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CNS Drug News

Issue No. 168 23rd August 2007


IN FOCUS Drugs denied to mild AD patients
The current mood of the schizophrenia market in UK
Page 3 A court in the UK has upheld the National Institute for Health and
Clinical Excellence's (NICE) decision that drugs for Alzheimer's disease
R&D Highlights (AD) should only be prescribed to those in the moderate stage of the
disease, denying their access to people with AD of mild severity.

Bayhill’s DNA vaccine against MS appears safe and In 2006, NICE recommended to the NHS that donepezil, galantamine
potentially efficacious and rivastigmine should only be considered as options in the
treatment of people with moderate AD, while memantine was only
Page 10 recommended as part of clinical studies for people with moderately-
Researchers identify active genes in ALS severe to severe disease. This meant that patients newly diagnosed
with mild AD were denied access to these medicines on the NHS. At
Page 11 the time it was announced, Eisai, the licence holder of donepezil, and
Pfizer condemned the decision and called it ''perverse.''
CCK finding offers potential for mood disorder and
epilepsy therapies Donepezil, marketed as Aricept by Eisai and co-promoted in the US
Page 28 with Pfizer, is a specific and reversible inhibitor of acetylcholinesterase
(AChE). Galantamine, marketed as Reminyl in the UK and Republic of
PRODUCT Highlights 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
EMEA accepts MAA filing for SNT-MC17 an AChE and butyrylcholinesterase inhibitor. Forest Laboratories
Page 14 markets memantine as Namenda in the US, whilst Lundbeck markets
the product as Ebixa, both under licence from Merz, which markets
Solvay submits complete responses to Luvox FDA it as Axura/Akatinol in a number of markets worldwide. The drug is a
approvable letters; bifeprunox not approvable voltage-dependent, moderate-affinity, uncompetitive NMDA-receptor
antagonist that blocks the effects of pathologically-elevated tonic
Page 20 levels of glutamate that may lead to neuronal dysfunction.
Anesiva receives FDA approval for Zingo The court's decision will certainly be a blow to the hopes of the
Page 24 pharmaceutical companies involved, patients and their families.
Indeed, Neil Hunt, Chief Executive of the Alzheimer's Society (www.
AGREEMENT Highlights 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
Icagen/Pfizer enter pact for pain and related disorders the treatment they need. Hunt believes that NICE failed to listen to the
Page 25 views of thousands of carers who told them drug treatments make a
huge difference to their lives.
Par granted North American rights to Zensana
Page 27 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
EDITOR since its launch in 1997. In Europe, the treatment of AD is dominated by
Lucy Vann the use of AChE inhibitors such as Aricept, Exelon and Razadyne, while
CONTRIBUTING EDITORS use of Ebixa has been slowly growing (source: CNS Drug Discoveries -
Ros Smallman, Fiona Cowie, What The Future Holds).
Matthew Dennis, Johanna Shiu, Sam Turner
Furthermore, the decision certainly adds more fuel to the ongoing
PUBLISHER debate over the cost of newly-developed/on-patent drugs and the
Eric Wigart rights/needs of patients. Although the NHS in the UK has to manage
Conditions of Sale its funds and evaluate drugs in relation to their effectiveness and cost,
• CNS Drug News must not be reproduced, abstracted, stored in a retrieval system those patients with mild AD are left asking why they are not worth
£2.50 a day.
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 Lucy Vann
Editor
©
Espicom Business Intelligence. All rights reserved.
pharma_editorial@espicom.com

Monitoring central nervous system drug developments worldwide


TABLE OF CONTENTS CNS Drug News

TABLE OF CONTENTS
Drugs denied to mild AD patients in UK.................................................................................1 Gene polymorphism predicts better ADHD outcome in teens.............................................18
In Focus.............................................................3 Medistem proposes SC therapy for autism............................................................................18
Modafinil shows potential for BPD........................................................................................18
The current mood of the schizophrenia market....................................................................3
Risperdal Consta compares favourably to oral Zyprexa........................................................19
NEURODEGENERATIVE DISORDERS.......................5 Scientists describe genetic variation linked to predisposition to schizophrenia................20
Parkinson's Disease - R&D Update........................................................5 Product News........................................................................................20
Loss of two neuron types may trigger PD symptoms...........................................................5 Solvay submits complete responses to Luvox FDA approvable letters; bifeprunox not
BrainStorm moves closer to clinical testing of SC product for PD........................................6 approvable..............................................................................................................................20
Product News........................................................................................6 Agreement News...................................................................................20
Higher dosage strength for Stalevo approved in the US.......................................................6 Noven to receive Daytrana sales milestone...........................................................................20
Alzheimer's Disease - R&D Update........................................................6 Avanir completes sale of FazaClo to Azur..............................................................................20
Multi-national study confirms Aricept's positive effects in severe AD................................6
UCF research links APP, SCs and potential AD treatment......................................................6 Analgesics/Anaesthetics................................21
Rochester team outlines method to reduce Abeta in the brain...........................................7 R&D Update.............................................................................................21
AD diagnostic patent issued in Europe..................................................................................8 Javelin initiates Phase III trial of intranasal ketamine...........................................................21
Study confirms role of metal ions in AD; DSMB clears continuation of Phase IIa PBT2 trial.....8 FDA accepts Acrux' IND for Fentanyl MDTS............................................................................21
Effectiveness of AD-mimicking mouse breeds questioned.................................................8 Encore reports positive preclinical data for ER ropivacaine gel............................................21
APNS/Lilly AD collaboration progresses................................................................................9 TorreyPines completes enrolment in Phase IIb tezampanel trial........................................21
Product News........................................................................................9 Hydra data reveal role of ion channel in pain receptor activation.......................................21
Judicial review upholds NICE recommendation of drugs for moderate AD only.................9 Merck/Neuromed discontinue development of pain drug candidate.................................22
Agreement News...................................................................................10 ReceptoPharm pain study produces positive results............................................................22
MRCT to humanise Intellect's Abeta-specific Abs for AD......................................................10 Avigen initiates clinical development of AV411 in the US.....................................................22
EPIX achieves discovery milestone in collaboration with GSK..............................................10 Verapamil for cluster headaches linked to heart problems..................................................22
Multiple Sclerosis - R&D Update..........................................................10 NeurAxon's NXN-188 safe and well tolerated; raises funds to advance pain therapeutics......23
Bayhill's DNA vaccine against MS appears safe and potentially efficacious........................10 Cephalon to file Fentora sNDA following positive Phase III data..........................................23
Eden Biodesign to develop vOX2:Fc.......................................................................................10 AstraZeneca releases R&D pipeline update...........................................................................23
Accentia files pre-IND application for Revimmune in refractory MS...................................11 Product News........................................................................................23
Cytokine demonstrates oral efficacy of small-molecule MIF inhibitors..............................11 FDA issues second approvable letter for Trexima..................................................................23
Opexa receives European patent notification for T-cell vaccine...........................................11 Sativex approved in Canada for cancer pain..........................................................................24
Other Neurodegenerative Disorders - R&D Update...........................11 FDA requests more time to review Frova sNDA.....................................................................24
Researchers identify active genes in ALS..............................................................................11 Eslax receives Japanese approval...........................................................................................24
SIRT1 activation shows potential for neurodegenerative diseases.....................................12 Anesiva receives FDA approval for Zingo...............................................................................24
Study demonstrates relevance of HD models.......................................................................12 Vimpat MAA submitted for DNP............................................................................................24
Motor neurons rescued by SC therapy in ALS model............................................................12 Ranbaxy receives FDA approval for generic Norco/Vicodin/Lortab.....................................24
Study uncovers differences in neurons from ESC lines.........................................................12 Agreement News...................................................................................24
KineMed raises funds to advance development of KM-801 for ALS....................................13 Ono obtains Japanese rights to CNS 7056.............................................................................24
Tikvah granted ODS for sodium phenylbutyrate's use in SMA.............................................13 Paladin signs licensing agreement for Glide Pharma's Glide SDI.........................................25
Product News........................................................................................13 Icagen/Pfizer enter pact for pain and related disorders.......................................................25
Xenazina approved in Italy.....................................................................................................13 EKR acquires US rights to Pacira's DepoDur...........................................................................25
EMEA accepts MAA filing for SNT-MC17................................................................................14 ProStrakan enters agreements with Orexo and LG...............................................................25
Agreement News...................................................................................14 Anti-Epileptics................................................25
Medtronic/Alnylam advance drug-device combinations collaboration.............................14 R&D Update.............................................................................................25
University of Alabama enters collaborative research pact with QRxPharma......................14 Valeant completes enrolment in first retigabine Phase III epilepsy study..........................25
Tikvah licenses Navinta technology.......................................................................................14 Ovation initiates clinical trial of iv carbamazepine...............................................................26
Paladin expands Canadian Elaprase distribution deal with Shire........................................15 Product News........................................................................................26
Cerebrovascular Disorders..........................15 FDA approves Cerebyx generics.............................................................................................26
R&D Update.............................................................................................15 Eating Disorders.............................................26
EC grants Chelsea two OMP designations for droxidopa......................................................15 R&D Update.............................................................................................26
Phase Ib trial of SRT501 in MELAS initiated...........................................................................15 Interim Phase I trodusquemine data presented...................................................................26
Anxiolytics/Sleep Disorders..........................15 Drugs used in Nausea & Vertigo.....................26
R&D Update.............................................................................................15 Agreement News...................................................................................26
Research identifies low expression of immune system gene in WBCs of narcolepsy patients....15 ProStrakan enters agreements with Orexo and LG...............................................................26
DSP discontinues AC-5216......................................................................................................15 Par granted North American rights to Zensana....................................................................27
Product News........................................................................................16 General Development News...........................27
Valeant begins distribution of Xyrem in Canada...................................................................16 R&D Update.............................................................................................27
Solvay submits complete responses to Luvox FDA approvable letters; bifeprunox not Lexicon's LX-6171 completes Phase I trials............................................................................27
approvable..............................................................................................................................16 Eisai updates clinical progress................................................................................................27
Agreement News...................................................................................16 Neuren sets out plans for Hamilton acquisition....................................................................27
sanofi-aventis/Chugai terminate Japanese marketing collaboration.................................16 CCK finding offers potential for mood disorder and epilepsy therapies..............................28
Antidepressants.............................................16 Pfizer set to triple its Phase III portfolio by 2009..................................................................28
R&D Update.............................................................................................16 Research offers hope for new antisense drug class..............................................................28
Gene variation increases chance of successful citalopram response...................................16 Noven completes JDS acquisition..........................................................................................29
DOV 21,947 safe and well tolerated in Phase Ib study..........................................................16 Product News........................................................................................29
DSP discontinues AC-5216......................................................................................................17 FDA approves first generic Dantrium injection.....................................................................29
Product News........................................................................................17 Agreement News...................................................................................29
FDA approves first escitalopram capsules.............................................................................17 Neurocrine in-licenses valnoctamide isomers from Yissum................................................29
Psychotic Disorders.......................................17 BrainStorm restructures agreement with Ramot.................................................................29
Valeant's candidate selection triggers payment to Ardea...................................................29
R&D Update.............................................................................................17
Johns Hopkins team develops mouse model of schizophrenia............................................17 COMPANY INDEX.................................................30
AstraZeneca releases R&D pipeline update...........................................................................17 COMPOUND INDEX..............................................31
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Espicom Business Intelligence 23rd August 2007
CNS Drug News IN FOCUS

In Focus
The 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.

