand, it may be good to have ESCs with a particular propensity for differentiation, because it may make it easier to get certain types of tissue. On the other hand, it may also limit the ability of these ESCs to fully replicate those types of tissues.

Furthermore, according to Sun, her technique for differentiating ESCs into mature neurons is likely to have important future research applications as the technique enables the production of pure cultures of functioning human neurons that can be genetically manipulated to mimic human disorders. Before, it was only possible to use mouse or other animal cells to model neurodegenerative diseases, but the genetic background is so different from that of humans that key aspects of diseases such as Alzheimer's could not be reproduced.

KineMed raises funds to advance development of KM-801 for ALS

KineMed has completed a US$15 million convertible notes offering, which will be used to advance the company's lead compound, KM-801, into clinical studies in 2008, for the treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease).

KM-801 is a small-molecule agent that in preclinical studies, has been shown to alter microtubule dynamics in nerve cells. KineMed researchers have discovered that patients with ALS have more rapid rates of turnover of microtubules, which are integral to the structure and functionality of the motor neurons affected by the disease. By using an agent that can slow down this rate of turnover, KineMed has shown in preclinical studies that it can restore balance to this key metabolic pathway and improve both symptoms and survival. The company's KM-801 programme is currently in IND-enabling studies to support the initiation of clinical trials next year.

Tikvah granted ODS for sodium phenylbutyrate's use in SMA

The FDA has granted Tikvah Therapeutics orphan drug status (ODS) for sodium phenylbutyrate, for the treatment of spinal muscular atrophy (SMA).

Sodium phenylbutyrate, a histone deacetylase inhibitor currently approved to treat urea cycle deficiency, has been identified in in vitro systems and in various animal models as an agent that can increase the level of SMN protein. Findings from in vitro studies, as well as pilot clinical work, suggest that phenylbutyrate treatment in SMA patients may improve motor function. Tikvah will be working in conjunction with the FDA and collaborative clinical trial groups focused on SMA to develop well-controlled, multi-centre trials to fully evaluate sodium phenylbutyrate in the treatment of SMA.

For details of Tikvah entering an agreement relating to a proprietary formulation of sodium phenylbutyrate, see Agreement News.

PRODUCT NEwSXenazina approved in Italy

Chiesi Farmaceutici has received approval of Xenazina (tetrabenazine) from the Agenzia Italiana del Farmaco in Italy, for the treatment of movement disorders associated with Huntington's disease (HD), as well as the treatment of moderate-to-severe tardive dyskinesia.

Providing…Product forecasts by value 2006 to 2011Patent expiry opportunities to 2016Generic market contextCompetitive evaluation with 18 company reviews

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THERAPY AREAS AND PRODUCTS ASSESSEDAsthma & COPD

Flixotide/Flovent (fluticasone propionate)Serevent (salmeterol xinafoate)Seretide/Advair (salmeterol xinafoate+fluticasone propionate)Pulmicort (budesonide)Combivent (ipratropium bromide+salbutamol)Xopenex (levalbuterol)

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InfluenzaRelenza (zanamivir)

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OsteoporosisMiacalcin (calcitonin-salmon)Fortical (calcitonin-salmon [rDNA origin])

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CNS Drug News

Xenazina, a dopamine-depleting agent, was exclusively licensed to Chiesi for commercialisation in Italy by Cambridge Laboratories in 2003.

This is the third major territory in the European roll-out of tetrabenazine, following launches of the product in Germany (as Nitoman) and France (as Xenazine). It is also available in South Africa, New Zealand, Australia and Canada, while in the US, a complete response was submitted to the FDA in February, in respect of an application for marketing approval for the treatment of chorea associated with HD.

EMEA accepts MAA filing for SNT-MC17

The EMEA has accepted the MAA filing for Santhera Pharmaceuticals' SNT-MC17 (idebenone), which was originally developed by Takeda, for the treatment of Friedreich's ataxia (FA). A milestone payment of EUR 3 million to Santhera from Takeda was triggered by this acceptance.

SNT-MC17, which has been granted orphan drug designation in the EU, could become the first approved product for the treatment of FA and will be marketed in Europe by Santhera's partner, Takeda. SNT-MC17 has shown clinical efficacy in FA patients on both neurological and cardiac endpoints in several clinical studies, and proved to be well tolerated in all studies thus far.

In a recently-completed clinical trial conducted in collaboration with the National Institutes of Health (NIH), Santhera tested the efficacy of three SNT-MC17 doses in patients with FA. Study results were announced in autumn 2006. The MAA file includes data generated in this study analysing a variety of neurological and cardiac outcome measures, supported by data from earlier clinical trials in FA conducted by academic institutions that demonstrated efficacy primarily in the treatment of the cardiac symptoms of this disease. The MAA recommends a starting dose of 450mg/day for patients below 45kg body weight and 900mg/day for patients of 45kg or above, with the option for the treating physician to use higher doses if needed.

The MAA file includes safety data generated by Santhera with SNT-MC17, as well as safety data from Takeda generated in its earlier preclinical and clinical development programme for the treatment of Alzheimer's disease. Santhera believes that the compound has the potential to be granted European marketing approval for the treatment of FA in the second half of 2008.

Santhera has decided, despite the MAA filing, to continue its ongoing Phase III trial with SNT-MC17 in Europe to collect additional safety and efficacy data in a wider population of FA patients, particularly for doses up to 1,350 and 2,250mg/day in the two body weight groups. Santhera amended the study protocol based on the findings of the NIH study to primarily evaluate the benefits of SNT-MC17 on the neurological aspects of FA. Santhera also offers all FA patients that participate and complete the EU Phase III trial the opportunity to enrol in an open-label extension study in which they will receive high-dose SNT-MC17.

AGREEmENT NEwSMedtronic/Alnylam advance drug-device combinations collaboration

Medtronic and Alnylam Pharmaceuticals are advancing their February 2005 collaboration, following positive preclinical data generated under the initial joint technology development phase of the programme.

Under the terms agreed, the companies will focus on developing a drug-device combination for the treatment of Huntington's disease (HD). The product is expected to consist of an RNA interference (RNAi) therapeutic targeting the HD gene that will be delivered by Medtronic's implantable infusion pump.

Preclinical data from Alnylam's HD programme provided a rationale to advance an RNAi therapeutic programme in this disease. The companies may jointly decide to collaborate on the development of similar drug-device combinations using Alnylam's RNAi therapeutics platform and Medtronic's implantable infusion pump for the treatment of other neurodegenerative diseases, such as Parkinson's disease.

The agreement has also been revised as a 50:50 relationship in the US. Medtronic will commercialise the therapy consisting of the identified RNAi compound and advanced delivery devices. In the US, Alnylam has the opportunity to invest in clinical development of this therapy through product launch. In Europe, Medtronic is solely responsible for development and commercialisation.

University of Alabama enters collaborative research pact with QRxPharma

The University of Alabama has entered into a collaborative research and licensing agreement with QRxPharma. The research programme is directed at re-engineering existing drug therapies for new clinical applications, including the treatment of Parkinson's disease (PD), dystonia and other neurological disorders.

The licensed technology relates to a particular gene that has been shown to suppress the harmful misfolding of proteins within cells. Many neurological diseases, including PD, dystonias, Huntington’s disease, amytrophic lateral sclerosis (Lou Gehrig's disease) and Alzheimer’s disease, involve the toxic effects of misfolded proteins that kill critical nerve cells in the brain.

Preclinical research at the University has demonstrated that co-expressing a gene coding for a protein named Torsin decreases the misfolding of other proteins associated with neurological diseases. QRxPharma's goal, based on work at the University, is to re-engineer existing drugs with a known history of use that activate the Torsin system and could therefore ameliorate these diseases at a causative level.

Tikvah licenses Navinta technology

Tikvah Therapeutics has entered into an exclusive worldwide licensing agreement with Navinta that encompasses unique solution formulations, including a proprietary formulation of sodium phenylbutyrate, as well as methods of use and treatments for a variety of neurodegenerative disorders, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (Lou Gehrig's disease) and multiple sclerosis, plus certain metabolic disorders.

The Navinta technology provides a platform for the preparation of non-viscous, concentrated solution formulations of drugs that incorporate various taste- and smell-masking components. Under the terms agreed, Tikvah will pay a licensing fee, potential milestones and royalty payments, in exchange for an exclusive worldwide licence to pursue the commercial development of the technology for the treatment of SMA and other neurodegenerative diseases. For details of the FDA granting Tikvah orphan drug status for sodium phenylbutyrate's use in SMA, see R&D Update.



CNS Drug News

Paladin expands Canadian Elaprase distribution deal with Shire

Paladin Labs has expanded its current exclusive Canadian distribution agreement with Shire Human Genetic Therapies. Under the agreement, Paladin will be distributing Elaprase (idursulfase) for Hunter syndrome (mucopolysaccharidosis II) in addition to Replagal (agalsidase alpha) for Fabry disease. Health Canada recently granted

Shire regulatory approval for Elaprase, indicated for enzyme-replacement therapy in patients with Hunter syndrome (see CNS 164).

Elaprase is designed to treat the underlying cause of Hunter syndrome by replacing iduronate-2-sulphatase (I2S). The product is a purified form of human I2S that is produced by recombinant DNA technology using a human cell line.

CEREBROVASCULAR DISORDERSR&D UPDATE

EC grants Chelsea two OMP designations for droxidopa

Chelsea Therapeutics International has been granted two orphan medicinal product (OMP) designations by the EC, for droxidopa in the treatment of orthostatic hypotension in patients with pure autonomic failure and patients with multiple system atrophy. These designations are based on a recommendation from the EMEA's COMP and follow the orphan drug designation granted by the FDA in January (see CNS 155).

Droxidopa, developed by and licensed from Dainippon Sumitomo Pharma, initially received Japanese approval in 1989, for the treatment of frozen gait and dizziness on standing associated with Parkinson's disease, and for the treatment of orthostatic hypotension, syncope or dizziness on standing associated with Shy-Drager syndrome and familial amyloidotic polyneuropathy. Additionally, in 2000, droxidopa received expanded marketing approval to include the prevention of vertigo, dizziness and weakness associated with orthostatic hypotension in haemodialysis patients.

Phase Ib trial of SRT501 in MELAS initiated

A Phase Ib trial has been initiated in Europe with Sirtris Pharmaceuticals' SRT501 in patients with mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), for which there are currently no known treatments.

The trial is designed to test the primary endpoints of SRT501's safety and pharmacokinetics in patients with MELAS. The drug will be administered to a group of 15 patients once daily for three months, while 15 other patients will receive placebo. Secondary endpoints include exercise tolerance, plus fasting blood glucose and insulin levels. Sirtris expects trial data by the end of 2008.

SRT501, Sirtris' proprietary version of resveratrol, activates SIRT1, a member of the human sirtuin family of enzymes. Specifically, SRT501 acts by increasing mitochondrial activity and may target metabolic diseases, such as Type II diabetes, as well as mitochondrial disorders, such as MELAS. For details of research on SIRT1 activation, see Neurodegenerative Disorders, Other Neurodegenerative Disorders - R&D Update.

ANXIOLyTICS/SLEEP DISORDERSR&D UPDATE

Research identifies low expression of immune system gene in WBCs of narcolepsy patients

According to research published in the 1st August issue of Sleep (2007;30:974-979), the MX2 gene, which is relevant to the immune system, is significantly less expressed in patients with narcolepsy compared to normal subjects. This finding underlies the abnormalities in the blood cells (BCs) of persons suffering from narcolepsy and is the first report to identify the biological markers of the disorder using gene expression in white BCs (WBCs).

Specific alterations in the immune system have been suggested to occur in narcolepsy, thus this study attempted to identify alterations in gene expression underlying the abnormalities in the BCs of narcoleptic patients.

A scientist at the Tokyo Institute of Psychiatry in Japan, conducted the study from a pool of total RNA from 12 narcolepsy with cataplexy patients and from 12 age- and sex-matched healthy controls. The pooled samples were initially screened for candidate genes for narcolepsy by differential display analysis using annealing control primers.

The second screening of the samples was carried out by semi-quantitative PCR using gene-specific primers. Finally, the expression levels of the candidate genes were further confirmed by quantitative real-time PCR using a new set of samples: 20 patients with narcolepsy-cataplexy and 20 healthy controls.

The second screening revealed differential expression of four candidate genes, among which MX2 was confirmed as a significantly downregulated gene in the WBCs of narcoleptic patients by quantitative real-time PCR.