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.

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Espicom Business Intelligence Page 
IN FOCUS 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/D2 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 D2 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; and
• heightened risk of mortality in the elderly population.

Risperdal (risperidone), J&J's 5-HT2/D2 antagonist, comes off patent in the US and Europe this year, while Abilify, Bristol-Myers Squibb/Otsuka's
5-HT1A/D2 partial agonist/5-HT2A antagonist, comes off patent in 2009. Seroquel, Eli Lilly's 5-HT2/D1/D2/D3 antagonist, Zyprexa (olanzapine), and
Pfizer's 5-HT1A/2A/2C/D2/D3/D4 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-HT15/5-HT2/D2 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.

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Espicom Business Intelligence 23rd August 2007
CNS Drug News NEURODEGENERATIVE DISORDERS

Bifeprunox, a D2 partial agonist with 5-HT1A 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/D3 partial agonist, acetylcholine M1 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/D3 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-HT2A 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 DISORDERS
dopamine neurons are gone, which is when some sort of threshold
Parkinson's Disease - R&D Update is crossed. The study looked at what happens while the dopamine
neurons are dying and people still appear to be healthy. The lack
Loss of two neuron types may trigger PD symptoms of symptoms until the death of most of the dopamine neurons
suggested the existence of a system that can temporarily compensate
Scientists from Emory University and the University of Georgia have for the loss of the dopamine.
suggested that the loss of two types of brain cells rather than just
one may trigger the onset of symptoms associated with Parkinson's It is known that norepinephrine is important for regulating the
disease (PD). activity of dopamine neurons, therefore the researchers suspected
that the dopamine and norepinephrine neurons function in concert.
The evidence, based on mouse models, shows a link between the As the dopamine neurons start dying, the norepinephrine neurons
loss of both norepinephrine and dopamine neurons and the delayed compensate by signalling the surviving dopamine cells to dramatically
onset of symptoms associated with PD. It was originally thought that increase their activity and the output of dopamine. Eventually, the
the loss of only dopamine neurons triggered symptoms. In light of this norepinephrine neurons die, the surviving dopamine neurons lose
study, which was published in the 16th August online edition of PNAS their ability to release extra dopamine and symptoms start to appear.
(10.1073/pnas.0702753104), it has been suggested that simultaneously
treating both the dopamine and norepinephrine loss could further To test their hypothesis, the researchers gave healthy, one-year-old
ameliorate the symptoms of PD. People do not start showing mice the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine,
symptoms of the disease until approximately 80 per cent of their at a dose that kills approximately 80 per cent of the dopamine cells,

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Espicom Business Intelligence Page 
NEURODEGENERATIVE DISORDERS CNS Drug News
but observed no motor impairments in the mice. Surprisingly, when The approval of the Stalevo 200mg dose (carbidopa 50mg+levodopa
they tested mice that were unable to synthesise norepinephrine and 200mg+entacapone 200mg) was based on a bioequivalence study
have trouble releasing dopamine properly, they observed symptoms with two tablets of Sinemet (levodopa+carbidopa) 100/25mg taken
of PD, including resting tremor, hunched posture and deficits in co- concomitantly with Comtan (entacapone 200mg), implicating the
ordinated movement. These results indicate that having a normal same safety and efficacy of the comparator.
complement of dopamine neurons is not enough for normal motor
function; norepinephrine also needs to be present to ensure proper
dopamine release. Alzheimer's Disease - R&D Update
BrainStorm moves closer to clinical testing of SC Multi-national study confirms Aricept's positive
product for PD effects in severe AD

BrainStorm Cell Therapeutics has reported preliminary results from The results of a multi-national study have indicated that patients
its first safety-supporting experiment, in which the company's entering the severe stage of Alzheimer's disease (AD) can show
human bone marrow-derived mesenchymal stem cells (SCs) were improvement in cognition and global function when treated with
transplanted into a healthy monkey. The SCs had been induced to Aricept (donepezil). The findings, which were published in the 31st
differentiate into neurotrophic factor-producing cells, according to the July issue of Neurology (2007;69:459-469), further affirm those from a
protocol developed by BrainStorm. study published in The Lancet (2006;367:1057-65) indicating positive
outcomes for nursing home patients who received treatment with
The monkey was treated daily with ciclosporin to prevent immune donezepil during the severe stage of the disease.
system rejection of the human-derived cells and was monitored for
a variety of parameters for a period of three months. Throughout The 24-week study included 343 men and women; 176 were given
this phase, the monkey appeared well and in good health, with a donezepil (10mg/day), while the rest received placebo. The study was
normal appetite and no apparent change in physical or behavioural conducted at 98 sites in Canada, the US, the UK, France and Australia
parameters. Blood tests, an MRI of the animal's brain and autopsy in 2006, with patients living in the community and/or assisted-living
examination of the internal organs were also found to be normal. settings.

Additionally, several human-originating cells were detected in sections Two well-established diagnostic tools were used to assess baseline
of the monkey's brain by staining the sections with an antibody. capacities and to monitor progress at eight, 16 and 24 weeks. Patients
The human transplanted cells were surrounded by macrophages, on donezepil showed significant improvement in their total scores
which may indicate a reaction of the monkey's immune system to on the Severe Impairment Battery, and in the CIBIC-Plus, significantly
the transplanted human cells and their initial rejection. BrainStorm's more patients taking the drug remained stable or improved compared
actual approach would involve autologous transplantation. With this to those on placebo. Cognitive function stabilised or improved in
strategy, no rejection is expected and there will be no need to use 63 per cent of people taking donepezil, compared to 39 per cent of
immunosuppressant drugs. those taking placebo. Compared to the placebo group, those taking
donepezil showed improvement in memory, language, attention and
Two additional healthy monkeys recently underwent transplantation recognising their own name. The donepezil group also showed less
with BrainStorm's human SCs. The monkeys will also be monitored for of a decline in social interaction, skills needed to complete a jigsaw
a period of three months for collection of additional data; so far, the puzzle and arranging sentences compared to the placebo group.
monkeys are in good health. Financing that BrainStorm received in
July will help to move forward the preparations necessary for carrying Donezepil was generally well tolerated by patients. The most common
out Phase I/II trials in patients with Parkinson's disease (PD), as well adverse effects occurring more frequently in the treatment group
as providing the funding and support needed to conduct additional were diarrhoea, insomnia, nausea, infection, urinary incontinence and
safety pharmacology studies. pain.

For details of BrainStorm restructuring an agreement relating to the Discovered by Eisai, donepezil is marketed as Aricept with Pfizer. In
differentiation of bone marrow-derived SCs, see General Development Canada, Aricept is marketed by Pfizer and was approved there for the
News, Agreement News. 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).
Product News
For details of a judicial review on the use of drugs, such as Aricept, in
Higher dosage strength for Stalevo approved in the the UK for AD of mild severity, see Product News, while for an update
US on Eisai's clinical progress, including a Phase III Aricept trial, see
General Development News, R&D Update.
On 2nd August, the FDA approved a new higher dose strength of
Stalevo (carbidopa+levodopa+entacapone), which is indicated for UCF research links APP, SCs and potential AD
Parkinson's disease patients with signs and symptoms of end-of-dose treatment
"wearing off".
As reported in the 24th July issue of PNAS (2007;104:12506-12511),
Stalevo, originated and manufactured by Orion, was approved scientists at the University of Central Florida (UCF), Karolinska Institutet
by the FDA in June 2003 and is marketed in the US by Novartis and the National Institutes of Health may have found a new way to
Pharmaceuticals. The product is already available in 50, 100 and treat Alzheimer's disease (AD). The researchers combined a technique
150mg strengths, and the new dose is expected to be available in for transplanting stem cells (SCs) into rats along with the recently-
October. developed cholinesterase inhibitor, phenserine, which reduces the

Page  ©
Espicom Business Intelligence 23rd August 2007
CNS Drug News NEURODEGENERATIVE DISORDERS

amount of an AD-related plaque. The combination triggered the


regeneration of neurons that are destroyed by AD and are necessary IBC's 2nd International Conference
Stem Cells:
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
Building the Bridge from
alterations in APP processing associated with neurodegenerative
conditions such as AD may prevent neuronal differentiation of hNSCs.
R&D to Commercialization
Thus, the scientists hypothesised that successful neuroplacement
therapy for AD may require regulating APP expression to favourable
levels to enhance neuronal differentiation of hNSCs.
Register by August 24 & Save!
The researchers treated AD model mice producing human APP with
phenserine, which is known to reduce the amount of APP in the brain.
Discover the most effective ways to
The APP level in the brains of treated mice was reduced by up to 50 maximize your collaborative
per cent, which would provide optimal conditions for the hNSCs to
become neurons. Under this environment, the research team found
and partnering efforts to create,
that SCs transplanted into the brain successfully produced neurons. maintain and profit from a stem
The scientists are now investigating whether a combination of
cell business
phenserine and NBI-18, a compound that is being developed by lead x Learn the proven tactics industry leaders
UCF researcher, Professor Kiminobu Sugaya, which increases brain SCs
by 600 per cent, could become another way to treat AD.
use to successfully overcome competitive
obstacles
Rochester team outlines method to reduce Abeta in x Analyze successful business models and
the brain
find out why they work
Scientists at the University of Rochester Medical Center are trying to
rid the brain of the amyloid build-up in patients with Alzheimer's
x Find out how and why large pharma is
disease (AD) by draining the toxic protein away. becoming a key player in the stem cell
The method is outlined in a paper published in the 12th August online
sector
edition of Nature Medicine (10.1038/nm1635). The scientists show how x Learn how to accelerate your stem cell
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
R&D activities and ensure a successful
to repair the process, dramatically reducing the levels of the toxic pathway to the clinic
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
x Hear updates of clinical trials on the road
with the disease. to commercialization from six industry
The approach does not take direct aim at the pathology that is
leading executives
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
Conveniently Co-Located with IBC’s International
that if they increase the body's ability to soak up amyloid, the brain Discovery-2-Diagnostics Conference giving you
responds, causing levels of the substance in the brain to decrease. access to network with over 1100 attendees on the
shared exhibit hall floor.
The team concentrated its efforts around a protein known as sLRP
(soluble low-density lipoprotein receptor-related protein). It was www.discovery2diagnostics.com
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 Register by August 24 & Save $100
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 When using VIP Code: D3218CNS
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
Call: (800) 390-4078
also be reflected in the brain. Fax: (941) 365-0104
Email: reg@ibcusa.com
The group decided to try to reduce Abeta levels in the body by
synthesising an altered, super-potent form of sLRP that binds Abeta www.IBCLifeSciences.com/stemcells
more efficiently than natural sLRP. In blood samples from patients