Although it is known that MX2 is known to be relevant to the immune system, its direct relationship to narcolepsy has not been elucidated. Further study is therefore required to explore the functional relationship between MX2 and narcolepsy, plus characterise the effect of interferons in the disorder.

DSP discontinues AC-5216

Dainippon Sumitomo Pharma (DSP) has released an update of its research and development pipeline, confirming that AC-5216, an anxiolytic and antidepressant that had been under re-evaluation for further development, has been discontinued. Novartis previously licensed exclusive global development rights to this compound outside of Japan, Korea, China and Taiwan.

CEREBROVASCULAR DISORDERS / ANXIOLyTICS/SLEEP DISORDERS


CNS Drug News

PRODUCT NEwSValeant begins distribution of Xyrem in Canada

Valeant Pharmaceuticals International has launched the Xyrem Success Program for Xyrem (sodium oxybate), the first product approved in Canada to treat cataplexy. Valeant has a licensing agreement with Jazz Pharmaceuticals for the Canadian rights to Xyrem, which calls for payments based on sales there.

Using a central pharmacy connected with the programme, Valeant will distribute Xyrem in Canada through its specialty sales force, with the product to be promoted exclusively to neurologists, psychiatrists, pulmonologists and sleep specialists who treat patients with narcolepsy.

Xyrem has demonstrated an acceptable safety profile in narcoleptics with cataplexy when administered in nightly divided doses of 6 to 9g, with a recommended starting dose of 4.5g/night. Its adverse-event profile was generally consistent with the known pharmacological

actions of sodium oxybate and intercurrent disease states, with the most commonly-reported adverse drug reactions (dizziness, nausea and headache) occurring in 17 to 25 per cent of patients.

Solvay submits complete responses to Luvox FDA approvable letters; bifeprunox not approvable

For details, see Psychotic Disorders, Product News.

AGREEmENT NEwSsanofi-aventis/Chugai terminate Japanese marketing collaboration

sanofi-aventis KK and Chugai Pharmaceutical (Roche) are terminating their Japanese marketing collaboration, effective 31st December. The collaboration included seven sanofi-aventis products that were being sold by Chugai; the marketing rights for the products, which include Amoban (zopiclone) for the treatment of sleep disorders, will be returned to sanofi-aventis accordingly.

ANTIDEPRESSANTSR&D UPDATE

Gene variation increases chance of successful citalopram response

A study by the National Institute of Mental Health (NIMH) has found that a variation in the gene, GRIK4, appears to make people with depression more likely to respond to citalopram than those without the variation. The increased likelihood was small, but when people had both this variation and one in a different gene shown to have a similarly small effect in an earlier study, they were 23 per cent more likely to respond to citalopram than those with neither variation.

The researchers studied DNA provided earlier by patients participating in the recently-completed NIMH, STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study. The trial showed that depressed patients who do not benefit from the first medication they try have a fair chance of being helped by others.

After the trial, researchers determined the DNA codes contained in 68 genes suspected of being involved in depression, collected from 1,297 of the patients who had participated in STAR*D. Comparing the DNA codes of those who had responded to citalopram and those who had not, it was found that responders were more likely to have a variation in a gene called HTR2A.

In the new study, which was published in the August issue of the American Journal of Psychiatry (2007;164:1181-1188), researchers examined the genetic material of more of the patients who had participated in STAR*D, for a total of 1,816 samples, and repeated the comparison of DNA from citalopram responders and non-responders. They discovered that people with the variation in the GRIK4 gene had a higher likelihood of response and again found that the variation in the HTR2A gene also made people more likely to respond.

The 23 per cent increase in likelihood of response to citalopram occurred in people who carried the favourable variations in both copies of both of the genes. People with fewer of the favourable

variations did not have as high a response rate, but were still more likely to respond than people with none of the favourable variations.The protein produced by HTR2A acts as a receptor on brain cells for serotonin.

The discovery that a variation in a serotonin-related gene could affect response to citalopram was not entirely surprising, since the serotonin system is known to be involved in depression and citalopram targets this system. However, GRIK4 makes a protein that acts as a receptor in a different neurotransmitter system, the glutamate system. Recent studies suggest that the glutamate system is also involved in depression, an assertion that is supported by the new finding.

Editor's note: citalopram was developed by Lundbeck for the long-term treatment of depression. It is licensed to Forest Laboratories for the US, where it is sold as Celexa, however a number of generic versions are now available.

DOV 21,947 safe and well tolerated in Phase Ib study

A preliminary analysis of Phase Ib study results has indicated that DOV Pharmaceutical's DOV 21,947 was safe and well tolerated at the doses examined, and produced a significant decline in plasma triglyceride (TG) levels. DOV intends to initiate a Phase II study with its lead triple reuptake inhibitor for the treatment of depression in the fourth quarter of 2007.

Prior studies with DOV 21,947 at up to 100mg/day demonstrated the safety and tolerability of this compound over dosing periods of up to ten days. The goal of the current trial was to confirm DOV 21,947's safety and tolerability over an eight-week period at escalating doses of up to 150mg/day.

This double-blind, placebo-controlled study enrolled 46 male and female subjects. Following a one-week placebo run-in, subjects received either escalating daily doses of DOV 21,947 50, 100 and 150mg/day (n=31) or placebo (n=15) for eight weeks. The study demonstrated that DOV 21,947 was safe and well tolerated in this dose range, with no reported serious adverse events (AEs). The proportion

ANTIDEPRESSANTS


CNS Drug News

of patients with treatment-emergent AEs was similar in the two treatment groups, with 36 and 47 per cent in the DOV 21,947 and placebo groups, respectively. Reported AEs with >3 per cent incidence in both the DOV 21,947- and placebo-treated arms included headache, nausea, diarrhoea and dizziness. No other reported AE with a >5 per cent incidence was observed in the DOV 21,947-treated subjects. The incidence of subjects that dropped out of the study due to AEs was 6.5 and 13.3 per cent in the DOV 21,947 and placebo groups, respectively.

In addition, preliminary analysis of the clinical chemistry laboratory data indicates that DOV 21,947-treated subjects had lowered plasma TG levels compared to placebo-treated subjects (p<0.015). This reduction in mean TG levels was noted following two weeks of treatment (approximately 23 per cent reduction), was maintained at the end of the DOV 21,947 treatment period (approximately 29 per cent reduction) and was reversed after the one-week wash-out period at the end of the study. This reduction in plasma TG levels is consistent with preclinical evidence that DOV 21,947 is able to produce a significant and sustained reduction in both TG levels and body weight in animal models of obesity.

Eight Phase I studies have now been completed with DOV 21,947. The double-blind, Phase II study scheduled for initiation later in 2007 will compare DOV 21,947 up to 100mg/day versus placebo in approximately 200 patients with major depressive disorder over a six-week treatment period. DOV expects the results from that study in the fourth quarter of 2008.

DSP discontinues AC-5216

For details, see Anxiolytics/Sleep Disorders, R&D Update.

PRODUCT NEwSFDA approves first escitalopram capsules

On 31st July, the FDA approved Alphapharm's (Merck KGaA) ANDA for escitalopram oxalate oral capsules 5, 10 and 20mg. There are currently no therapeutic equivalents available for this product.

On receipt of notification from Alphapharm that it had filed an ANDA with a Paragraph IV certification for a generic equivalent to the antidepressant, Lexapro (escitalopram), Forest Laboratories stated that it believed its patents on Lexapro were valid and strong, and the company therefore did not expect a generic product to be available until at least after the expiration of its substance patent, including patent extension, which will be in 2011. In October 2005, Forest and Lundbeck announced an agreement with Alphapharm with regard to US Patent Re. No. 34,712, which was licensed to Forest by Lundbeck on an exclusive basis in the US and relates to Lexapro. Pursuant to the terms of the settlement agreement, the companies confirmed that they would appoint Alphapharm as the exclusive distributor of generic versions of Lexapro, which may be launched under certain scenarios. Forest would receive a portion of the profit from such sales.

PSyCHOTIC DISORDERSR&D UPDATE

Johns Hopkins team develops mouse model of schizophrenia

Johns Hopkins researchers have genetically engineered the first mouse that models both the anatomical and behavioural defects of schizophrenia. In contrast to current animal studies that rely on drugs that can only mimic the manifestations of schizophrenia, such as delusions, mood changes and paranoia, this new mouse is based on a genetic change relevant to the disease. Thus, it is thought that this mouse should greatly help with understanding disease progression and developing new therapies.

Animal models of schizophrenia have been hard to design since many different causes underlie this disease. However, Dr Akira Sawa and his colleagues took advantage of the recent discovery of a major risk factor for this disease, the DISC1 (disrupted in schizophrenia) gene, which makes a protein that helps nerve cells to assume their proper positions in the brain.

The researchers generated mice that make an incomplete, shortened form of the DISC1 protein, in addition to the regular type. The short form of the protein attaches to the full-length one, disrupting its normal duties.

As these mice matured, they became more agitated when placed in an open field, had trouble finding hidden food and did not swim as long as regular mice; such behaviours parallel the hyperactivity, smell defects and apathy observed in patients with schizophrenia. MRI also revealed characteristic defects in brain structure, including enlarged lateral ventricles. According to Sawa, whose work was published in

the 3rd August online edition of PNAS (10.1073/pnas.0704774104), the defects in these mice were not as severe as those typically seen in people with schizophrenia, because more than one gene is required to trigger the clinical disease. However, he believes that this mouse model will help to fill many gaps in schizophrenia research. The model can be used to explore how external factors, such as stress or viruses, may worsen symptoms and the animals can be bred with other strains of genetically-engineered mice to try to pinpoint additional schizophrenia genes.

AstraZeneca releases R&D pipeline update

AstraZeneca has released an update of its research and development pipeline, which has been significantly enhanced by the addition of the MedImmune portfolio, with 14 products in clinical development and a further 28 projects; the majority of the MedImmune portfolio is in monoclonal antibodies and vaccines.

The overall pipeline now includes 157 projects. Since 1st February, 20 projects have progressed to their next phase of development, 53 compounds have been added (including 42 new projects from MedImmune, 14 of which are clinical) and 16 compounds have been withdrawn. Ten new molecules have had their first dosing in humans since 1st February, bringing the year-to-date total to 14, a record number for AstraZeneca, with a number of additional opportunities planned for the second half of the year.

In July, AstraZeneca submitted an sNDA to the FDA for a new indication for the use of Seroquel (quetiapine) for the maintenance treatment of patients with bipolar I disorder as adjunct to mood stabiliser, based on data from two clinical trials. Pooled data showed a greater incidence of blood glucose increases to hyperglycaemic levels in patients randomised to Seroquel+mood stabiliser than in those

PSyCHOTIC DISORDERS


CNS Drug News

randomised to placebo+mood stabiliser. Seroquel's US Prescribing Information has been updated to include additional details regarding these data.

Discontinued projects in the neuroscience area include AZD9272 and AZD6538, both in neuropathic pain.

Gene polymorphism predicts better ADHD outcome in teens

The results of an imaging study conducted by National Institute of Mental Health (NIMH) researchers have shown that brain areas that control attention were thinnest in children with attention deficit hyperactivity disorder (ADHD) who carried a polymorphism of a particular gene. However, the affected areas, on the right side of the brain's outer mantle, achieved normal thickness during the teenage years in these children, coinciding with clinical improvement. Although this particular gene version increased risk for ADHD, it also predicted better clinical outcomes and higher IQ than two other common versions of the same gene in youths with ADHD.

According to the scientists, whose work was published in the August issue of the Archives of General Psychiatry (2007;64:921-931), these findings suggest that ADHD is at the far end of a continuum of normal traits, and probably stems from interactions between several such genes and non-genetic factors.

When the NIMH researchers first reported that normalisation of right cortex thickening was associated with better clinical outcomes in ADHD, there were few clues indicating a genetic connection. Yet evidence from several previous studies led the team to suspect involvement of an ADHD-implicated version of a gene that codes for a receptor protein, which binds to dopamine. This version of the dopamine D

4 receptor gene, called the 7-repeat variant, accounts for

approximately 30 per cent of the genetic risk for ADHD, making it by far the strongest candidate gene implicated in the disorder.