23rd August 2007 ©


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NEURODEGENERATIVE DISORDERS CNS Drug News
with AD, the modified version of sLRP, known as LRP-IV, soaked up and zinc. PBT2 is currently in a Phase IIa AD trial, meanwhile, further
and virtually eliminated Abeta. The compound had an even more leads from the MPAC library are currently being validated for clinical
dramatic effect in mice with features of AD: LRP-IV lowered the levels development in other neurodegenerative disorders.
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 In addition...
those that did not receive LRP-IV, and they had 65 per cent more blood
flow in their brains in response to brain stimulation. An independent Data Safety Monitoring Board (DSMB) has reviewed
blinded data from over 50 patients and confirmed that Prana's Phase
The team is now working with Socratech to create a form of LRP-IV IIa trial of PBT2 in patients with early AD is safe to continue as per the
that could be tested in people and it is hoped that such a product will original protocol. A total of 55 patients (or approximately 70 per cent
be ready for trials within two years. of the planned 80 patients) have been randomised and 30 patients
have completed dosing, with no treatment-related serious adverse
AD diagnostic patent issued in Europe events or withdrawals. As planned, patient dosing is expected to be
completed by the end of 2007.
A patent application, entitled: "Neurosteroids as Markers for
Alzheimer's disease," has been granted by the European Patent Office. This is a double-blind, placebo-controlled, safety and tolerability
Patent No. 1254251, which took effect on 15th August, protects the study of PBT2 in patients with mild forms of AD. In addition, the trial
invention of a quick and simple blood test that is capable of predicting is investigating the effect of PBT2 on multiple cerebrospinal fluid (CSF)
and leading to an early diagnosis of Alzheimer's disease (AD). The and blood biomarkers that have been directly associated with the
novel innovation presents dehydroepiandrosterone as the biological aetiology of AD. Outcomes will include measures of CSF Abeta and tau
marker to detect AD and other neurodegenerative diseases. The levels, as well as neurocognitive and behavioural changes.
patent has been exclusively licensed to Samaritan Pharmaceuticals by
Georgetown University. Effectiveness of AD-mimicking mouse breeds
questioned
Samaritan is planning to take the appropriate steps to fulfil patent
registration requirements in the following European countries: Austria, A research team, including scientists from Heinrich-Heine University
Belgium, Switzerland, Liechtenstein, Germany, Spain, France, the UK, and the University of Mainz, has indicated that recently-developed
Ireland, Italy, the Netherlands and Sweden. mouse breeds that mimic the symptoms of Alzheimer's disease (AD)
may not be as effective as previously assumed. According to the
Study confirms role of metal ions in AD; DSMB clears results, which were published in the 24th August issue of the Journal
continuation of Phase IIa PBT2 trial of Biological Chemistry (2007;282:24504-24513), in some mouse
breeds, drugs that had been shown to reduce levels of amyloid beta
Research published in the 14th August edition of PNAS (2007;104:13313- (Abeta) had only minor or no effect on these mice.
13318) by Emory University and University of Georgia scientists has
confirmed the pivotal pathological role of metal ions in Alzheimer's Most compounds being developed for AD try to prevent Abeta
disease (AD) and potentially other major neurodegenerative disorders. 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
The multi-institutional team has shown how interactions between
on mice that carry mutations in the gene that produces amyloid
amyloid beta (Abeta) and the biological metals, copper and zinc, can
precursor protein (APP) proteins, leading to an excess of APP, which,
induce conformational alterations to the Abeta protein, causing it to
when cleaved, generate too many Abeta peptides. New mouse
adopt a multitude of toxic forms.
breeds have recently been created to also carry mutant genes for the
protein, presenilin, which is part of gamma secretase. These mutations
The investigators noted that subtle variations in the chemical cause gamma secretase to cut APP in a slightly different way than in
environment of the brain can radically influence the binding of normal mice, which also leads to an accumulation of Abeta peptides.
copper to a specific sequence of Abeta to generate both fibrillar and Mouse breeds that carry both APP and presenilin mutations develop
non-fibrillar (oligomeric) forms of the protein. The oligomeric forms symptoms earlier and the disease has a more aggressive course.
of Abeta, in particular, are currently the subject of great interest in
AD research as the best validated therapeutic target in the disease. In the new study, the researchers noticed that chemical compounds
The team also emphasised that the findings have relevance to other that had been shown to reduce Abeta deposits did not affect some
neurodegenerative conditions, including Parkinson's disease, where of these new mouse breeds. The findings indicate that these mouse
metal binding is believed to modulate or induce the pathological breeds may not reflect what may really happen in the brains of
aggregation of proteins. patients with AD if they were treated with such compounds in future
clinical studies. Indeed, these compounds may seem to be ineffective
Previously, scientists at Prana Biotechnology have promoted the on these mice, while it is actually the mouse breed that is to blame.
concept that changes in brain chemistry associated with the ageing
process cause subtle fluctuations in the regulation of copper, zinc and The researchers suggest using mouse breeds that carry only APP
iron, permitting toxic interactions with the Abeta protein. According mutations for further studies of compounds that block or reduce the
to Prana, the PNAS study lends further endorsement to the company's activity of gamma secretase. These breeds are probably more reliable
therapeutic approach in neurodegeneration, which is to intercede than the ones that carry both APP and presenilin mutations, because
in the metal-dependent process of target protein aggregation. they cause less aggressive symptoms.
Prana's therapeutic approach uses MPAC (metal protein attenuating
compound) technology, comprising orally-bioavailable small The scientists also propose creating a mouse breed in which the
molecules that specifically target such pathological interactions. PBT2, presenilin mutation does not affect both members of the pair
the company's lead compound, was designed to inhibit the formation of chromosomes that carry the gene (as is the case in current
of toxic Abeta oligomers resulting from interactions with copper transgenic mice), but only one of the chromosomes. Such a breed,

Page  ©
Espicom Business Intelligence 23rd August 2007
CNS Drug News NEURODEGENERATIVE DISORDERS

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 23 - 25 October 2007
probably better reflect what actually happens in the brains of patients The Royal Garden Hotel
with AD. London, United Kingdom

The researchers are now planning to investigate how presenilin CNS disorders: today’s science to
mutations cause Abeta peptides to be overproduced and to tomorrow’s market
understand how promising chemical compounds block gamma
secretase or reduce its function. CNS disorders are one of the leading causes of mortality
worldwide. According to reports, neurological disorders
APNS/Lilly AD collaboration progresses affect over 1 billion people globally. The prevalence of these
disorders is rising, principally driven by a global aging
Applied NeuroSolutions (APNS) has provided an update on the population. However there is a lack of blockbuster drugs and
progress of its collaboration with Eli Lilly to develop drugs that will targeted therapies to cater for the number of patients and
halt the progression of Alzheimer's disease (AD) by interfering with the range of disorders.
early stages of tau pathology.
NeuroDrug 2007 focuses on drug discovery and development
The collaboration management, working teams and external across the CNS sector. Our agenda focuses on novel
resources are up and running, with all key assets and proprietary tools therapeutic targets for neurological, neurodegenerative and
having been transferred to support ongoing work by Lilly, Dr Peter psychiatric disorders. Key learning include case studies on
Davies (a Founding Scientist at APNS) and APNS. Lilly is providing cutting edge drugs and therapies, lead optimisation, novel
substantial resources to the collaboration. biomarkers and imaging, latest approaches to drug delivery
and crossing the blood brain barrier.
Progress on a proprietary APNS target, the first tau-related target to
be advanced by the collaboration, has been described as 'rapid' by The best mix of expert speakers from the
Lilly management. High-throughput in vitro and cell-based screens pharmaceutical and biotech sectors
have been established, as has a correlation between the in vitro and
cell-based potency of active compounds. Additionally, multiple Our senior level speakers come from world class
compounds that have been selected from the hits successfully cross pharmaceutical companies, leading biotechs and unrivalled
the blood-brain barrier. medical research centres. Represented companies include
GlaxoSmithKline, AstraZeneca, Johnson & Johnson, Wyeth,
The APNS proprietary target successfully passed its first internal Eli Lilly, Boehringer Ingelheim, Schering-Plough, UCB
milestone in the second quarter of 2007 and is on schedule for the Pharma, Lundbeck, Pierre Fabre, Otsuka Maryland
next key internal milestone by the end of the year. APNS anticipates Medicinal Laboratories, Oxford BioMedica and the
achieving its first paid milestone in late 2008/early 2009. Foundation for the NIH. 90% of speakers are CxO’s,
Therapeutic Area Heads, Directors or Presidents. Advances
in CNS drug discovery and development are best achieved
Product News through knowledge sharing and collaborations.
Judicial review upholds NICE recommendation of Eli Lilly explains why this is a must
drugs for moderate AD only attend event

A legal challenge to the recommendation of the UK's National Institute "Neurodrug 2007 offers an excellent insight into multiple
for Health and Clinical Excellence (NICE) that drugs for Alzheimer's aspects of CNS drug discovery. The meeting has topics that
disease (AD) should only be prescribed to those in the moderate stage relate to most CNS disorders such as new technology, drug
of the disease has failed. delivery, biomarkers and more specific focused topics such
as small molecule, viral delivery and stem cell approaches to
In April, the High Court granted Eisai, the licence holder of Aricept treat neurodegeneration. The varied approaches taken for
(donepezil), and Pfizer, its co-promotion partner, permission to certain diseases should make an interesting meeting with
proceed to a Judicial Review in order to challenge NICE's decision to opportunity to discuss and network".
refuse NHS support of drugs for new patients in the UK with AD of
mild severity (see CNS 159). Dr Michael J. O'Neill, Research Advisor,
Neurodegeneration Drug Team, Eli Lilly
The judge ruled in favour of NICE on five out of the six grounds bought
in court, including finding that:
3 easy ways to register
• NICE did appropriately take into account the benefits these drugs
bring to carers; Online: www.lifescienceworld.com/2007/neuro
• NICE appropriately reflected the costs of long-term care in its Email: julie.phillips@terrapinn.com
calculations; Tel: +44 (0) 207 539 4336
• NICE did not breach principles of procedural fairness by providing Event code: 14/1318 / Espicom
a "read-only" version of the economic model;

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Espicom Business Intelligence Page 
NEURODEGENERATIVE DISORDERS CNS Drug News
• NICE was not irrational in concluding that there is no cumulative of Alzheimer's disease. As part of the collaboration, EPIX received
benefit to patients after six months of treatment with these total initial payments of US$35 million, including US$17.5 million
drugs; and through the purchase of its common stock at a premium, and may be
• NICE's assessment and consideration of the AD 2000 study was eligible to earn up to US$1.2 billion in milestones across the four GPCR
not irrational. programmes. Under the terms agreed, EPIX is also entitled to receive
tiered double-digit royalties of sales by GSK on all collaboration-
The judge ruled against NICE on one of the six grounds bought developed product sales.
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 Multiple Sclerosis - R&D Update
English is not their first language in its technology appraisal guidance.
Bayhill's DNA vaccine against MS appears safe and
As a result of the decision, NICE's guidance stands and the drugs potentially efficacious
continue to be recommended only for people with moderate AD.
With regard to the one ruling against it, NICE stated that it was always According to research published in the 13th August online issue
the organisation's intention that people with learning disabilities or of the Archives of Neurology (10.1001/archneur.64.10.nct70002), a
whose first language is not English should have equal access to the newly-developed DNA vaccine, BHT-3009, appears to be safe and
drugs in the moderate stage of AD. NICE will re-issue its guidance to may produce beneficial changes in the brains and immune systems of
the NHS to make this clear. individuals with multiple sclerosis (MS).

For details of Aricept studies, see R&D Update and General Researchers at the Montréal Neurological Institute and colleagues
Development News, R&D Update. 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-
Agreement News remitting or secondary-progressive MS who were not taking any other
disease-modifying drugs.
MRCT to humanise Intellect's Abeta-specific Abs for
AD For enrolment, the patients were also required to have either one to
five gadolinium-enhancing lesions on screening brain MRI, a relapse
Medical Research Council Technology (MRCT) has entered into an in the previous two years, or disease worsening in the previous two
agreement under which it will use its proprietary technology and years. After one, three, five and nine weeks, participants received
advanced know-how to humanise Intellect Neurosciences' amyloid intramuscular injections of placebo or BHT-3009 (0.5, 1.5 or 3mg),
beta (Abeta)-specific monoclonal antibodies (Abs) for the treatment of with or without atorvastatin 80mg. After 13 weeks, participants who
Alzheimer's disease (AD). The Abs are intended to be used as a form initially received placebo received four injections of BHT-3009.
of passive immunisation to promote clearance from the brain of the
endogenous soluble AD toxin, Abeta. There were no increases in clinical relapses, disability, drug-associated
laboratory abnormalities, adverse events, or the number and volume
Under the terms agreed, Intellect will pay MRCT milestone payments of contrast-enhancing lesions on brain MRI with BHT-3009 compared
related to the development and commercialisation of the humanised to placebo treatment. In fact, there was a trend toward a decrease in
Abs and a royalty based on sales of the resulting drug products. the number and volume of contrast-enhancing lesions in the brains of
Intellect is the holder of patents in Japan and other countries related patients treated with BHT-3009 compared to placebo.
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 The vaccine also produced beneficial antigen-specific immune
triggering adverse reactions because of their specificity. changes, consisting of a marked decrease in the proliferation
of interferon gamma–producing, myelin-reactive CD4+ T-cells
EPIX achieves discovery milestone in collaboration from peripheral blood and a reduction in titres of myelin-specific
with GSK auto-antibodies from cerebral spinal fluid, as assessed by protein
microarrays. Interestingly, the researchers did not observe a substantial
EPIX Pharmaceuticals has achieved an initial milestone under its benefit of the atorvastatin combination compared with BHT-3009
collaboration with GlaxoSmithKline related to the first of three alone. Based on these results, a randomised, Phase IIb trial with BHT-
discovery-stage programmes. Using its proprietary, integrated 3009 in approximately 290 patients is under way.
computational-medicinal chemistry approach to drug discovery, EPIX
has identified three lead candidates that will move forward into lead Eden Biodesign to develop vOX2:Fc
optimisation in this first collaborative G-protein coupled receptor
(GPCR) discovery programme. Under the collaboration, EPIX is Eden Biodesign has been selected by the University of Birmingham
entitled to receive a US$3 million milestone payment from GSK in the in the UK to develop and produce vOX2:Fc, a novel therapeutic
next 30 days. The companies have agreed upon the three discovery candidate for the treatment of autoimmune diseases, such as multiple
programme targets and are making significant progress on each sclerosis and rheumatoid arthritis.
programme.
This novel drug candidate is being investigated by Dr David
EPIX and GSK entered into the worldwide, multi-target strategic Blackbourn and his research team, and has attracted interest from
collaboration in December 2006, to discover, develop and market a number of biotech and pharmaceutical companies. According to
novel medicines targeting four GPCRs for the treatment of a variety of Blackbourn, clinical applications for this novel therapy could range
diseases, including EPIX' novel 5-HT4 partial agonist programme, PRX- from autoimmune diseases, such as rheumatoid arthritis, to asthma
03140, which is in early-stage clinical development for the treatment and allergy.

Page 10 ©
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CNS Drug News NEURODEGENERATIVE DISORDERS

Accentia files pre-IND application for Revimmune in other autoimmune and inflammatory diseases in which MIF has
refractory MS been identified as a pathogenic factor. The inhibitors were especially
effective in treating disease that had already started.
Accentia Biopharmaceuticals has filed a preliminary IND (pre-
IND) application with the FDA for Revimmune (high-dose Opexa receives European patent notification for T-cell
cyclophosphamide) in the treatment of refractory multiple sclerosis vaccine
(MS). The company has requested a meeting with the Agency within
the next 60 days to discuss a proposed pivotal Phase III trial involving Opexa Therapeutics has received notification that the European
approximately 270 patients with relapsing-remitting MS, with a Patent Office intends to issue a patent for "Autologous T Cell Vaccine
primary endpoint of improvement in function (reversal of disability). Materials and Method." This patent application is related to a unique
According to Accentia, its proposal to use the restoration of neurologic method-specific approach for generating a T-cell vaccine that attacks
function as the endpoint will be the first filed with the FDA. 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
Based on a clinical study at the Johns Hopkins University School months.
of Medicine, which showed a 42 per cent average improvement in
function, the company believes that Revimmune holds the potential to Studies have indicated that T-cell vaccination with peripheral blood-
restore function in many patients who have acute deficits due to MS. derived autologous myelin peptide selected T-cells in MS patients
In addition, it believes that the long-term follow-up with patients in resulted in the in vivo induction of CD8+ cytotoxic T-cells and
the proposed 48-week trial will demonstrate that Revimmune induces CD4+CD25+FoxP3 regulatory T-cells (Tregs) specific for T-cell vaccine.
not only a reduction of the risk of exacerbations, but potentially, also The induction of anti-idiotypic cytotoxic CD8+ effector T-cells and
long-lasting remissions and/or cures in patients with MS. anti-ergotypic CD4+CD25+FoxP3-positive Tregs is believed to provide
a therapeutically effective dual mechanism of protection to patients
Developed by a team at Johns Hopkins, Revimmune temporarily treated with Tovaxin, an investigational T-cell vaccine that is currently
eliminates peripheral immune cells, including the immune cells in a Phase IIb trial.
causing the autoimmunity, while selectively sparing haematopoeitic
stem cells (SCs) in the bone marrow. Investigators at Johns Hopkins The observed regulatory immune responses have been shown to
discovered that SCs uniquely have high levels of a particular protective collectively correlate with clinical improvement in treated patients.
enzyme that can be measured in advance of therapy, which makes Patients treated in Opexa's open-label, Phase I/II studies have
them impervious to Revimmune, and allows the surviving SCs to experienced an approximately 90 per cent average reduction
give rise to a new immune system over two to three weeks. The in annualised relapse rate, minimal side effects and observed
newly-reconstituted peripheral immune system typically lacks the improvement in average EDSS scores.
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
Other Neurodegenerative Disorders
to allow patients to recover at home while their immune system - R&D Update
reconstitutes itself over a two- to three-week period. Revimmune
includes a risk-management programme to enhance patient safety by Researchers identify active genes in ALS
ensuring appropriate patient selection, supportive care and tracking
of outcomes data. A group led by researchers at the Translational Genomics Research
Institute has conducted a whole-genome analysis and identified more
Cytokine demonstrates oral efficacy of small- than 50 genetic abnormalities in people with sporadic amyotrophic
molecule MIF inhibitors lateral sclerosis (ALS; Lou Gehrig's disease), a discovery that provides
expanded opportunities for developing therapies to treat this
Cytokine PharmaSciences has reported that recent experiments with disorder.
its small-molecule macrophage migration inhibitory factor (MIF)
inhibitors demonstrated oral efficacy in animal models of multiple The researchers, whose work was published in the 1st August online
sclerosis (MS) and arthritis. Based on these results, the company is issue of the NEJM (10.1056/NEJMoa070174), conducted the analysis
advancing one of these compounds into preclinical development. using almost 767,000 SNPs found in 386 white patients with sporadic
ALS and 542 neurologically-normal white controls. The associations
MIF is linked to many conditions, including arthritis, inflammatory of SNPs with sporadic ALS were confirmed in two independent
bowel disease, asthma, cancer and sepsis, as well as other infections replication populations.
and autoimmune disorders. Neutralisation of MIF biological activity
has been shown to have a protective effect against these diseases. The investigators identified ten genetic loci that are significantly
Cytokine has an extensive patent portfolio focused on MIF, covering associated (p<0.05) with sporadic ALS in three of the independent
various methods for neutralisation, including small molecules. patient and control series, plus an additional 41 loci that had significant
associations in two of the three series.
These compounds were shown to be effective in animal models of MS
and arthritis when administered orally. The MS animal experiments The team identified genes likely to play a role in cell function that
were conducted in the laboratories of Drs Abhay Satoskar and controls nerve adhesion, offering a major new avenue for ALS
Caroline C Whitacre, both of Ohio State University. According to research. The findings indicate that these genes produce a molecular
Satoskar, the therapeutic efficacy of these compounds was positive, adhesive that attaches motor neurons to muscle. It appears that in
with no outward signs of toxicity, and these findings indicate that ALS, the nerve is able to peel off the muscle and, when that occurs
small-molecule MIF inhibitors are viable drug candidates for treating repeatedly, the nerves die.