For the current study, the researchers scanned and determined the D

4 gene types of 105 children with ADHD (with 222 neuro-anatomical

MRIs) and 103 healthy controls (total of 220 MRIs), then re-imaged them through their teenage years. Sixty-seven subjects with ADHD (64 per cent) had follow-up clinical evaluations (mean follow-up, six years).

The results showed that almost one-quarter of youths with ADHD and approximately one-sixth of the healthy controls had at least one copy of the 7-repeat polymorphism. Nearly two-thirds of the children with ADHD and three-quarters of the healthy controls had the most common 4-repeat version; fewer than one-tenth in each group had a 2-repeat version.

While the 7-repeat version was linked to thinner attention-controlling cortex in both ADHD and healthy subjects, it appeared to confer an advantage only among youths with ADHD. For example, participants with ADHD who lacked at least one copy of this 7-repeat variant had significantly lower IQs and more than half of them still had pronounced ADHD symptoms when followed-up approximately six years later, compared to only 21 per cent of those with at least one copy of the 7-repeat variant. There was also a trend toward better overall functioning among those with at least one copy of the 7-repeat variant at follow-up.

The MRI scans revealed that 7-repeat carriers with ADHD started out with the thinnest cortex areas important for controlling attention (right orbitofrontal and posterior parieto-occipital). The next thinnest

areas were observed in children with ADHD who did not have the 7-repeat version, followed by healthy children with the 7-repeat. Healthy children lacking the 7-repeat had the thickest cortex, but this did not appear to affect their IQ. However, the researchers note that other studies have found correlations between cortex thickness and certain measures of memory and intelligence.

In 7-repeat carriers with ADHD, the attention-controlling areas thickened to normal by the age of 16 years. Gene variants of two other dopamine system components showed few such anatomical correlates, confirming that the findings were specific to the D

4 receptor

gene. According to the scientists, evidence suggests that the 7-repeat may be a relatively new variant, which may have been favoured through evolution because such traits proved adaptive for survival.

The researchers are following-up with studies on the relationship between cortex thickness and cognitive features of ADHD, such as working memory and the ability to inhibit responses.

Medistem proposes SC therapy for autism

Medistem Laboratories has filed intellectual property (IP) and published a paper describing a novel method of selecting specific subsets of autistic patients for treatment with a combination of cellular therapies.

The paper, which was published in the 27th June online issue of the Journal of Translational Medicine (10.1186/1479-5876-5-30), proposes that the combined use of mesenchymal stem cells (SCs) and cord blood CD34+ cells may be useful in the treatment of autism, while the patent application, entitled: "Stem Cell Therapy for Autism," covers patient selection, therapeutic combinations and various SC types for the treatment of autism.

Based on positive case report data from one of its licensees, Medistem plans to explore the possibility of seeking regulatory approval in the US for a Phase I trial involving its novel SC therapeutic methods for the treatment of autism. The company is now seeking and initiating discussions with clinical collaborators and patient interest groups in the US.

Modafinil shows potential for BPD

A preliminary study of 85 patients with bipolar disorder (BPD) has indicated that modafinil, a drug used to treat patients with sleep disorders, might also control the depressive symptoms associated with BPD.

Modafinil is approved by the FDA to treat patients who suffer from excessive sleepiness associated with narcolepsy, obstructive sleep apnoea and shift work sleep disorder, and is marketed as Provigil by Cephalon. During the depressive phase of BPD, the symptoms include excessive sleepiness and fatigue, therefore researchers wondered if modafinil could address these symptoms in patients with the disorder.

Half of the patients in the randomised, double-blind, placebo-controlled study, which was conducted at five sites and published in the August issue of the American Journal of Psychiatry (2007;164:1242-1249), were given modafinil 100-200mg/day, while the other half were given placebo over a six-week period. While the trial was small, 44 per cent of those receiving modafinil reported feeling better, while 39 per cent said their symptoms were in remission after six weeks. This compares to 23 and 18 per cent, respectively, in the control group. Modafinil was not associated with any greater risk of the manic and depressive mood swings associated with BPD.

PSyCHOTIC DISORDERS


CNS Drug News

How exactly modafinil works to promote wakefulness or improve mood in BPD is not completely understood. Indeed, it appears to have an entirely different mechanism of action compared to other psychostimulants.

Risperdal Consta compares favourably to oral Zyprexa

Data published in the August edition of the British Journal of Psychiatry (2007:191;131-139) have shown that patients receiving Janssen-Cilag's (Johnson & Johnson) Risperdal Consta (risperidone long-acting injection) experienced a higher incidence of significant clinical improvements, as well as greater improvements in measures of disorganised thinking at 12 months, than those taking Eli Lilly's Zyprexa (olanzapine) orally. With the efficacy and safety of long-acting injectable risperidone having not previously been compared with that of an oral atypical antipsychotic, the study was conducted in 377 patients with DSM–IV schizophrenia or schizoaffective disorder. Patients were randomised to receive long-acting risperidone 25 or 50mg every 14 days or oral olanzapine 5 to 20mg/day. J&J Pharmaceutical Research & Development completed the statistical analysis.

The controlled, open-label, head-to-head study recruited participants at 48 centres worldwide. A total of 318 patients were randomised to risperidone and 300 to olanzapine, of which 160 and 187 patients, respectively, completed the 12-month trial. The primary measure of efficacy was the change in total score on the PANSS from baseline to endpoint for both short- (13 weeks) and long-term (12 months) outcomes.

According to the results, long-acting risperidone was at least as effective as oral olanzapine in the 13-week phase, with significant improvements in the PANSS total and factor scores from baseline to month 12 and endpoint seen in both groups of patients in the 12-month phase. Few patients discontinued treatment because of an adverse event, and the study concluded that both treatments were efficacious and well tolerated.

The efficacy results suggested that in the long-term, patients might benefit more from treatment with long-acting risperidone injection than with oral olanzapine. Risperidone achieved clinical improvements (20 per cent minimum reduction in PANSS total scores) in significantly more patients compared with olanzapine at 12 months (91 vs 79 per cent; p<0.001), plus at the trial's long-term endpoint (12 months), a significantly greater improvement on one PANSS factor score (disorganised thoughts) was seen in patients receiving risperidone than in those receiving olanzapine. However, significantly greater improvements were seen in anxiety/depression in the olanzapine group.

The trial data also suggest that long-acting risperidone may have a less pronounced effect on weight gain and body mass index (BMI) than olanzapine. The mean weight gain change in the risperidone group was 1.7kg compared to 4kg in the olanzapine group at the study endpoint (p<0.05) and BMI was 0.6kg/m2 compared to 1.4kg/m2, respectively (p<0.05).

Sexually-related side effects were reported by 3 per cent of the patients in each group. Severity of adverse events relating to movement disorders was mild in both groups, although these events were more frequent (25 per cent) in the risperidone group than in the olanzapine group (15 per cent). Five patients discontinued treatment (for any reason) in the olanzapine group, compared to one in the risperidone group. For details of sales forecasts for Risperdal and Zyprexa, see In Focus.

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An expanding market, a growing

population, a regulatory

regime supportive of the generics sector, robust

domestic production and many untapped opportunities.

Is Brazil the place for generic companies to be?

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

www.espicom.com/brazilgen

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

•••

••

•

••

Includes A weAlth of InformAtIon not AvAIlABle In

englIsh elsewhere!

Marketforecasts andtrend analysis!

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

report, published in April 2007

PSyCHOTIC DISORDERS

©Espicom Business IntelligencePage �0 �3rd August �007

CNS Drug News

Scientists describe genetic variation linked to predisposition to schizophrenia

Scientists at the University of Oxford in the UK, the National Institutes of Health and the National Institute of Mental Health have provided new insight into how a gene is related to schizophrenia. In the 17th August issue of the Journal of Biological Chemistry (2007;282:24343-24351), the researchers describe, for the first time, a genetic variation that causes a gene to be overexpressed in the human brain.

Although the exact causes of schizophrenia are yet to be determined, scientists agree that the disease is due, in part, to genetic variations. In the current study, the investigators identified some clues as to what goes wrong with one of the DNA variations.

In an Icelandic population, scientists originally found that genetic variations in a DNA sequence close to a gene that produces a protein called Neuregulin 1 (NRG1) were associated with schizophrenia, but how the NRG1 gene was affected remained unknown. In 2006, one of the researchers found that one of these DNA variations is associated with increased expression of a novel type of NRG1, called type IV, which is one of the six known NRG1 protein isoforms, in the brains of patients with schizophrenia.

The role of this protein in the brain is not completely understood, but the other types of NRG1 proteins are involved in controlling how the brain develops and functions in adults. In this study, the researchers showed that NRG1 type IV is specifically expressed in the brain, unlike the other types of NRG1. Also, the scientists showed that this protein is 3.5-times more abundant in foetal than adult brains, supporting the protein’s important role in the developing brain. The team hopes that by understanding how this novel protein works in the brain, it may be possible to target it in people with the disease.

The scientists showed that the genetic change that causes overproduction of NRG1 type IV is part of a promoter. The research revealed that alteration of the promoter in the genetic sequence linked to schizophrenia resulted in altered amounts of NRG1 type IV.

The team now plans to further investigate the role of NRG1 type IV in brain development and behaviour, plus determine how various alterations of the NRG1 gene lead to schizophrenia.

PRODUCT NEwSSolvay submits complete responses to Luvox FDA approvable letters; bifeprunox not approvable

The FDA has accepted for review the submission of the complete response by Solvay Pharmaceuticals to its approvable letter for Luvox CR (fluvoxamine) extended-release capsules. The NDA for Luvox CR seeks marketing approval for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder and for the treatment of social anxiety disorder. The PDUFA action date is 22nd December.

Furthermore, the FDA has also accepted the submission of the complete response by Solvay to the approvable letter for Luvox immediate-release tablets, with a PDUFA action date of 21st December. In January, Jazz Pharmaceuticals licensed from Solvay the right to market Luvox CR and Luvox in the US. Solvay retains the right to market both products in other territories around the world. Subject to the receipt of FDA approval, Jazz expects to launch Luvox CR in the US during the first quarter of 2008.

In addition...

Solvay and Wyeth Pharmaceuticals have received an action letter from the FDA in response to the NDA for bifeprunox, an atypical antipsychotic that was reviewed for the acute treatment of schizophrenia, as well as the maintenance of stable adult patients. The Agency stated that the drug was not approvable at this time.

The FDA stated that bifeprunox demonstrated effectiveness in the long-term maintenance study and indicated that a second positive maintenance study could be sufficient to support a maintenance claim for the drug. The companies will meet with the Agency to discuss study design and to assess how this additional study, combined with ongoing and planned trials, might support a maintenance indication.

Although the FDA acknowledged that bifeprunox separated from placebo in two short-term studies in the acute setting, it concluded that the efficacy data, when compared to reference drugs, were not sufficient for approval.

The Agency also requested further information regarding human metabolism of bifeprunox, plus additional information regarding a complex case of a patient who died while participating in one of the trials.

AGREEmENT NEwSNoven to receive Daytrana sales milestone

Shire's net sales of Daytrana (methylphenidate transdermal system) have triggered the second of three potential US$25 million milestone payments to Noven Pharmaceuticals. Payment of this milestone was triggered upon Shire's net sales of Daytrana exceeding US$50 million in the 12 months preceding 30th June. Under the terms agreed, a third US$25 million milestone is payable upon Shire's achievement of US$75 million in annual net sales of Daytrana.

Daytrana, licensed globally to Shire, was launched in June 2006. Payment of the first milestone was triggered upon Shire's net sales of the product exceeding US$25 million in 2006. Daytrana is currently the only transdermal product approved for the treatment of attention deficit hyperactivity disorder for children aged six to 12 years.

Avanir completes sale of FazaClo to Azur

Avanir Pharmaceuticals has completed the sale of the currently-marketed antipsychotic drug, FazaClo (clozapine), to Azur Pharma. Upon closing the transaction, Avanir received an up-front payment of US$42 million, plus an additional US$1.9 million in working capital adjustments.

Azur has also assumed Avanir's future earn-out obligations to the prior owner of Alamo Pharmaceuticals, which it acquired in 2006, payable upon the achievement of certain sales milestones. Avanir will finalise the transfer of FazaClo business operations to Azur in the coming months.

Avanir believes that the net payments from the sale, plus the cash, cash equivalents and unrestricted investments in securities, will be sufficient to finance operating expenses through the end of the next fiscal year, including the initiation of the planned confirmatory Phase III trial of Zenvia (dextromethorphan+quinidine) in patients with involuntary emotional expression disorder.