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NEURODEGENERATIVE DISORDERS CNS Drug News
SIRT1 activation shows potential for The Wisconsin team transplanted the cells on one side of the spinal
neurodegenerative diseases cord and used the untreated side to compare the affects of the
transplanted cells and their chemical secretions. The areas where the
The activation of SIRT1, a member of the sirtuin family of enzymes, researchers saw the human cells were the only areas where protection
has been shown to be neuroprotective in an animal model of optic of motor neurons was observed. However, while the motor neurons
neuritis, one of the first signs of multiple sclerosis. The work is exposed to GDNF were protected, the team was unable to detect the
significant because it shows that a SIRT1 activator is neuroprotective connections between the neurons and the muscles they govern. Even
and thus has the potential to be therapeutic for a range of in animals that had lots of motor neurons surviving, the researchers
neurodegenerative diseases of ageing. did not see the muscle connection, which explained why they did not
see functional recovery.
Sirtuins are a recently-discovered class of enzymes that appear to
affect the ageing process in mammals, and increase the number and Although the obvious next step in the research is to try and determine
function of mitochondria. According to the findings, which were the reasons why the protected motor neurons are unable to connect
published in the August issue of Investigative Ophthalmology and with muscles, the work is thought to further support movement
Visual Science (2007;48:3602-3609), resveratrol, a SIRT1 activator, toward clinical trials. Indeed, the cells are believed to be safe and
reduced the loss of retinal ganglion cells and preserved axonal do increase the survival of the motor neurons, which may be very
function in a preclinical model of optic neuritis. A single intravitreal important for patients who lose neurons every day. However, it was
dose of SRT501, Sirtris Pharmaceuticals' proprietary formulation of noted that it is not a trivial intervention, as a hole has to be drilled in
resveratrol, was sufficient for neuroprotection. Furthermore, this the spinal cord to deliver the cells releasing GDNF. Nevertheless, there
neuroprotective effect was shown to be SIRT1-dependent because it are few options for these patients and the researchers plan to continue
was blocked by sirtinol, a SIRT1 inhibitor. For details of a Phase Ib trial to move forward with this approach.
with SRT501, see Cerebrovascular Disorders, R&D Update.
Study uncovers differences in neurons from ESC lines
Study demonstrates relevance of HD models
In comparing neurons generated from two National Institutes of
An international team of researchers, led by a scientist from Ecole Health-approved embryonic stem cell (ESC) lines, scientists have
Polytechnique Fédérale de Lausanne in Switzerland, has published uncovered significant differences in the mature, functioning neurons
a benchmark study showing that gene expression in several animal generated from each line. The discovery, which was published in
models of Huntington's disease (HD) closely resembles that of human the 10th August online edition of PNAS (10.1073/pnas.0706199104),
HD patients. The results, published in the 1st August issue of Human implies that culture conditions during ESC generation, which have
Molecular Genetics (2007;16:1845-1861), validate the applicability of yet to be identified, can influence the developmental properties of
using animal models to study human disease and may have important human ESCs. Furthermore, the report also describes a new technique
consequences for the pertinence of these models in preclinical drug for producing functioning neurons from SCs that may be important
testing. for creating models of human neurodegenerative diseases.

Yi Sun, an SC biologist at the University of California, Los Angeles,


Motor neurons rescued by SC therapy in ALS model
and her colleagues developed procedures to differentiate the two SC
lines first into neural progenitor cells and then into mature neurons,
A team of scientists from the University of Wisconsin-Madison has
and were also able to purify those neurons for study. To investigate
shown that it is possible to rescue the dying neurons characteristic of
how the neurons functioned, the researchers developed a culture
amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease).
technique that induced the newly-produced neurons to establish
synapses with one another. Through functional analyses of these
The work, conducted in a rat model of ALS and published in the 1st
neurons, the team found that the two ESC lines differentiated into two
August online edition of PLoS ONE (10.1371/journal.pone.0000689),
distinct types of neurons that are found in different parts of the brain.
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
The researchers next performed electrophysiological studies of the
disease. However, while the motor neurons within the spinal cord are
synaptic connections between the neurons. They found that the
protected by the growth factor, their ability to maintain connections
neurons derived from the two cell lines have completely different
with the muscles they control was not observed. At the early stages of
properties in terms of what type of synapses they develop and over
disease, the researchers saw almost 100 per cent protection of motor
what time course this happens during culture. In addition, the studies
neurons, but when they looked at the function of these animals, they
showed that the neurons derived from the two cell lines used different
saw no improvement; the muscles were not responding.
neurotransmitters to communicate with one another.
In the study, neural progenitor cells derived from human foetal tissue
Sun and her colleagues also compared the microRNAs (miRNAs)
were engineered to secrete glial cell line-derived neurotrophic factor
produced by the two types of neurons. Their analysis showed that as
(GDNF), an agent that has been shown to protect neurons, but is very
the ESCs matured into neural progenitors and neurons, the expression
difficult to deliver to specific regions of the brain. The engineered cells
of the miRNA genes specific to ESCs dropped thousands of times and
were then implanted in the spinal cords of rats afflicted with a form of
those specific to brain cells increased thousands of times. When the
ALS.
researchers compared the two lines, they found differences in miRNA
gene expression that might contribute to this neuronal bias in the
GDNF has a very high affinity for motor neurons in the spinal cord.
lines. It is thought that the differences among ESC lines could have
When implanted, the GDNF-secreting cells survived well and in 80
implications for potential treatments using the cells. For example, if
per cent of the animals, the team saw maturing transplants. In fact,
a motor neuron disease is to be treated, those types of neurons are
the implanted cells demonstrated an affinity for the areas of the spinal
needed, whereas if it is a forebrain disease such as Huntington's, ESCs
cord where motor neurons were dying.
are needed that differentiate into that type of neuron. The differences

Page 12 ©
Espicom Business Intelligence 23rd August 2007
CNS Drug News NEURODEGENERATIVE DISORDERS

in neurons produced by cell lines may offer both advantages and


A new market-leading strategic analysis from Espicom
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 EmErging OppOrtunitiEs
in inhalatiOn & nasal
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
spray gEnEric Drugs
applications as the technique enables the production of pure cultures From emerging specialist manufacturers to
of functioning human neurons that can be genetically manipulated established companies seeking new opportunities,
to mimic human disorders. Before, it was only possible to use mouse
or other animal cells to model neurodegenerative diseases, but the
alternative drug-delivery technologies are
genetic background is so different from that of humans that key increasingly being seen as a route to a competitive
aspects of diseases such as Alzheimer's could not be reproduced. edge in the generics industry.
KineMed raises funds to advance development of This new report from Espicom provides a complete
KM-801 for ALS review of the emerging opportunities and operating
environment for inhalation and nasal spray drugs.
KineMed has completed a US$15 million convertible notes offering,
which will be used to advance the company's lead compound, KM- Providing…
801, into clinical studies in 2008, for the treatment of amyotrophic • Product forecasts by value 2006 to 2011
lateral sclerosis (ALS; Lou Gehrig's disease). • Patent expiry opportunities to 2016
KM-801 is a small-molecule agent that in preclinical studies, has
• Generic market context
been shown to alter microtubule dynamics in nerve cells. KineMed • Competitive evaluation with 18 company
researchers have discovered that patients with ALS have more rapid reviews
rates of turnover of microtubules, which are integral to the structure
and functionality of the motor neurons affected by the disease. By
THERAPY AREAS AND PRODUCTS ASSESSED
using an agent that can slow down this rate of turnover, KineMed Asthma & COPD
has shown in preclinical studies that it can restore balance to this key • Flixotide/Flovent (fluticasone propionate)
metabolic pathway and improve both symptoms and survival. The • Serevent (salmeterol xinafoate)
company's KM-801 programme is currently in IND-enabling studies to • Seretide/Advair (salmeterol
support the initiation of clinical trials next year.
xinafoate+fluticasone propionate)
Tikvah granted ODS for sodium phenylbutyrate's use • Pulmicort (budesonide)
in SMA • Combivent (ipratropium bromide+salbutamol)
• Xopenex (levalbuterol)
The FDA has granted Tikvah Therapeutics orphan drug status (ODS)
for sodium phenylbutyrate, for the treatment of spinal muscular Allergic rhinitis
atrophy (SMA). • Flixonase (fluticasone propionate)
• Rhinocort (budesonide)
Sodium phenylbutyrate, a histone deacetylase inhibitor currently • Nasonex (mometasone furoate)
approved to treat urea cycle deficiency, has been identified in in vitro
systems and in various animal models as an agent that can increase
• Nasacort (triamcinolone acetonide)
the level of SMN protein. Findings from in vitro studies, as well as pilot
clinical work, suggest that phenylbutyrate treatment in SMA patients
Influenza
may improve motor function. Tikvah will be working in conjunction • Relenza (zanamivir)
with the FDA and collaborative clinical trial groups focused on SMA
to develop well-controlled, multi-centre trials to fully evaluate sodium Migraine
phenylbutyrate in the treatment of SMA. • Imigran (sumatriptan)
• Zomig (zolmitriptan)
For details of Tikvah entering an agreement relating to a proprietary
formulation of sodium phenylbutyrate, see Agreement News. Osteoporosis
• Miacalcin (calcitonin-salmon)
Product News • Fortical (calcitonin-salmon [rDNA origin])
Xenazina approved in Italy Anaesthesia
• Ultane (sevoflurane)
Chiesi Farmaceutici has received approval of Xenazina (tetrabenazine) • Suprane (desflurane)
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. www.espicom.com/ins
23rd August 2007 ©
Espicom Business Intelligence Page 13
NEURODEGENERATIVE DISORDERS CNS Drug News
Xenazina, a dopamine-depleting agent, was exclusively licensed to Under the terms agreed, the companies will focus on developing a
Chiesi for commercialisation in Italy by Cambridge Laboratories in drug-device combination for the treatment of Huntington's disease
2003. (HD). The product is expected to consist of an RNA interference
(RNAi) therapeutic targeting the HD gene that will be delivered by
This is the third major territory in the European roll-out of Medtronic's implantable infusion pump.
tetrabenazine, following launches of the product in Germany (as
Nitoman) and France (as Xenazine). It is also available in South Africa, Preclinical data from Alnylam's HD programme provided a rationale
New Zealand, Australia and Canada, while in the US, a complete to advance an RNAi therapeutic programme in this disease. The
response was submitted to the FDA in February, in respect of an companies may jointly decide to collaborate on the development of
application for marketing approval for the treatment of chorea similar drug-device combinations using Alnylam's RNAi therapeutics
associated with HD. platform and Medtronic's implantable infusion pump for the
treatment of other neurodegenerative diseases, such as Parkinson's
EMEA accepts MAA filing for SNT-MC17 disease.