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R&D UPDATEJavelin initiates Phase III trial of intranasal ketamine

Javelin Pharmaceuticals has dosed the first patient in a Phase III trial that is designed to extend observations in a pilot study of PMI-150 (intranasal ketamine) in treating breakthrough pain.

Up to 90 patients with breakthrough cancer pain from the US are planned to be randomised in this multi-centre, double-blind, crossover, placebo-controlled study. Cancer patients with daily breakthrough pain episodes are eligible for treatment and will receive seven active and three placebo treatments. The primary measure of efficacy is the sum of the differences from initial pain intensity, as measured on a 0-10 scale during the first 60 minutes after dosing.

Javelin is developing PMI-150 for several intended indications and anticipates undertaking additional clinical studies aimed at broadening the compound's potential indications. The company believes that PMI-150 is optimised for use as a pain medication and may offer a safe, non-opioid alternative for the treatment of moderate-to-severe pain. Prior randomised, double-blind, placebo-controlled, Phase II studies of PMI-150 have demonstrated rapid, statistically significant relief of moderate-to-severe postoperative and breakthrough pain.

The company has begun to assemble an NDA for this product candidate for an initial indication as an emergency analgesic for military and civilian use, and plans to submit it to the FDA in 2008. Clinical efficacy trials to support this initial NDA have been completed. A later sNDA is planned for the indication of breakthrough cancer pain.

FDA accepts Acrux' IND for Fentanyl MDTS

Acrux' IND application for Fentanyl MDTS has been accepted by the FDA, meaning that the company will now proceed with a Phase I trial to test the delivery of fentanyl across the skin using its patented metered-dose transdermal spray system.

The study will commence in the second half of 2007, with the aim of demonstrating that Acrux' MDTS formulation delivers fentanyl into the bloodstream of healthy volunteers in quantities that are known to be safe and effective in controlling chronic pain.

Encore reports positive preclinical data for ER ropivacaine gel

Encore Therapeutics has reported data from two preclinical studies demonstrating that ETI-211, its intradermal extended-release (ER) ropivacaine gel formulation for postoperative pain management, has a markedly-improved safety and pharmacokinetic (PK) profile when compared to the currently-marketed ropivacaine solution formulation.

No apparent toxicity was shown with the ETI-211 gel at the highest ropivacaine dose used (2,054mg/kg), in contrast to the 54mg/kg lethal dose for the solution formulation. The PK study showed that ETI-211 produced an ER profile lasting for six days and a five- to ten-fold reduction in C

max compared with the currently-marketed

solution formulation. The controlled and sustained PK profile is desirable since ETI-211 is designed to maintain the drug at the local site of administration, and the PK result is consistent with previously-reported sustained pain relief efficacy data.

ETI-211 is a proprietary non-liposomal phospholipid gel formulation that incorporates the drug in a single-phase depot system. The gel is capable of delivering the drug for three to seven days with low burst potential, and is made with existing injectable phospholipids and other components that have been used in previous FDA-approved drug products. Previously-reported results indicated that ETI-211 outperformed another liposomal anaesthetic depot formulation in terms of duration of action in preclinical models.

TorreyPines completes enrolment in Phase IIb tezampanel trial

TorreyPines Therapeutics has completed enrolment in its Phase IIb trial of tezampanel for the treatment of acute migraine headache. Tezampanel is an AMPA/kainate receptor antagonist that offers a non-opioid, non-vascular and non-serotonergic approach to the management of pain.

The double-blind, placebo-controlled, multi-centre trial has reached its targeted enrolment of 300 patients suffering a single migraine attack, with or without aura. Patients are randomised to one of four arms and receive a 40, 70 or 100mg single, subcutaneous dose of tezampanel, or placebo. The purpose of the trial is to identify a dose, or a range of doses, that could be used in a Phase III development programme in acute migraine. The primary efficacy endpoint is headache pain relief at two hours post-dose. Secondary efficacy endpoints include pain free status at two hours, sustained pain relief and sustained pain free at 24 hours, headache recurrence and relapse. Additional measures include assessments of functional disability and patient satisfaction, relief of migraine-associated symptoms (such as nausea, vomiting, photophobia and phonophobia), as well as various assessments that characterise speed of treatment onset. Safety, tolerability and plasma pharmacokinetic data will also be evaluated.

Hydra data reveal role of ion channel in pain receptor activation

Data published in the 8th August online issue of PNAS (10.1073/pnas.0705924104) have revealed a key role of the transient receptor potential ion channel, TRPA1, in the formalin pain model, which is widely used for evaluating the effects of analgesic compounds in laboratory animals. These data contradict long-standing views of how formalin induces pain and advance TRPA1 as an attractive target for analgesic drug development.

For a long time, it has been believed that the pain induced in the formalin model was based on generalised tissue damage and inflammatory response generated by formalin. The new research shows that the acute pain induced by formalin is actually due to activation of TRPA1.

For the combined in vitro and in vivo study, researchers at Hydra Biosciences and the University of California, San Francisco, set out to determine whether TRPA1 activation could account for formalin's ability to activate pain receptors. The active component of formalin, formaldehyde, is similar in structure and reactivity to pain-inducing

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irritants found in air pollutants and mustard oil, which are known activators of TRPA1. The scientists found that formalin activated cells expressing human or rat TRPA1, but not those lacking the ion channel. These responses in TRPA1-positive cells could be attenuated with a selective TRPA1 inhibitor identified at Hydra, HC-030031. It was also found that while sensory neurons isolated from normal mice responded to formalin exposure with increased intracellular calcium ion concentrations, those from TRPA1-deficient mice did not. Rat neurons treated with HC-030031 were similarly resistant to formalin stimulation.

Treatment with HC-030031 also substantially reduced formalin-mediated pain responses in rats, such as flinching, licking and lifting responses. This decrease in pain response was not only apparent during the early phase (Phase I) of the formalin response, but also persisted in the later phase (Phase II). Phase I is thought to reflect the acute pain response, while Phase II is proposed to be caused by central sensitisation. Phase I and II formalin responses were also reduced in mice lacking functional TRPA1, providing further confirmation of the channel's role in pain receptor activation.

Hydra is investigating TRPA1 as part of its Ion Channel Program, a research and development effort focused on the TRP family of novel non-selective cation channels. TRP channels respond to a variety of stimuli and may act as multi-modal signal integrators in a number of tissues, including sensory neurons. Because the members of the TRP family have low homology to each other and to other classes of ion channels, Hydra sees significant opportunity for developing drugs that can potently and selectively target individual TRPs for the treatment of medical conditions such as pain, inflammation, pulmonary disorders, hypertension and renal disease.

Merck/Neuromed discontinue development of pain drug candidate

Merck & Co and Neuromed Pharmaceuticals have decided to discontinue development of NMED-160 (also known as MK-6721), a Phase II N-type calcium channel blocker for the treatment of chronic pain. A joint research collaboration will continue to evaluate alternate, earlier-stage therapeutic candidates.

While no serious adverse events with MK-6721 were observed in clinical trials in which up to a 1,600mg single dose was administered, the parties have determined that the compound does not demonstrate the ideal pharmaceutical characteristics considered necessary to advance it further in development.

ReceptoPharm pain study produces positive results

ReceptoPharm (Nutra Pharma) has successfully completed a study of RPI-78, which is being developed for the treatment of pain. The continuing pain studies, being conducted in collaboration with Soochow University, recently found that RPI-78 was successful in controlling pain with a long duration of effect.

The latest data demonstrate that RPI-78 was as effective as morphine at blocking pain signals in that part of the brain that signals the presence of pain. It was also confirmed that the drug did not use an opioid mechanism. Moreover, the duration of RPI-78's effect was superior to morphine's. According to ReceptoPharm, it believes that the data from this and previous studies may be sufficient to commence a Phase I trial in subjects with severe pain.

Clinical studies with early formulations of RPI-78 revealed that the drug was effective in subjects with pain from terminal cancer, arthritis, headaches and amputations, even where morphine was ineffective.

Additionally, the treatment revealed no toxicity and subjects reported no side effects. Low-dose, bi-weekly injections were found to control pain in many subjects for periods reaching four years.

Avigen initiates clinical development of AV411 in the US

Avigen has received approval from the FDA to proceed with the development of AV411 (ibudilast) in the US. The first Phase I trial for the drug in the US, where it is treated as an NCE, will be a maximum tolerated dose study that is designed to build on data from Avigen's Phase I and exploratory Phase IIa studies in Australia.

This larger US trial is designed to assess the safety and tolerability of AV411, and is also intended to assess the effect of food on the compound's pharmacokinetics and tolerability. In the study, healthy male and female volunteers will be randomised into cohorts of escalating doses of orally-administered, delayed-release AV411 capsules or placebo. The study may involve the dosing of up to 48 subjects. In parallel, Avigen's Australian Phase IIa trial is expected to provide safety and initial efficacy data of AV411 in patients with diabetic neuropathic pain and is expected to report by the end of 2007.

AV411 is a first-in-class, orally-bioavailable small molecule that suppresses the pro-inflammatory cytokines, interleukin (IL)-1 beta, TNF alpha and IL-6, and may upregulate the anti-inflammatory cytokine, IL-10. The compound modulates glial cell function, an important contributor to chronic pain, as well as opioid dependence and withdrawal.

Avigen plans to design larger efficacy studies of AV411 in the US for neuropathic pain and other indications, such as opioid withdrawal and dependence. While ibudilast is approved in Asia at doses of up to 30mg/day, Avigen believes that the US Phase I trial will allow further development of the drug at higher doses, which may be optimal for the neurological applications that the company is pursuing.

Verapamil for cluster headaches linked to heart problems

According to research published in the 14th August issue of Neurology (2007;69:668-675), verapamil, which is increasingly used to prevent cluster headaches, can cause heart problems, such as arrhythmia and heart block. The scientists, from the National Hospital for Neurology and Neurosurgery in the UK and the University of California, San Franciso, recommend that those patients taking the drug for cluster headaches should be closely monitored with frequent ECGs for the potential development of such conditions.

The study involved 108 people with an average age of 44 years. The participants started taking verapamil and then had an ECG and an increase in the dosage of the drug every two weeks until the headaches were stopped or the patient started experiencing side effects.

Arrhythmia was observed in 21 patients (19 per cent) taking the drug. Thirteen (12 per cent) had first-degree heart block at 240 to 960mg/day, with one requiring a permanent pacemaker. Four patients had junctional rhythm and one had second-degree heart block. Four patients had right bundle branch block.

There was bradycardia (heart rate <60 beats per minute) in 39 patients (36 per cent), but in only four cases was this severe enough to warrant stopping verapamil treatment.

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CNS Drug News

The investigators noted that 217 people taking the drug were initially supposed to take part in the study, but 42 per cent of them did not have the ECGs carried out to monitor their heart activity. Many of the patients reported that either they or their local services were reluctant to undertake such frequent tests, or they were not aware of the need for the heart monitoring. Since this drug is relatively new for use in cluster headaches, the researchers raised the possibility that some healthcare providers are not aware of the problems that can come with its use, however, in concluding, the team strongly recommended ECG monitoring in all patients with cluster headache on verapamil, to observe for the potential development of atrioventricular block and symptomatic bradycardia.

In the future, the scientists believe that the benefit of taking verapamil to alleviate the pain of cluster headaches has to be balanced against the risk of causing a heart abnormality that could progress into a more serious problem.

Editor's note: verapamil is a specific calcium antagonist that was developed by Knoll (Abbott) and is largely indicated for the treatment of hypertension, angina and cardiac arrhythmia. It is marketed under various tradenames, including Verelan, by Elan. The drug has been off-patent in the US since 19th July 1983 and a number of generic equivalents are available in various dosage strengths.

NeurAxon's NXN-188 safe and well tolerated; raises funds to advance pain therapeutics

NeurAxon has reported positive data from its Phase I trial assessing the safety and establishing the pharmacokinetic profile of the investigational drug candidate, NXN-188. This first-in-class, dual-action small molecule is being developed for the treatment of acute migraine and incorporates both 5-HT agonism and inhibition of neuronal nitric oxide synthase (nNOS), an enzyme involved in modulating pain and CNS neuronal sensitisation.

The double-blind, placebo-controlled, dose-escalation study enrolled healthy volunteers who were randomised to receive single oral doses of either placebo or NXN-188. Nine active drug dose levels were evaluated. Subjects were monitored for adverse events and pharmacokinetic parameters. The results indicate that NXN-188 was well tolerated, with no drug-related adverse events reported.