The EMEA has accepted the MAA filing for Santhera Pharmaceuticals' The agreement has also been revised as a 50:50 relationship in the US.
SNT-MC17 (idebenone), which was originally developed by Takeda, for Medtronic will commercialise the therapy consisting of the identified
the treatment of Friedreich's ataxia (FA). A milestone payment of EUR 3 RNAi compound and advanced delivery devices. In the US, Alnylam
million to Santhera from Takeda was triggered by this acceptance. has the opportunity to invest in clinical development of this therapy
through product launch. In Europe, Medtronic is solely responsible for
SNT-MC17, which has been granted orphan drug designation in the development and commercialisation.
EU, could become the first approved product for the treatment of FA
and will be marketed in Europe by Santhera's partner, Takeda. SNT- University of Alabama enters collaborative research
MC17 has shown clinical efficacy in FA patients on both neurological
pact with QRxPharma
and cardiac endpoints in several clinical studies, and proved to be well
tolerated in all studies thus far.
The University of Alabama has entered into a collaborative research
In a recently-completed clinical trial conducted in collaboration with and licensing agreement with QRxPharma. The research programme
the National Institutes of Health (NIH), Santhera tested the efficacy is directed at re-engineering existing drug therapies for new clinical
of three SNT-MC17 doses in patients with FA. Study results were applications, including the treatment of Parkinson's disease (PD),
announced in autumn 2006. The MAA file includes data generated dystonia and other neurological disorders.
in this study analysing a variety of neurological and cardiac outcome
measures, supported by data from earlier clinical trials in FA conducted The licensed technology relates to a particular gene that has been
by academic institutions that demonstrated efficacy primarily in shown to suppress the harmful misfolding of proteins within cells.
the treatment of the cardiac symptoms of this disease. The MAA Many neurological diseases, including PD, dystonias, Huntington’s
recommends a starting dose of 450mg/day for patients below 45kg disease, amytrophic lateral sclerosis (Lou Gehrig's disease) and
body weight and 900mg/day for patients of 45kg or above, with the Alzheimer’s disease, involve the toxic effects of misfolded proteins
option for the treating physician to use higher doses if needed. that kill critical nerve cells in the brain.

The MAA file includes safety data generated by Santhera with SNT- Preclinical research at the University has demonstrated that co-
MC17, as well as safety data from Takeda generated in its earlier expressing a gene coding for a protein named Torsin decreases the
preclinical and clinical development programme for the treatment misfolding of other proteins associated with neurological diseases.
of Alzheimer's disease. Santhera believes that the compound has QRxPharma's goal, based on work at the University, is to re-engineer
the potential to be granted European marketing approval for the existing drugs with a known history of use that activate the Torsin
treatment of FA in the second half of 2008. system and could therefore ameliorate these diseases at a causative
level.
Santhera has decided, despite the MAA filing, to continue its ongoing
Phase III trial with SNT-MC17 in Europe to collect additional safety Tikvah licenses Navinta technology
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.
Tikvah Therapeutics has entered into an exclusive worldwide
Santhera amended the study protocol based on the findings of the
licensing agreement with Navinta that encompasses unique
NIH study to primarily evaluate the benefits of SNT-MC17 on the
solution formulations, including a proprietary formulation of sodium
neurological aspects of FA. Santhera also offers all FA patients that
phenylbutyrate, as well as methods of use and treatments for a variety
participate and complete the EU Phase III trial the opportunity to enrol
of neurodegenerative disorders, including spinal muscular atrophy
in an open-label extension study in which they will receive high-dose
(SMA), amyotrophic lateral sclerosis (Lou Gehrig's disease) and multiple
SNT-MC17.
sclerosis, plus certain metabolic disorders.

Agreement News 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
Medtronic/Alnylam advance drug-device the terms agreed, Tikvah will pay a licensing fee, potential milestones
combinations collaboration and royalty payments, in exchange for an exclusive worldwide
licence to pursue the commercial development of the technology
Medtronic and Alnylam Pharmaceuticals are advancing their February for the treatment of SMA and other neurodegenerative diseases. For
2005 collaboration, following positive preclinical data generated under details of the FDA granting Tikvah orphan drug status for sodium
the initial joint technology development phase of the programme. phenylbutyrate's use in SMA, see R&D Update.

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Espicom Business Intelligence 23rd August 2007
CNS Drug News CEREBROVASCULAR DISORDERS / ANXIOLYTICS/SLEEP DISORDERS

Paladin expands Canadian Elaprase distribution deal Shire regulatory approval for Elaprase, indicated for enzyme-
with Shire replacement therapy in patients with Hunter syndrome (see CNS
164).
Paladin Labs has expanded its current exclusive Canadian
distribution agreement with Shire Human Genetic Therapies. Under Elaprase is designed to treat the underlying cause of Hunter syndrome
the agreement, Paladin will be distributing Elaprase (idursulfase) for by replacing iduronate-2-sulphatase (I2S). The product is a purified
Hunter syndrome (mucopolysaccharidosis II) in addition to Replagal form of human I2S that is produced by recombinant DNA technology
(agalsidase alpha) for Fabry disease. Health Canada recently granted using a human cell line.

Cerebrovascular Disorders
Phase Ib trial of SRT501 in MELAS initiated
R&D Update
A Phase Ib trial has been initiated in Europe with Sirtris Pharmaceuticals'
EC grants Chelsea two OMP designations for SRT501 in patients with mitochondrial encephalopathy lactic acidosis
droxidopa and stroke-like episodes (MELAS), for which there are currently no
known treatments.
Chelsea Therapeutics International has been granted two orphan
medicinal product (OMP) designations by the EC, for droxidopa in the The trial is designed to test the primary endpoints of SRT501's safety
treatment of orthostatic hypotension in patients with pure autonomic and pharmacokinetics in patients with MELAS. The drug will be
failure and patients with multiple system atrophy. These designations administered to a group of 15 patients once daily for three months,
are based on a recommendation from the EMEA's COMP and follow the while 15 other patients will receive placebo. Secondary endpoints
orphan drug designation granted by the FDA in January (see CNS 155). include exercise tolerance, plus fasting blood glucose and insulin
levels. Sirtris expects trial data by the end of 2008.
Droxidopa, developed by and licensed from Dainippon Sumitomo
Pharma, initially received Japanese approval in 1989, for the treatment
SRT501, Sirtris' proprietary version of resveratrol, activates SIRT1, a
of frozen gait and dizziness on standing associated with Parkinson's
disease, and for the treatment of orthostatic hypotension, syncope member of the human sirtuin family of enzymes. Specifically, SRT501
or dizziness on standing associated with Shy-Drager syndrome and acts by increasing mitochondrial activity and may target metabolic
familial amyloidotic polyneuropathy. Additionally, in 2000, droxidopa diseases, such as Type II diabetes, as well as mitochondrial disorders,
received expanded marketing approval to include the prevention such as MELAS. For details of research on SIRT1 activation, see
of vertigo, dizziness and weakness associated with orthostatic Neurodegenerative Disorders, Other Neurodegenerative Disorders -
hypotension in haemodialysis patients. R&D Update.

Anxiolytics/Sleep Disorders
The second screening of the samples was carried out by semi-
R&D Update quantitative PCR using gene-specific primers. Finally, the expression
levels of the candidate genes were further confirmed by quantitative
Research identifies low expression of immune system real-time PCR using a new set of samples: 20 patients with narcolepsy-
gene in WBCs of narcolepsy patients cataplexy and 20 healthy controls.

According to research published in the 1st August issue of Sleep The second screening revealed differential expression of four
(2007;30:974-979), the MX2 gene, which is relevant to the immune candidate genes, among which MX2 was confirmed as a significantly
system, is significantly less expressed in patients with narcolepsy downregulated gene in the WBCs of narcoleptic patients by
compared to normal subjects. This finding underlies the abnormalities quantitative real-time PCR.
in the blood cells (BCs) of persons suffering from narcolepsy and is
the first report to identify the biological markers of the disorder using Although it is known that MX2 is known to be relevant to the immune
gene expression in white BCs (WBCs). system, its direct relationship to narcolepsy has not been elucidated.
Further study is therefore required to explore the functional
Specific alterations in the immune system have been suggested to relationship between MX2 and narcolepsy, plus characterise the effect
occur in narcolepsy, thus this study attempted to identify alterations of interferons in the disorder.
in gene expression underlying the abnormalities in the BCs of
narcoleptic patients. DSP discontinues AC-5216

A scientist at the Tokyo Institute of Psychiatry in Japan, conducted Dainippon Sumitomo Pharma (DSP) has released an update of its
the study from a pool of total RNA from 12 narcolepsy with cataplexy research and development pipeline, confirming that AC-5216, an
patients and from 12 age- and sex-matched healthy controls. The anxiolytic and antidepressant that had been under re-evaluation for
pooled samples were initially screened for candidate genes for further development, has been discontinued. Novartis previously
narcolepsy by differential display analysis using annealing control licensed exclusive global development rights to this compound
primers. outside of Japan, Korea, China and Taiwan.

23rd August 2007 ©


Espicom Business Intelligence Page 15
ANTIDEPRESSANTS CNS Drug News
actions of sodium oxybate and intercurrent disease states, with the
Product News most commonly-reported adverse drug reactions (dizziness, nausea
and headache) occurring in 17 to 25 per cent of patients.
Valeant begins distribution of Xyrem in Canada
Solvay submits complete responses to Luvox FDA
Valeant Pharmaceuticals International has launched the Xyrem Success approvable letters; bifeprunox not approvable
Program for Xyrem (sodium oxybate), the first product approved in
Canada to treat cataplexy. Valeant has a licensing agreement with For details, see Psychotic Disorders, Product News.
Jazz Pharmaceuticals for the Canadian rights to Xyrem, which calls for
payments based on sales there.
Agreement News
Using a central pharmacy connected with the programme, Valeant
will distribute Xyrem in Canada through its specialty sales force, with sanofi-aventis/Chugai terminate Japanese marketing
the product to be promoted exclusively to neurologists, psychiatrists, collaboration
pulmonologists and sleep specialists who treat patients with
narcolepsy. sanofi-aventis KK and Chugai Pharmaceutical (Roche) are terminating
their Japanese marketing collaboration, effective 31st December. The
Xyrem has demonstrated an acceptable safety profile in narcoleptics collaboration included seven sanofi-aventis products that were being
with cataplexy when administered in nightly divided doses of 6 to 9g, sold by Chugai; the marketing rights for the products, which include
with a recommended starting dose of 4.5g/night. Its adverse-event Amoban (zopiclone) for the treatment of sleep disorders, will be
profile was generally consistent with the known pharmacological returned to sanofi-aventis accordingly.

Antidepressants
variations did not have as high a response rate, but were still more
R&D Update likely to respond than people with none of the favourable variations.
The protein produced by HTR2A acts as a receptor on brain cells for
Gene variation increases chance of successful serotonin.
citalopram response
The discovery that a variation in a serotonin-related gene could affect
A study by the National Institute of Mental Health (NIMH) has found response to citalopram was not entirely surprising, since the serotonin
that a variation in the gene, GRIK4, appears to make people with system is known to be involved in depression and citalopram targets
depression more likely to respond to citalopram than those without this system. However, GRIK4 makes a protein that acts as a receptor
the variation. The increased likelihood was small, but when people in a different neurotransmitter system, the glutamate system.
had both this variation and one in a different gene shown to have a Recent studies suggest that the glutamate system is also involved in
similarly small effect in an earlier study, they were 23 per cent more depression, an assertion that is supported by the new finding.
likely to respond to citalopram than those with neither variation.
Editor's note: citalopram was developed by Lundbeck for the long-term
The researchers studied DNA provided earlier by patients participating treatment of depression. It is licensed to Forest Laboratories for the US,
in the recently-completed NIMH, STAR*D (Sequenced Treatment where it is sold as Celexa, however a number of generic versions are
Alternatives to Relieve Depression) study. The trial showed that now available.
depressed patients who do not benefit from the first medication they
try have a fair chance of being helped by others. DOV 21,947 safe and well tolerated in Phase Ib study

After the trial, researchers determined the DNA codes contained in 68 A preliminary analysis of Phase Ib study results has indicated that DOV
genes suspected of being involved in depression, collected from 1,297 Pharmaceutical's DOV 21,947 was safe and well tolerated at the doses
of the patients who had participated in STAR*D. Comparing the DNA examined, and produced a significant decline in plasma triglyceride
codes of those who had responded to citalopram and those who had (TG) levels. DOV intends to initiate a Phase II study with its lead triple
not, it was found that responders were more likely to have a variation reuptake inhibitor for the treatment of depression in the fourth
in a gene called HTR2A. quarter of 2007.

In the new study, which was published in the August issue of the Prior studies with DOV 21,947 at up to 100mg/day demonstrated the
American Journal of Psychiatry (2007;164:1181-1188), researchers safety and tolerability of this compound over dosing periods of up
examined the genetic material of more of the patients who had to ten days. The goal of the current trial was to confirm DOV 21,947's
participated in STAR*D, for a total of 1,816 samples, and repeated the safety and tolerability over an eight-week period at escalating doses
comparison of DNA from citalopram responders and non-responders. of up to 150mg/day.
They discovered that people with the variation in the GRIK4 gene had
a higher likelihood of response and again found that the variation in This double-blind, placebo-controlled study enrolled 46 male and
the HTR2A gene also made people more likely to respond. female subjects. Following a one-week placebo run-in, subjects
received either escalating daily doses of DOV 21,947 50, 100 and
The 23 per cent increase in likelihood of response to citalopram 150mg/day (n=31) or placebo (n=15) for eight weeks. The study
occurred in people who carried the favourable variations in both demonstrated that DOV 21,947 was safe and well tolerated in this dose
copies of both of the genes. People with fewer of the favourable range, with no reported serious adverse events (AEs). The proportion

Page 16 ©
Espicom Business Intelligence 23rd August 2007
CNS Drug News PSYCHOTIC DISORDERS

of patients with treatment-emergent AEs was similar in the two DSP discontinues AC-5216
treatment groups, with 36 and 47 per cent in the DOV 21,947 and
placebo groups, respectively. Reported AEs with >3 per cent incidence For details, see Anxiolytics/Sleep Disorders, R&D Update.
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
Product News
and 13.3 per cent in the DOV 21,947 and placebo groups, respectively. FDA approves first escitalopram capsules
In addition, preliminary analysis of the clinical chemistry laboratory On 31st July, the FDA approved Alphapharm's (Merck KGaA) ANDA for
data indicates that DOV 21,947-treated subjects had lowered plasma escitalopram oxalate oral capsules 5, 10 and 20mg. There are currently
TG levels compared to placebo-treated subjects (p<0.015). This no therapeutic equivalents available for this product.
reduction in mean TG levels was noted following two weeks of
treatment (approximately 23 per cent reduction), was maintained at On receipt of notification from Alphapharm that it had filed an ANDA
the end of the DOV 21,947 treatment period (approximately 29 per with a Paragraph IV certification for a generic equivalent to the
cent reduction) and was reversed after the one-week wash-out period antidepressant, Lexapro (escitalopram), Forest Laboratories stated
at the end of the study. This reduction in plasma TG levels is consistent that it believed its patents on Lexapro were valid and strong, and the
with preclinical evidence that DOV 21,947 is able to produce a company therefore did not expect a generic product to be available
significant and sustained reduction in both TG levels and body weight until at least after the expiration of its substance patent, including
in animal models of obesity. patent extension, which will be in 2011. In October 2005, Forest and
Lundbeck announced an agreement with Alphapharm with regard to
Eight Phase I studies have now been completed with DOV 21,947. US Patent Re. No. 34,712, which was licensed to Forest by Lundbeck
The double-blind, Phase II study scheduled for initiation later in on an exclusive basis in the US and relates to Lexapro. Pursuant to the
2007 will compare DOV 21,947 up to 100mg/day versus placebo in terms of the settlement agreement, the companies confirmed that
approximately 200 patients with major depressive disorder over a six- they would appoint Alphapharm as the exclusive distributor of generic
week treatment period. DOV expects the results from that study in the versions of Lexapro, which may be launched under certain scenarios.
fourth quarter of 2008. Forest would receive a portion of the profit from such sales.

Psychotic Disorders
the 3rd August online edition of PNAS (10.1073/pnas.0704774104),
R&D Update the defects in these mice were not as severe as those typically seen in
people with schizophrenia, because more than one gene is required
Johns Hopkins team develops mouse model of to trigger the clinical disease. However, he believes that this mouse
schizophrenia 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,
Johns Hopkins researchers have genetically engineered the first may worsen symptoms and the animals can be bred with other
mouse that models both the anatomical and behavioural defects of strains of genetically-engineered mice to try to pinpoint additional
schizophrenia. In contrast to current animal studies that rely on drugs schizophrenia genes.
that can only mimic the manifestations of schizophrenia, such as
delusions, mood changes and paranoia, this new mouse is based on AstraZeneca releases R&D pipeline update
a genetic change relevant to the disease. Thus, it is thought that this
mouse should greatly help with understanding disease progression AstraZeneca has released an update of its research and development
and developing new therapies. pipeline, which has been significantly enhanced by the addition of the
MedImmune portfolio, with 14 products in clinical development and
Animal models of schizophrenia have been hard to design since many a further 28 projects; the majority of the MedImmune portfolio is in
different causes underlie this disease. However, Dr Akira Sawa and monoclonal antibodies and vaccines.
his colleagues took advantage of the recent discovery of a major risk
factor for this disease, the DISC1 (disrupted in schizophrenia) gene, The overall pipeline now includes 157 projects. Since 1st February,
which makes a protein that helps nerve cells to assume their proper 20 projects have progressed to their next phase of development,
positions in the brain. 53 compounds have been added (including 42 new projects from
MedImmune, 14 of which are clinical) and 16 compounds have been
The researchers generated mice that make an incomplete, shortened withdrawn. Ten new molecules have had their first dosing in humans
form of the DISC1 protein, in addition to the regular type. The short since 1st February, bringing the year-to-date total to 14, a record
form of the protein attaches to the full-length one, disrupting its number for AstraZeneca, with a number of additional opportunities
normal duties. planned for the second half of the year.

As these mice matured, they became more agitated when placed in In July, AstraZeneca submitted an sNDA to the FDA for a new
an open field, had trouble finding hidden food and did not swim as indication for the use of Seroquel (quetiapine) for the maintenance
long as regular mice; such behaviours parallel the hyperactivity, smell treatment of patients with bipolar I disorder as adjunct to mood
defects and apathy observed in patients with schizophrenia. MRI also stabiliser, based on data from two clinical trials. Pooled data showed a
revealed characteristic defects in brain structure, including enlarged greater incidence of blood glucose increases to hyperglycaemic levels
lateral ventricles. According to Sawa, whose work was published in in patients randomised to Seroquel+mood stabiliser than in those

23rd August 2007 ©


Espicom Business Intelligence Page 17
PSYCHOTIC DISORDERS CNS Drug News
randomised to placebo+mood stabiliser. Seroquel's US Prescribing areas were observed in children with ADHD who did not have the 7-
Information has been updated to include additional details regarding repeat version, followed by healthy children with the 7-repeat. Healthy
these data. children lacking the 7-repeat had the thickest cortex, but this did not
appear to affect their IQ. However, the researchers note that other
Discontinued projects in the neuroscience area include AZD9272 and studies have found correlations between cortex thickness and certain
AZD6538, both in neuropathic pain. measures of memory and intelligence.