Preclinical studies comparing NXN-188 to triptans demonstrated that the compound has multiple potential advantages over triptan therapy. These benefits may include increased efficacy, tolerability, safety, treatment window and response rates, plus reduced rebound headache. Based on the new results, NeurAxon plans to advance NXN-188 into a Phase IIa proof-of-concept study in the third quarter of 2007.

In addition...

NeurAxon, which has generated a portfolio of next-generation pain therapeutics targeting nNOS, has closed a US$32 million series B financing, the proceeds of which will be used to accelerate the clinical development of its product candidates.

Cephalon to file Fentora sNDA following positive Phase III data

Cephalon has reported positive results from a 12-week, Phase III trial of Fentora (fentanyl buccal tablet) [C-II] in patients with breakthrough pain associated with a broad range of chronic non-cancer pain conditions. The study achieved statistical significance on the primary

endpoint, with results across the 12 weeks of treatment showing both statistically significant and clinically relevant outcomes for patients with breakthrough pain who were already receiving and were tolerant to opioid therapy for their underlying persistent pain.

The double-blind, placebo-controlled, variable-dose trial included 148 patients. The primary endpoint was the Sum of Pain Intensity Differences from five to 60 minutes, as assessed after 12 weeks of treatment. Patients treated with Fentora showed a statistically significant improvement on the primary endpoint (p<0.0001) compared with placebo and the drug was generally well tolerated, with side effects consistent with those in the currently-approved label.

Fentora is approved only for the management of breakthrough pain in patients with cancer who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain. This third and final controlled study completes Cephalon's Phase III programme and the company plans to submit these data to the FDA in the fourth quarter as part of its sNDA.

AstraZeneca releases R&D pipeline update

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

PRODUCT NEwSFDA issues second approvable letter for Trexima

The FDA has issued a second approvable letter for Trexima (sumatriptan+naproxen), which is being developed by GlaxoSmithKline and Pozen.

The Agency has requested that Pozen further addresses its concern, prior to approval, about the potential implications from one preclinical in vitro chromosomal aberration study (one of four standard genotoxicity assays) in which genotoxicity was seen for the combination of naproxen+sumatriptan, but not with either component alone. None of the other three standard genotoxicity studies (Ames test, mouse lymphoma TK assay, in vivo mouse micronucleus assay) demonstrated any genotoxicity for the combination. The companies intend to request a meeting with the FDA as quickly as possible to discuss the necessary steps to address the Agency's concerns.

In January, Pozen and GSK responded to the Agency's first approvable letter, submitting additional safety data from clinical trials, data from GSK's database and additional in vitro preclinical data. In the second approvable letter, no additional information regarding the cardiovascular safety of Trexima was requested. The companies agreed to conduct a prospective study after approval to evaluate the effects on blood pressure during chronic, intermittent treatment.

Trexima was the proposed brandname for the product candidate combining sumatriptan 85mg, as the succinate salt, formulated with RT Technology, and naproxen 500mg in a single tablet. Several new names are under consideration at the FDA, but pending a final decision on a new name, the product will still be referred to as Trexima.

The FDA previously determined that Trexima is effective as an acute treatment for migraine headaches. Pozen and GSK will continue to work with the Agency on revisions to the proposed package insert and tradename.



CNS Drug News

Sativex approved in Canada for cancer pain

On 1st August, GW Pharmaceuticals' cannabis-derived pharmaceutical therapy, Sativex, was approved in Canada for use as adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate-to-severe pain during the highest-tolerated dose of strong opioid therapy for persistent background pain. Administered as a buccal spray, Sativex is composed primarily of tetrahydrocannabinol and cannabidiol.

Marketed there by Bayer, Sativex was first indicated in Canada in 2005, as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis. Health Canada has approved Sativex for both indications under the NOC/c policy, which includes a commitment to ongoing clinical research.

The efficacy of Sativex has been demonstrated in a double-blind, placebo-controlled, parallel-group study in patients with cancer pain. Participants in the study had advanced cancer and were experiencing pain that was not responding adequately to strong opioid medication (eg, morphine). In addition to study medication, all patients remained on their existing opioid and other analgesic medication during the trial. In this study, Sativex achieved a statistically significant improvement in pain relief, in comparison with placebo. The study further showed that in patients with advanced cancer who were already taking the strongest available pain treatments, more than four out of ten patients taking Sativex were able to achieve a further clinically important reduction in pain.

In clinical trials, the most frequent side effects with Sativex included nausea, fatigue, dizziness and application site reactions. These were usually mild or moderate in severity and often resolved with down-titration or interruption of treatment.

FDA requests more time to review Frova sNDA

The FDA has requested an extension of the 19th August review date in order to have more time to review the sNDA for Frova (frovatriptan) 2.5mg tablets, for the additional indication of short-term (six days) prevention of menstrual migraine. Vernalis currently co-promotes Frova with its North American licensing partner, Endo Pharmaceuticals.

The FDA indicated that it will provide a revised timeline to Endo and Vernalis. Until the companies receive further information, they intend to continue with their existing commercial plan. The FDA has not currently requested any additional information or clinical trial data.

Eslax receives Japanese approval

The Japanese Ministry of Health, Labour and Welfare has approved rocuronium bromide, Organon's (Akzo Nobel) neuromuscular-blocking agent for use during general anaesthesia, under the brandname, Eslax. This muscle relaxant has a fast onset of action and is widely used in the US, Canada and many European countries (marketed under the brandnames, Zemuron/Esmeron).

Nippon Organon is preparing to introduce the drug in the course of this year. Eslax' rapid onset of action allows almost all patients to be intubated within approximately one minute of its administration. Additionally, it will come in a ready-to-use solution and no active metabolites with the drug have been identified in clinical trials, to date, which further contributes to safety and ease of continuous infusion.

Anesiva receives FDA approval for Zingo

On 16th August, the FDA approved Anesiva's Zingo (lidocaine hydrochloride monohydrate) powder intradermal injection system, which provides rapid, topical, local analgesia to reduce the pain associated with venous access procedures, such as intravenous (iv) insertions or blood draws, in children aged three to 18 years. Zingo is an easy-to-administer, single-use, needlefree system containing 0.5mg sterile lidocaine powder.

Data from two pivotal, placebo-controlled, Phase III studies, which collectively enrolled 1,109 patients across 15 US clinical centres, demonstrated that Zingo provided statistically significant pain relief in children aged three to 18 years undergoing venous access procedures, such as iv line placements. These data indicated that treatment with Zingo quickly and effectively reduced pain when given just one to three minutes prior to the venous access procedure. Zingo was well tolerated, with the most common adverse reactions being erythema, petechiae and oedema at the site of administration. Anesiva is now studying Zingo in a large Phase III trial in adults. The company will use the data generated in that trial as the basis for an FDA filing to expand the label to include adults.

Vimpat MAA submitted for DNP

Schwarz Pharma (UCB) has filed an MAA for Vimpat (lacosamide) as therapy for diabetic neuropathic pain (DNP) with the EMEA, which has been accepted for review. Vimpat, taken as an oral tablet, has been dosed twice daily in clinical trials. Possible tablet strengths range from 50 to 300mg.

Vimpat is an anticonvulsant drug of a new generation with a novel dual mode of action, acting on CRMP-2 (collapsing response mediator protein-2) and sodium channel slow inactivation. Vimpat has not shown clinically relevant interactions with other anti-epileptic drugs, oral contraceptives or food, neither have oedema or weight gain been reported during the clinical trial programme. Dizziness and nausea were the most commonly-reported side effects, whereas somnolence was notably low. An MAA for Vimpat as adjunctive therapy for adult patients with epilepsy with partial onset seizures was accepted for review by the EMEA in May. Filing in the US is planned for the fourth quarter of 2007.

Ranbaxy receives FDA approval for generic Norco/Vicodin/Lortab

On 16th August, Ranbaxy Laboratories received FDA approval to manufacture and market hydrocodone bitartrate+acetaminophen tablets in 7.5/750, 10/500, 5/500 and 10/325mg strengths. The formulations are bioequivalent and have the same therapeutic effect as that of the reference listed drugs: Norco Tablets 10/325mg (Watson Pharmaceuticals), Vicodin Tablets 5/500mg and Vicodin ES Tablets 7.5/750mg (Abbott Laboratories), and Lortab Tablets 10/500mg (UCB). Ranbaxy's tablets are indicated for the relief of moderate-to-moderately severe pain and will be launched in a November time period.

AGREEmENT NEwSOno obtains Japanese rights to CNS 7056

Ono Pharmaceutical has obtained the exclusive rights in Japan to develop and commercialise CeNeS Pharmaceuticals' CNS 7056, a benzodiazepine that is being developed as a general anaesthetic and



CNS Drug News

short-acting sedative. Under the terms agreed, Ono will pay up-front and milestone payments based on development stage, as well as royalties on sales of CNS 7056.

CNS 7056 is a short-acting general anaesthetic and sedative that acts on GABA-A receptors. Preclinical studies demonstrate that after intravenous administration, the compound rapidly induces deep sedation that is maintained during continuous administration. Importantly, the sedative effects rapidly disappear after cessation of administration. The rapid offset of effect of the compound is due to its metabolism by esterase enzymes that are widely distributed throughout the body. It is therefore anticipated that CNS 7056 could be clinically developed as a sedative agent for the induction and maintenance of anaesthesia, plus as a sedative for mechanical ventilation in the intensive care unit.

CeNeS plans to start a Phase I study in the US in the first half of 2008, while Ono expects to start a Phase I study in Japan as early as the second half of 2008.

Paladin signs licensing agreement for Glide Pharma's Glide SDI

Paladin Labs has entered into an exclusive licence and distribution agreement to develop and market Glide Pharmaceutical Technologies' (Glide Pharma) innovative Glide SDI (solid-dose injector) needlefree drug-delivery products in Canada. Under the terms agreed, Paladin will assume responsibility for local clinical trials, registration, marketing, sales and distribution of at least three of Glide Pharma's pipeline products, which include needlefree versions of sumatriptan for the treatment of migraine and fentanyl for breakthrough pain.

The companies expect the first product under this agreement to be filed for Canadian regulatory approval in 2009. Further terms were not disclosed.

Icagen/Pfizer enter pact for pain and related disorders

Icagen has entered into a worldwide collaboration and licensing agreement with Pfizer for the discovery, development and commercialisation of compounds that modulate three specific sodium ion channels as new potential treatments for pain and related disorders. Under the terms agreed, the companies will combine resources to identify compounds that target these three ion channels in a global research and development collaboration. The companies will form a joint research committee to monitor and oversee the

collaboration. Pfizer will fund all aspects of the collaboration, including the research and preclinical development efforts at Icagen, in addition to having exclusive worldwide rights to commercialise products that result from the partnership. Pfizer will make an equity investment in Icagen in connection with the collaboration.

The ion channel targets included in the collaboration are important in the generation of electrical signals in nerve fibres that mediate the initiation, transmission and sensation of pain. In preclinical studies, compounds identified by Icagen have demonstrated efficacy in pain models. Icagen has also established a broad portfolio of intellectual property in this area, covering multiple promising compounds targeting sodium channels.

Under the terms of the agreement, Pfizer will provide US$38 million in committed funding to Icagen over the first two years of the collaboration, including an initial up-front licence fee of US$12 million, up to US$15 million through an equity commitment, plus R&D funding. The equity commitment comprises an initial investment in Icagen common stock in the amount of US$5 million at fair market value on the effective date of the agreement and an equity put option, exercisable by Icagen, to sell to Pfizer at market value up to US$10 million of common stock, subject to certain terms and conditions, at any time during the first 18 months following the signing of the agreement. Additionally, Icagen is eligible to receive US$359 million in research, development, regulatory and commercialisation milestones for each product. Icagen is also eligible to receive tiered royalties, against which the commercialisation milestones are creditable, depending upon sales achieved.

EKR acquires US rights to Pacira's DepoDur

EKR Therapeutics has acquired exclusive US marketing and distribution rights to DepoDur (morphine extended-release liposome injection) from Pacira Pharmaceuticals, which will continue to manufacture the product. DepoDur, which utilises DepoFoam technology, is the only extended-release opioid that is approved by the FDA for epidural use.

A single injection of DepoDur into the lumbar epidural space may provide pain relief for up to 48 hours following major surgery without the restrictions and potential complications associated with an in-dwelling epidural catheter.

ProStrakan enters agreements with Orexo and LG

For details, see Drugs Used in Nausea & Vertigo, Agreement News.

ANTI-EPILEPTICSR&D UPDATE

Valeant completes enrolment in first retigabine Phase III epilepsy study

Valeant Pharmaceuticals International has completed enrolment in the first retigabine pivotal study, RESTORE (Retigabine Efficacy and Safety Trials for Partial Onset Epilepsy) 1. The RESTORE trials are two large, randomised, double-blind, placebo-controlled, multi-centre, parallel-group, pivotal Phase III studies that will evaluate the safety and efficacy of retigabine, a first-in-class neuronal potassium channel opener, in patients with refractory partial onset seizures who are receiving one, two or three concomitant anti-epileptic drugs.

The primary endpoint of RESTORE 1 is a change in total partial seizure frequency per four weeks from baseline to the double-blind period (titration phase and maintenance phase). For EMEA review, the primary endpoint is the proportion of responders, where a responder is defined as a patient experiencing a reduction of at least 50 per cent in total partial seizure frequency per four weeks from baseline to double-blind period. A total of 306 patients have been enrolled into RESTORE 1, which is being conducted at 49 sites across the US, Argentina, Mexico, Brazil and Canada, and Valeant anticipates the study's completion in the first quarter of 2008.

RESTORE 2, the second pivotal trial in the programme, is targeted to enrol 510 patients and is being conducted in 72 sites across Europe, Israel, Australia, South Africa and the US, with full enrolment expected

ANTI-EPILEPTICS


CNS Drug News

in the autumn. At the completion of these trials, retigabine will have been studied in more than 1,500 subjects, including more than 1,100 patients with epilepsy. More than 350 of these patients will have taken retigabine for 12 or more months, including a few who have taken the drug for over six years. To date, >80 per cent of eligible patients have chosen to enter into the open-label extension studies that follow directly from the RESTORE programme.

Ovation initiates clinical trial of iv carbamazepine

Ovation Pharmaceuticals has expanded its CNS development pipeline with the initiation of a pivotal clinical trial to support an NDA for intravenous (iv) carbamazepine in adult patients with epilepsy. To date, there have been no iv options for patients that are therapeutically equivalent to oral carbamazepine when replacement therapy is required.

As the first and only injectable form of the widely-used oral anti-epileptic drug, carbamazepine, the product is an important alternative for patients with epilepsy who may be hospitalised or otherwise temporarily unable to take oral carbamazepine. The trial is designed to evaluate the bioequivalence of the iv doses with oral doses, as well as assess the safety, tolerability and pharmacokinetics of iv carbamazepine relative to orally-administered carbamazepine. Fifteen investigative sites around the US have begun recruiting patients with

epilepsy who are currently on stable doses of oral carbamazepine. The sequential, open-label, 65-day study has already accepted more than 40 patients and plans to enrol 96 in total.

PRODUCT NEwSFDA approves Cerebyx generics

On 6th August, the FDA approved the first generic versions of Pfizer's Cerebyx (fosphenytoin), with the following companies' applications having been cleared: Abraxis BioScience, Apotex, Baxter, Bedford (Ben Venue Laboratories [Boehringer Ingelheim]), Hospira, Teva Pharmaceutical Industries, Wockhardt and IV Therapeutics.

Cerebyx is used for the control of generalised convulsive status epilepticus, as well as the prevention and treatment of seizures occurring during neurosurgery. It can also be substituted, short-term, for oral phenytoin. Abraxis has confirmed that it expects to commence marketing its fosphenytoin sodium injection 100mg/2mL and 500mg/10mL vials, which are preservative- and latex-free, during August.

In addition, GeneraMedix has launched its preservative-free fosphenytoin sodium injection, 50mg phenytoin sodium equivalent/mL in 2 and 10mL vials in the US.

EATING DISORDERSR&D UPDATE

Interim Phase I trodusquemine data presented

At the IBC's 12th Annual World Congress on Drug Discovery & Development of Innovative Therapeutics, held from 6th to 8th August, in Boston, MA, Genaera presented interim data from the first Phase I study of trodusquemine (MSI-1436) for the treatment of obesity.

The presentation summarised the design of the double-blind, randomised, placebo-controlled, single ascending-dose study to evaluate the safety and pharmacokinetics (PKs) of trodusquemine

in otherwise healthy obese volunteers. The presentation included interim data from the initial cohorts in the trial, which included safety and PK data from 20 treated subjects and eight vehicle controls in four sequential dose groups. The PK profiles, thus far, show a predictable pattern, with minimal between-subject variability and linearity across the range of doses studied. To date, no serious adverse events have been reported. It was emphasised that further study is needed to establish dose-limiting toxicity and proof-of-concept in humans.

Trodusquemine is the first drug candidate that acts both centrally and peripherally to selectively inhibit the established, validated target, protein tyrosine phosphatase-1B (PTP-1B). By inhibiting PTP-1B, the drug is expected to decrease appetite and normalise blood glucose.

DRUGS USED IN NAUSEA & VERTIGOAGREEmENT NEwS

ProStrakan enters agreements with Orexo and LG

Orexo has entered into a joint-venture (JV) agreement with ProStrakan in the Nordic territories, in order to establish a sales operation that will be equally owned. The new entity will have Nordic sales rights for both companies' portfolio, which will include currently-marketed and future products, such as Sancuso (granisetron), ProStrakan's transdermal patch for the prevention of chemotherapy-induced nausea and vomiting (CINV), plus Rapinyl (fentanyl), Orexo's patented product for the treatment of cancer breakthrough pain, to which ProStrakan holds European distribution rights. ProStrakan's existing Swedish affiliate, ProStrakan AB, will be used as the JV company. Orexo is investing £1.3 million (SKr 17.9 million), through a directed share issue, to acquire 50

per cent of the company. The JV will initially trade as ProStrakan AB from its offices in Malmo, Sweden. ProStrakan has entered into an exclusive supply agreement with the JV for the commercialisation of its current products in the Nordic countries. Sales will be booked on a 50:50 basis by the parent companies, and costs and profits will be similarly shared.

In addition...

LG Life Sciences has signed an exclusive distribution agreement for Sancuso. Under the terms agreed, ProStrakan will receive up-front and milestone payments, subject to the achievement of certain approvals and sales targets, of up to US$6 million. ProStrakan will exclusively supply Sancuso to LG and receive an undisclosed royalty rate on sales generated by LG in South Korea. ProStrakan submitted an NDA to the FDA in June and an MAA across Europe in July. Following approval in

EATING DISORDERS / DRUGS USED IN NAUSEA & VERTIGO


CNS Drug News

the US, LG will seek approval for Sancuso in South Korea. ProStrakan's transdermal patch delivers granisetron, an established 5-HT

3 receptor

antagonist that treats CINV, steadily into the bloodstream without the need for injection or having to swallow pills. ProStrakan reported positive results from the pivotal Phase III programme on Sancuso in patients undergoing multi-day chemotherapy in December 2006.

Par granted North American rights to Zensana

Par Pharmaceutical Companies has entered into an exclusive licensing agreement with Hana Biosciences for the development and commercialisation of Zensana (ondansetron) Oral Spray (OS) in North America. Hana licensed exclusive US and Canadian rights to the product from NovaDel Pharma in October 2004. Zensana is the first 5-HT

3 antagonist to deliver ondansetron, an anti-emetic therapy used in

the prevention of nausea and vomiting as a result of chemotherapy, radiation and surgery, in an OS formulation.

Under the terms agreed, Par gains exclusive North American rights to Zensana and will have primary responsibility for the compound's development, all regulatory filings with the FDA, and sales and marketing. Hana will receive an initial payment of US$5 million through the sale of common stock at a share price of US$2, a 25 per cent premium. Hana may also receive up to US$45 million in development and commercialisation milestone payments. Following Zensana's approval, Hana will be eligible to receive royalty payments on sales exceeding specified levels.

Simultaneous to this sublicence, NovaDel and Hana have amended their licence agreement for Zensana in North America. The key financial provisions of the agreement remain unchanged, with NovaDel expecting to receive a milestone payment upon approval and royalties ranging from 15 to 25 per cent of net sales upon successful commercialisation of the drug. Par and NovaDel anticipate collaborating on the development of a formulation of Zensana.

GENERAL DEVELOPmENT NEwSR&D UPDATE

Lexicon's LX-6171 completes Phase I trials

LX-6171, an oral drug candidate for cognitive disorders, has successfully completed Phase I trials. According to Lexicon Pharmaceuticals, the safety and exposure profile that was observed in this phase encourages it to proceed with further development and the company anticipates progressing the compound into Phase II trials.

The recently-completed Phase Ib trial of LX-6171 was designed as a randomised, double-blind, placebo-controlled, multiple ascending-dose study to evaluate safety, tolerability and pharmacokinetics over seven days of dosing in normal, healthy young (age 18-50 years) and elderly (age 65-80 years) volunteers. LX-6171 was well tolerated at all dose levels and showed good systemic exposure. Over the seven-day trial, no dose-limiting toxicities were observed and exposure levels supported a once-daily dosing regimen.

LX-6171 is an oral drug candidate that was generated by Lexicon's small-molecule drug-discovery team and is being developed to treat disorders characterised by cognitive impairment, such as Alzheimer's disease, schizophrenia or vascular dementia. Its target, a membrane protein that is expressed exclusively in the CNS, was identified through Lexicon's Genome 5000 programme through the study of mouse knockouts that showed enhanced learning and memory. LX-6171 is a potent oral inhibitor of its target and reproduces these effects in animal models.

LX-6171 is being developed under a product development collaboration with Symphony Capital Partners and its co-investors. Under the terms of the arrangement, US$45 million was provided to Symphony Icon, a newly-created company established to fund and accelerate development of Lexicon's first three product candidates and to hold the licence to the intellectual property. An additional US$15 million of equity capital was provided directly to Lexicon for general corporate purposes.

Lexicon expects to receive full audited results of its Phase I trials in the third quarter of 2007 and anticipates filing with European regulatory authorities for approval of its Phase II plans in the fourth quarter. Pending regulatory approval, the company plans to initiate Phase II trials in the first quarter of 2008.

Eisai updates clinical progress

Eisai has released an update on its progress with clinical studies since April. It confirmed that:

a Phase III trial has been initiated with the Alzheimer's disease therapy, Aricept (donepezil), for a sustained-release formulation of the product, which was originally approved as a tablet formulation; the Dainippon Sumitomo Pharma-originated product, Zonegran (zonisamide), which is currently indicated for adjunctive therapy in the treatment of adult patients with partial seizures, has entered a Phase III trial for epilepsy monotherapy in Europe; anda Phase II study with E2007, a compound that selectively antagonises the AMPA-type glutamate receptor, has been initiated for neuropathic pain in the US.

For details of a further Aricept study and a judicial review affecting its use in the UK, see Neurodegenerative Disorders, Alzheimer's Disease - R&D Update and Product News, respectively.

Neuren sets out plans for Hamilton acquisition

Neuren Pharmaceuticals is looking to acquire Hamilton Pharmaceuticals in a transaction that is expected to position the company as a key player in the CNS field, specialising in the cognitive and psychological effects of CNS injury. Hamilton's shareholders have unanimously approved the transaction, while Neuren has yet to seek shareholder approval. A definitive legal agreement is being prepared.

Through the acquisition, Neuren will obtain a Phase IIb compound, Motiva, which is from the acetam class of compounds and being developed for psychological and cognitive disorders resulting from stroke, traumatic brain injury, and Alzheimer's and Parkinson's diseases. Exclusive rights to develop and commercialise Motiva intellectual property in the US and EU were licensed to Hamilton by Daiichi Pharmaceutical (now Daiichi Sankyo) in 2004. The compound already has proven clinical safety and efficacy in 1,700 patients.

Neuren will not be retaining any Hamilton management and no cash payment will be made for the acquisition. The company will acquire 100 per cent of Hamilton in exchange for US$4.4 million in Neuren ordinary shares at the average closing share price for the last

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GENERAL DEVELOPmENT NEwS


CNS Drug News

five trading days prior to the 31st July announcement, in addition to contingent Motiva-related milestones, such as successful completion of Phase II, initiation of a Phase III pivotal study, first filing of an NDA or equivalent and first approval of an NDA or equivalent. The three major venture capital investors from Hamilton, Vivo Ventures, CNF Investments and Index Ventures, will become shareholders in Neuren through the transaction, and upon closing, Vivo Ventures and CNF will invest US$3 million in the company.

Motiva has been studied in two randomised clinical trials, which showed clinically and statistically significant efficacy of the drug, and in 2006, a third trial in post-stroke patients was suspended due to poor contract research organisation execution. Motiva's FDA-approved IND remains open and there are sufficient quantities of the compound available to complete a Phase II trial. In 2008, Neuren intends to conduct a larger Phase II trial of Motiva, with a broader range of endpoints and tighter patient attributes. The company will thereby be conducting one Phase III trial and three Phase II trials in 2008, all focusing on cognitive and psychological effects of acute CNS injury, with results expected by early 2009.

CCK finding offers potential for mood disorder and epilepsy therapies

Researchers at the University of California, Irvine have discovered a novel molecular switch that powerfully modulates nerve cell activity, which offers the potential for new mood disorder and epilepsy treatments.

For this research, which was published in the 5th August online issue of Nature Neuroscience (10.1038/nn1952), the scientists investigated the role of the natural substance, cholecystokinin (CCK), in modulating communication between cells in the brain. CCK is one of the most abundant peptides in the brain and is linked to psychiatric disorders such as anxiety, depression and schizophrenia.

The study looked at the hippocampus, damage or alterations to which can cause cognitive disorders, epilepsy and mental illness. Using electrophysiological measurements, the researchers showed that CCK functions in the brain as an extremely specific switch with a highly-unusual dual action. On the one hand, CCK enhances the synthesis and release of natural endocannabinoid substances from a particular class of nerve cells known to modulate neuronal excitability in brain circuits critical for cognition and mood, while on the other hand, CCK robustly increases electrical activity in a different class of nerve cells that play critical roles in learning and memory.

According to the investigators, by linking CCK actions to endocannabinoids, the study provides novel possibilities for the future development of therapies for a number of neurological diseases. The link between CCK and cannabinoids can now be further investigated to determine how its modulation by either pharmacological or genetic means alters excitability in the hippocampus.

Pfizer set to triple its Phase III portfolio by 2009

Further to its recent pipeline update, Pfizer has confirmed that it now has 99 programmes in development, with 38 in Phase I, 47 in Phase II, 11 in Phase III and three in registration, awaiting action from regulatory authorities. Since December 2006, three compounds have entered Phase III, 14 have entered Phase II and seven have entered Phase I, while a total of 13 programmes were discontinued. The company reiterated that the number of Phase II programmes reflects continued progress towards its target of tripling its Phase III portfolio by 2009. It is also targeting having a steady stream of four new medicines per

year from internal research and development, starting in 2011. While the total number of Phase I compounds has declined since 2006, the majority of Pfizer's Phase I starts are targeted for the second half of 2007.

The pipeline includes 17 potential treatments for pain and inflammation, as well as 17 for neurological disorders. The update also includes 85 new molecular entities, plus 14 potential new indications or enhancements for medicines, including Lyrica (pregabalin) and Geodon (ziprasidone).

The updated pipeline shows eight candidates for pain, with an additional nine in the related area of inflammation. Data from a Phase II trial of S,S-reboxetine, a selective norepinephrine reuptake inhibitor, in patients with fibromyalgia, are encouraging. Phase II trials have progressed as monotherapy or in combination with pregabalin for post-herpetic neuralgia and a Phase II trial is being planned for painful diabetic neuropathy.

For PF-4383119, Pfizer has completed a Phase IIa trial in osteoarthritis (OA) with a positive read-out and as a result, will complete a multi-dose trial in OA, plus initiate studies in other settings of pain, during 2007. A Phase II trial recently started to compare PF-592379 with oxycodone in severe OA pain.

Pfizer has received approval for Lyrica's fibromyalgia indication, which is an important line extension in the US. The product is currently in Phase III testing for epilepsy monotherapy and generalised anxiety disorder (GAD) in the US, as well as Phase II for restless legs syndrome. Additionally, Geodon is in Phase II for adjunctive bipolar depression and Phase III for bipolar relapse prevention (for forecasts of Geodon's future sales, see In Focus).

Pfizer is continuing with work on alpha-2-delta compounds for patients with neurological disorders and is proceeding with broad confirmatory development of PD-332334, which is in Phase II studies for the treatment of GAD. Pfizer scientists continue to believe that molecules with this mechanism of action are potentially important new therapies for the treatment of illnesses such as insomnia and vasomotor symptoms. The company also has several new approaches to the treatment of Alzheimer's disease in ongoing Phase II trials.

Research offers hope for new antisense drug class

According to research published in the 14th August issue of Neurology (2007;69:699-700), a new type of treatment significantly reduces the severity of muscle weakness in myasthenia gravis (MG), giving hope for a new class of antisense drugs to treat neurological disorders.

The drug, oral EN101 antisense, inhibits the production of acetylcholine esterase, an important enzyme in the function of neuromuscular junctions. This is the first time that the scientists from the Hadassah Hebrew University Medical Center in Israel have been able to show that antisense is effective and safe when taken orally for a neurological disease.

For the study, 16 people with MG were given daily doses of oral EN101 antisense for four days and monitored for one month. Four of the people later took the drug for one month.

The study found that oral antisense reduced disease severity by an average of 46 per cent, with patients experiencing improvements in both muscle function and swallowing time, as well as the disappearance of a drooping eyelid. Side effects reported during the study were dryness of the eyes and mouth.



CNS Drug News

It is hoped that this discovery may have implications beyond MG. Further study is needed to investigate whether oral antisense may become another mode of therapy in neuromuscular disease. The researchers noted that these preliminary results should be evaluated with caution since this was an open-label study. Further research is under way to investigate the effects of this drug over a longer period of time.

Editor's note: EN101 (now known as Monarsen) was awarded orphan drug status by the FDA and is in development by Ester Neurosciences, which supported the current study.

Noven completes JDS acquisition

Noven Pharmaceuticals has completed its acquisition of JDS Pharmaceuticals, a specialty pharmaceutical company that currently markets two branded prescription psychiatry products in the US: Lithobid (lithium carbonate) for bipolar disorder (BPD) and Pexeva (paroxetine) for depression, panic disorder, obsessive-compulsive disorder and generalised anxiety disorder. The company also has a pending NDA for Stavzor (valproic acid softgel) in BPD, migraine and epilepsy, as well as a product in Phase III trials, Lithium QD (once-daily lithium) for BPD. JDS' non-hormonal product, Mesafem (low-dose paroxetine mesylate), which is entering Phase III development for vasomotor symptoms associated with menopause, is also complementary with Noven's expertise in women's health. The purchase price for the acquisition was US$125 million cash paid at closing on 14th August, plus the assumption of approximately US$10 million in net non-contingent liabilities.

PRODUCT NEwSFDA approves first generic Dantrium injection

On 25th July, the FDA approved US WorldMeds' dantrolene injection 20mg/vial, which is the first therapeutically-equivalent injectable version of Procter & Gamble's Dantrium. Used in the treatment of spasticity in stroke, multiple sclerosis, cerebral palsy and spinal cord injury, P&G's product was first approved in 1979.

AGREEmENT NEwSNeurocrine in-licenses valnoctamide isomers from Yissum

Neurocrine Biosciences has entered into an exclusive worldwide licensing agreement for the development and commercialisation of valnoctamide stereoisomers with Yissum Research Development of the Hebrew University of Jerusalem in Israel. Valnoctamide and its individual stereoisomers have been shown to be active in a number of preclinical models and have the potential to treat epilepsy, bipolar disorder (BPD) and neuropathic pain. The parent compound is a uniform combination of four valnoctamide stereoisomers that was marketed as an anxiolytic in several European countries.

While from the same chemical class as valproate, which is currently approved for use in the treatment of epilepsy, migraine prophylaxis and BPD, in preclinical studies completed, to date, this stereoisomer of valnoctamide has not been associated with the safety concerns (ie, teratogenicity and hepatotoxicity) of valproate and its related analogues. The clinical development of one of the stereoisomers of valnoctamide is intended to offer patients suffering from neurological

and psychiatric disorders a safer and potentially more efficacious treatment option. Neurocrine intends to initiate clinical studies after submitting an IND application in the first half of 2008.

BrainStorm restructures agreement with Ramot

BrainStorm Cell Therapeutics has reached a restructured research and licence agreement with Ramot at Tel Aviv University with respect to payment obligations for its technology licence, plus the Double U Fund, a lender to the company, has also come to an agreement over funds owed to it by BrainStorm. The waiver and release from Ramot ensures that BrainStorm's technology licence is securely held by the company.

BrainStorm holds rights to develop and commercialise NurOwn patent-pending technology, which allows for the differentiation of bone marrow-derived stem cells (SCs) into functional neurons and astrocytes, as demonstrated in animal models, through the licensing agreement with Ramot. For details of preclinical testing with BrainStorm's human bone marrow-derived mesenchymal SCs, see Neurodegenerative Disorders, Parkinson's Disease - R&D Update.

Valeant's candidate selection triggers payment to Ardea

Ardea Biosciences has received the first milestone payment of US$0.5 million from Valeant Pharmaceuticals International under the companies' December 2006 collaboration. Valeant's selection of several pre-IND candidates for its next-generation potassium channel opener programme triggered this milestone payment, which recognises the continuing progress in the identification of novel next-generation compounds to treat serious diseases. The companies agreed to collaborate exclusively to design a series of compounds to treat neurological disorders.

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Abbott ............................................................................................................................................4, 23, 24Abraxis BioScience ..............................................................................................................................26Accentia Biopharmaceuticals ........................................................................................................ 11Acrux ...........................................................................................................................................................21Akzo Nobel .........................................................................................................................................4, 24Alnylam Pharmaceuticals ................................................................................................................14Alphapharm ............................................................................................................................................17ALZA ..............................................................................................................................................................4Anesiva ......................................................................................................................................................24Apotex........................................................................................................................................................26Applied NeuroSolutions ......................................................................................................................9Ardea Biosciences ................................................................................................................................29AstraZeneca .................................................................................................................................4, 17, 23Avanir Pharmaceuticals ....................................................................................................................20Avigen ........................................................................................................................................................22Azur Pharma ...........................................................................................................................................20Baxter .........................................................................................................................................................26Bayer ......................................................................................................................................................4, 24Bayer Schering Pharma ........................................................................................................................4Bayhill Therapeutics ...........................................................................................................................10Ben Venue Laboratories ...................................................................................................................26Boehringer Ingelheim .......................................................................................................................26BrainStorm Cell Therapeutics ...................................................................................................6, 29Bristol-Myers Squibb .............................................................................................................................4Cambridge Laboratories ..................................................................................................................14CeNeS Pharmaceuticals ....................................................................................................................24Cephalon ...........................................................................................................................................18, 23Chelsea Therapeutics .........................................................................................................................15Chiesi Farmaceutici .............................................................................................................................13Chugai Pharmaceutical .....................................................................................................................16Clinical Data ..........................................................................................................................................3, 4Cytokine PharmaSciences ............................................................................................................... 11Daiichi Sankyo .......................................................................................................................................27Dainippon Sumitomo Pharma ..........................................................................................5, 15, 27DOV Pharmaceutical ..........................................................................................................................16Ecole Polytechnique Fédérale de Lausanne ..........................................................................12Eden Biodesign .....................................................................................................................................10Eisai ................................................................................................................................................1, 6, 9, 27EKR Therapeutics .................................................................................................................................25Elan ..............................................................................................................................................................23Eli Lilly ................................................................................................................................................4, 9, 19Emory University ................................................................................................................................5, 8Encore Therapeutics ...........................................................................................................................21Endo Pharmaceuticals .......................................................................................................................24EPIX Pharmaceuticals .........................................................................................................................10Ester Neurosciences ............................................................................................................................29Forest Laboratories ..................................................................................................................1, 16, 17Genaera .....................................................................................................................................................26GeneraMedix ..........................................................................................................................................26Georgetown University .......................................................................................................................8GlaxoSmithKline .......................................................................................................................4, 10, 23Glide Pharma ..........................................................................................................................................25GW Pharmaceuticals ..........................................................................................................................24Hadassah Hebrew University Medical Center ......................................................................28Hamilton Pharmaceuticals ..............................................................................................................27Hana Biosciences ..................................................................................................................................27Hebrew University of Jerusalem ..................................................................................................29Heinrich-Heine University ..................................................................................................................8Hospira.......................................................................................................................................................26Hydra Biosciences ................................................................................................................................21Icagen .........................................................................................................................................................25Intellect Neurosciences .....................................................................................................................10IV Therapeutics ......................................................................................................................................26Janssen-Cilag .................................................................................................................................... 4, 19Janssen Pharmaceutica .......................................................................................................................1Javelin Pharmaceuticals ...................................................................................................................21Jazz Pharmaceuticals ..................................................................................................................16, 20JDS Pharmaceuticals ..........................................................................................................................29Johns Hopkins .................................................................................................................................11, 17Johns Hopkins University ................................................................................................................ 11Johnson & Johnson ....................................................................................................................1, 4, 19Karolinska Institutet ...............................................................................................................................6KineMed ....................................................................................................................................................13Knoll ............................................................................................................................................................23Lexicon Pharmaceuticals ............................................................................................................ 5, 27LG Life Sciences .....................................................................................................................................26Lundbeck .............................................................................................................................1, 4, 5, 16, 17Medical Research Council Technology .....................................................................................10MedImmune ...........................................................................................................................................17

Medistem Laboratories .....................................................................................................................18Medtronic .................................................................................................................................................14Merck & Co ..........................................................................................................................................3, 22Merck KGaA .............................................................................................................................................17Merck Sharp & Dohme .........................................................................................................................3Merz................................................................................................................................................................1Montréal Neurological Institute ...................................................................................................10National Hospital for Neurology and Neurosurgery .........................................................22National Institute of Mental Health ............................................................................. 16, 18, 20National Institutes of Health ........................................................................................6, 12, 14, 20Navinta.......................................................................................................................................................14NeurAxon .................................................................................................................................................23Neuren Pharmaceuticals ..................................................................................................................27Neurocrine Biosciences ....................................................................................................................29Neuromed Pharmaceuticals ..........................................................................................................22NovaDel Pharma ..................................................................................................................................27Novartis .......................................................................................................................................1, 4, 6, 15Noven Pharmaceuticals .............................................................................................................20, 29Nutra Pharma .........................................................................................................................................22Ohio State University ......................................................................................................................... 11Ono Pharmaceutical ...........................................................................................................................24Opexa Therapeutics ........................................................................................................................... 11Orexo ...................................................................................................................................................25, 26Organon ...............................................................................................................................................4, 24Orion ..............................................................................................................................................................6Otsuka ...........................................................................................................................................................4Ovation Pharmaceuticals .................................................................................................................26Pacira Pharmaceuticals .....................................................................................................................25Paladin Labs .....................................................................................................................................15, 25Par Pharmaceutical Companies ...................................................................................................27Pfizer ..........................................................................................................................1, 4, 6, 9, 25, 26, 28Pozen ..........................................................................................................................................................23Prana Biotechnology .............................................................................................................................8Procter & Gamble .................................................................................................................................29ProStrakan .................................................................................................................................25, 26, 27QRxPharma .............................................................................................................................................14Ranbaxy Laboratories ........................................................................................................................24ReceptoPharm .......................................................................................................................................22Roche ..................................................................................................................................................... 5, 16Samaritan Pharmaceuticals ...............................................................................................................8sanofi-aventis .................................................................................................................................... 4, 16Santhera Pharmaceuticals ...............................................................................................................14Schwarz Pharma ...................................................................................................................................24Shanghai Jiao Tong University .........................................................................................................3Shire................................................................................................................................................. 1, 15, 20Sirtris Pharmaceuticals ...............................................................................................................12, 15Socratech .....................................................................................................................................................8Solvay .............................................................................................................................................5, 16, 20Soochow University ............................................................................................................................22Symphony Capital Partners ............................................................................................................27Takeda ........................................................................................................................................................14Tel Aviv University ...........................................................................................................................5, 29Teva Pharmaceutical Industries ....................................................................................................26Tikvah Therapeutics ....................................................................................................................13, 14Tokyo Institute of Psychiatry ..........................................................................................................15TorreyPines Therapeutics ................................................................................................................21Translational Genomics Research Institute ............................................................................ 11UCB ..............................................................................................................................................................24University College London ................................................................................................................3University of Alabama .......................................................................................................................14University of Birmingham................................................................................................................10University of California ................................................................................................ 12, 21, 22, 28University of Central Florida ..............................................................................................................6University of Edinburgh .......................................................................................................................3University of Georgia .......................................................................................................................5, 8University of Glasgow ...........................................................................................................................3University of Mainz .................................................................................................................................8University of North Carolina ..............................................................................................................4University of Oxford ......................................................................................................................3, 20University of Rochester ........................................................................................................................7University of Wisconsin-Madison ................................................................................................12US WorldMeds .......................................................................................................................................29Valeant Pharmaceuticals International ...................................................................... 16, 25, 29Vernalis ......................................................................................................................................................24Watson Pharmaceuticals ..................................................................................................................24Wockhardt ...............................................................................................................................................26Wyeth ....................................................................................................................................................5, 20Yissum Research Development ....................................................................................................29

COmPANy INDEXCOmPANy INDEX


CNS Drug News

Abilify ............................................................................................................................................................4AC-5216 ...............................................................................................................................................15, 17acetaminophen ....................................................................................................................................24ACP-103 ........................................................................................................................................................5agalsidase alpha ...................................................................................................................................15Akatinol ........................................................................................................................................................1amisulpride ................................................................................................................................................4Amoban ....................................................................................................................................................16Aricept ...................................................................................................................................1, 6, 9, 10, 27asenapine ....................................................................................................................................................4AV411 ..........................................................................................................................................................22Axura .............................................................................................................................................................1AZD9272 ...................................................................................................................................................18BHT-3009 ..................................................................................................................................................10bifeprunox ...................................................................................................................................5, 16, 20blonanserin ................................................................................................................................................5cannabidiol..............................................................................................................................................24carbamazepine .....................................................................................................................................26carbidopa ....................................................................................................................................................6Celexa .........................................................................................................................................................16Cerebyx .....................................................................................................................................................26chlorpromazine........................................................................................................................................4citalopram ................................................................................................................................................16clozapine .........................................................................................................................................4, 5, 20Clozaril ..........................................................................................................................................................4CNS 7056 ............................................................................................................................................24, 25cyclophosphamide ............................................................................................................................. 11Dantrium...................................................................................................................................................29dantrolene ...............................................................................................................................................29Daytrana ...................................................................................................................................................20DepoDur ...................................................................................................................................................25dextromethorphan .............................................................................................................................20donepezil....................................................................................................................................1, 6, 9, 27DOV 21,947 .......................................................................................................................................16, 17droxidopa .................................................................................................................................................15E2007 ..........................................................................................................................................................27Ebixa ...............................................................................................................................................................1Elaprase .....................................................................................................................................................15EN101 .................................................................................................................................................. 28, 29entacapone ................................................................................................................................................6escitalopram ...........................................................................................................................................17Eslax .............................................................................................................................................................24Esmeron ....................................................................................................................................................24ETI-211 ........................................................................................................................................................21Exelon ............................................................................................................................................................1FazaClo ......................................................................................................................................................20fentanyl................................................................................................................................21, 23, 25, 26Fentanyl MDTS ......................................................................................................................................21Fentora.......................................................................................................................................................23fluvoxamine ............................................................................................................................................20fosphenytoin ..........................................................................................................................................26Frova ...........................................................................................................................................................24frovatriptan .............................................................................................................................................24galantamine ...............................................................................................................................................1Geodon ................................................................................................................................................4, 28granisetron .......................................................................................................................................26, 27Haldol ............................................................................................................................................................4haloperidol .................................................................................................................................................4HC-030031 ...............................................................................................................................................22hydrocodone ..........................................................................................................................................24ibudilast .....................................................................................................................................................22idebenone ...............................................................................................................................................14idursulfase ................................................................................................................................................15Invega ............................................................................................................................................................4ketamine ...................................................................................................................................................21KM-801 ......................................................................................................................................................13lacosamide...............................................................................................................................................24levodopa ......................................................................................................................................................6Lexapro ......................................................................................................................................................17lidocaine ...................................................................................................................................................24lithium carbonate ................................................................................................................................29Lithobid .....................................................................................................................................................29Lortab .........................................................................................................................................................24Luvox ...................................................................................................................................................16, 20LX-6171 ................................................................................................................................................. 5, 27Lyrica ...........................................................................................................................................................28memantine .................................................................................................................................................1Mesafem ...................................................................................................................................................29methylphenidate .................................................................................................................................20MK-6721 ....................................................................................................................................................22modafinil ...........................................................................................................................................18, 19Monarsen .................................................................................................................................................29morphine...................................................................................................................................22, 24, 25

Motiva .................................................................................................................................................27, 28MSI-1436 ....................................................................................................................................................26N-desmethylclozapine .........................................................................................................................5Namenda .....................................................................................................................................................1naproxen ..................................................................................................................................................23NBI-18 ............................................................................................................................................................7Nipolet ..........................................................................................................................................................4Nitoman ....................................................................................................................................................14NMED-160 ................................................................................................................................................22Norco ..........................................................................................................................................................24NXN-188 ....................................................................................................................................................23olanzapine .......................................................................................................................................... 4, 19ondansetron ...........................................................................................................................................27paliperidone ..............................................................................................................................................4paroxetine ................................................................................................................................................29PBT2................................................................................................................................................................8PD-332334 ................................................................................................................................................28perphenazine ............................................................................................................................................4Pexeva ........................................................................................................................................................29PF-4383119 ...............................................................................................................................................28PF-592379 .................................................................................................................................................28phenserine .............................................................................................................................................6, 7PMI-150 ......................................................................................................................................................21pregabalin ................................................................................................................................................28Provigil .......................................................................................................................................................18PRX-03140 ................................................................................................................................................10quetiapine ............................................................................................................................................4, 17quinidine ..................................................................................................................................................20Rapinyl .......................................................................................................................................................26Razadyne .....................................................................................................................................................1reboxetine ................................................................................................................................................28Reminyl .........................................................................................................................................................1Replagal ....................................................................................................................................................15resveratrol .........................................................................................................................................12, 15retigabine ..........................................................................................................................................25, 26Revimmune ............................................................................................................................................. 11Risperdal .............................................................................................................................................. 4, 19risperidone ......................................................................................................................................... 4, 19rivastigmine ...............................................................................................................................................1rocuronium bromide .........................................................................................................................24ropivacaine ..............................................................................................................................................21RPI-78 ..........................................................................................................................................................22Sancuso ..............................................................................................................................................26, 27Sativex ........................................................................................................................................................24Seroquel .........................................................................................................................................4, 17, 18SNT-MC17 .................................................................................................................................................14sodium oxybate ....................................................................................................................................16sodium phenylbutyrate.............................................................................................................13, 14Solian .............................................................................................................................................................4SRT501 .................................................................................................................................................12, 15Stalevo ..........................................................................................................................................................6Stavzor .......................................................................................................................................................29sumatriptan ..................................................................................................................................... 23, 25tetrabenazine ..................................................................................................................................13, 14tetrahydrocannabinol .......................................................................................................................24tezampanel .............................................................................................................................................21Thorazine .....................................................................................................................................................4Tovaxin ....................................................................................................................................................... 11Trexima ......................................................................................................................................................23Trilafon ..........................................................................................................................................................4trodusquemine .....................................................................................................................................26valnoctamide .........................................................................................................................................29valproic acid ............................................................................................................................................29verapamil .......................................................................................................................................... 22, 23Verelan .......................................................................................................................................................23Vicodin .......................................................................................................................................................24Vimpat........................................................................................................................................................24vOX2:Fc ......................................................................................................................................................10Xenazina ............................................................................................................................................13, 14Xenazine ...................................................................................................................................................14Xyrem .........................................................................................................................................................16Zeldox ...........................................................................................................................................................4Zemuron ...................................................................................................................................................24Zensana .....................................................................................................................................................27Zenvia .........................................................................................................................................................20Zingo ...........................................................................................................................................................24ziprasidone .........................................................................................................................................4, 28Zonegran ..................................................................................................................................................27zonisamide ..............................................................................................................................................27zopiclone ..................................................................................................................................................16zotepine .......................................................................................................................................................4Zyprexa ................................................................................................................................................. 4, 19

COmPOUND INDEXCOmPOUND INDEX

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