Gene polymorphism predicts better ADHD outcome In 7-repeat carriers with ADHD, the attention-controlling areas
in teens thickened to normal by the age of 16 years. Gene variants of two
other dopamine system components showed few such anatomical
The results of an imaging study conducted by National Institute of correlates, confirming that the findings were specific to the D4 receptor
Mental Health (NIMH) researchers have shown that brain areas that gene. According to the scientists, evidence suggests that the 7-repeat
control attention were thinnest in children with attention deficit may be a relatively new variant, which may have been favoured
hyperactivity disorder (ADHD) who carried a polymorphism of a through evolution because such traits proved adaptive for survival.
particular gene. However, the affected areas, on the right side of the
brain's outer mantle, achieved normal thickness during the teenage The researchers are following-up with studies on the relationship
years in these children, coinciding with clinical improvement. between cortex thickness and cognitive features of ADHD, such as
Although this particular gene version increased risk for ADHD, it also working memory and the ability to inhibit responses.
predicted better clinical outcomes and higher IQ than two other
common versions of the same gene in youths with ADHD. Medistem proposes SC therapy for autism

According to the scientists, whose work was published in the August Medistem Laboratories has filed intellectual property (IP) and
issue of the Archives of General Psychiatry (2007;64:921-931), these published a paper describing a novel method of selecting specific
findings suggest that ADHD is at the far end of a continuum of normal subsets of autistic patients for treatment with a combination of cellular
traits, and probably stems from interactions between several such therapies.
genes and non-genetic factors.
The paper, which was published in the 27th June online issue of the
When the NIMH researchers first reported that normalisation of right Journal of Translational Medicine (10.1186/1479-5876-5-30), proposes
cortex thickening was associated with better clinical outcomes in that the combined use of mesenchymal stem cells (SCs) and cord
ADHD, there were few clues indicating a genetic connection. Yet blood CD34+ cells may be useful in the treatment of autism, while the
evidence from several previous studies led the team to suspect patent application, entitled: "Stem Cell Therapy for Autism," covers
involvement of an ADHD-implicated version of a gene that codes patient selection, therapeutic combinations and various SC types for
for a receptor protein, which binds to dopamine. This version of the the treatment of autism.
dopamine D4 receptor gene, called the 7-repeat variant, accounts for
approximately 30 per cent of the genetic risk for ADHD, making it by Based on positive case report data from one of its licensees, Medistem
far the strongest candidate gene implicated in the disorder. plans to explore the possibility of seeking regulatory approval in the
US for a Phase I trial involving its novel SC therapeutic methods for
For the current study, the researchers scanned and determined the the treatment of autism. The company is now seeking and initiating
D4 gene types of 105 children with ADHD (with 222 neuro-anatomical discussions with clinical collaborators and patient interest groups in
MRIs) and 103 healthy controls (total of 220 MRIs), then re-imaged the US.
them through their teenage years. Sixty-seven subjects with ADHD
(64 per cent) had follow-up clinical evaluations (mean follow-up, six Modafinil shows potential for BPD
years).
A preliminary study of 85 patients with bipolar disorder (BPD) has
The results showed that almost one-quarter of youths with ADHD indicated that modafinil, a drug used to treat patients with sleep
and approximately one-sixth of the healthy controls had at least one disorders, might also control the depressive symptoms associated
copy of the 7-repeat polymorphism. Nearly two-thirds of the children with BPD.
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 Modafinil is approved by the FDA to treat patients who suffer from
2-repeat version. excessive sleepiness associated with narcolepsy, obstructive sleep
apnoea and shift work sleep disorder, and is marketed as Provigil by
While the 7-repeat version was linked to thinner attention-controlling Cephalon. During the depressive phase of BPD, the symptoms include
cortex in both ADHD and healthy subjects, it appeared to confer an excessive sleepiness and fatigue, therefore researchers wondered if
advantage only among youths with ADHD. For example, participants modafinil could address these symptoms in patients with the disorder.
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 Half of the patients in the randomised, double-blind, placebo-
pronounced ADHD symptoms when followed-up approximately six controlled study, which was conducted at five sites and published in
years later, compared to only 21 per cent of those with at least one the August issue of the American Journal of Psychiatry (2007;164:1242-
copy of the 7-repeat variant. There was also a trend toward better 1249), were given modafinil 100-200mg/day, while the other half were
overall functioning among those with at least one copy of the 7-repeat given placebo over a six-week period. While the trial was small, 44 per
variant at follow-up. cent of those receiving modafinil reported feeling better, while 39
per cent said their symptoms were in remission after six weeks. This
The MRI scans revealed that 7-repeat carriers with ADHD started out compares to 23 and 18 per cent, respectively, in the control group.
with the thinnest cortex areas important for controlling attention Modafinil was not associated with any greater risk of the manic and
(right orbitofrontal and posterior parieto-occipital). The next thinnest depressive mood swings associated with BPD.

Page 18 ©
Espicom Business Intelligence 23rd August 2007
CNS Drug News PSYCHOTIC DISORDERS

How exactly modafinil works to promote wakefulness or improve


mood in BPD is not completely understood. Indeed, it appears to Market An expanding
have an entirely different mechanism of action compared to other forecasts and market, a

BiOequivalent generiC drugs in Brazil


psychostimulants.
trend analysis! growing
Risperdal Consta compares favourably to oral population,
Zyprexa
a regulatory
Data published in the August edition of the British Journal of regime supportive of the
Psychiatry (2007:191;131-139) have shown that patients receiving
Janssen-Cilag's (Johnson & Johnson) Risperdal Consta (risperidone generics sector, robust
long-acting injection) experienced a higher incidence of significant domestic production and
clinical improvements, as well as greater improvements in measures
of disorganised thinking at 12 months, than those taking Eli Lilly's many untapped opportunities.
Zyprexa (olanzapine) orally. Is Brazil the place for generic
With the efficacy and safety of long-acting injectable risperidone companies to be?
having not previously been compared with that of an oral atypical
antipsychotic, the study was conducted in 377 patients with DSM–IV The world’s major emerging
schizophrenia or schizoaffective disorder. Patients were randomised
to receive long-acting risperidone 25 or 50mg every 14 days or economies are attracting much
oral olanzapine 5 to 20mg/day. J&J Pharmaceutical Research & investment and interest. Brazil is not
Development completed the statistical analysis. least among them, and it is easy to see
The controlled, open-label, head-to-head study recruited participants why with a population of 189 million
at 48 centres worldwide. A total of 318 patients were randomised to and a GDP of US$978 billion in 2007.
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 Key areas addressed:
to endpoint for both short- (13 weeks) and long-term (12 months) • 5-year market forecast to 2012
outcomes.
• The generics market in context
According to the results, long-acting risperidone was at least as • Review of the product registration
effective as oral olanzapine in the 13-week phase, with significant procedure
improvements in the PANSS total and factor scores from baseline
to month 12 and endpoint seen in both groups of patients in the 12- • Pricing issues and reimbursement
month phase. Few patients discontinued treatment because of an • Political, legal and economic
adverse event, and the study concluded that both treatments were
efficacious and well tolerated.
assessment
• Insightful review of 20 major
OppOrtunities and Challenges fOr

The efficacy results suggested that in the long-term, patients might domestic and foreign players in
benefit more from treatment with long-acting risperidone injection
than with oral olanzapine. Risperidone achieved clinical improvements the market
(20 per cent minimum reduction in PANSS total scores) in significantly • Detailed product registration data
more patients compared with olanzapine at 12 months (91 vs 79 per • Who produces what?
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 All this and more can be found in
improvements were seen in anxiety/depression in the olanzapine
group. this new 200-page management
report, published in April 2007
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 Includes A weAlth
study endpoint (p<0.05) and BMI was 0.6kg/m2 compared to 1.4kg/m2,
respectively (p<0.05). of InformAtIon
Sexually-related side effects were reported by 3 per cent of the not AvAIlABle In
patients in each group. Severity of adverse events relating to
movement disorders was mild in both groups, although these events
englIsh elsewhere!
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. www.espicom.com/brazilgen
23rd August 2007 ©
Espicom Business Intelligence Page 19
PSYCHOTIC DISORDERS CNS Drug News
Scientists describe genetic variation linked to In addition...
predisposition to schizophrenia
Solvay and Wyeth Pharmaceuticals have received an action letter
Scientists at the University of Oxford in the UK, the National Institutes from the FDA in response to the NDA for bifeprunox, an atypical
of Health and the National Institute of Mental Health have provided antipsychotic that was reviewed for the acute treatment of
new insight into how a gene is related to schizophrenia. In the 17th schizophrenia, as well as the maintenance of stable adult patients. The
August issue of the Journal of Biological Chemistry (2007;282:24343- Agency stated that the drug was not approvable at this time.
24351), the researchers describe, for the first time, a genetic variation
that causes a gene to be overexpressed in the human brain. The FDA stated that bifeprunox demonstrated effectiveness in the
long-term maintenance study and indicated that a second positive
Although the exact causes of schizophrenia are yet to be determined, maintenance study could be sufficient to support a maintenance claim
scientists agree that the disease is due, in part, to genetic variations. for the drug. The companies will meet with the Agency to discuss
In the current study, the investigators identified some clues as to what study design and to assess how this additional study, combined with
goes wrong with one of the DNA variations. ongoing and planned trials, might support a maintenance indication.

In an Icelandic population, scientists originally found that genetic Although the FDA acknowledged that bifeprunox separated from
variations in a DNA sequence close to a gene that produces a protein placebo in two short-term studies in the acute setting, it concluded
called Neuregulin 1 (NRG1) were associated with schizophrenia, but that the efficacy data, when compared to reference drugs, were not
how the NRG1 gene was affected remained unknown. In 2006, one of sufficient for approval.
the researchers found that one of these DNA variations is associated
with increased expression of a novel type of NRG1, called type IV, The Agency also requested further information regarding human
which is one of the six known NRG1 protein isoforms, in the brains of metabolism of bifeprunox, plus additional information regarding a
patients with schizophrenia. complex case of a patient who died while participating in one of the
trials.
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 Agreement News
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 Noven to receive Daytrana sales milestone
3.5-times more abundant in foetal than adult brains, supporting the
protein’s important role in the developing brain. The team hopes that Shire's net sales of Daytrana (methylphenidate transdermal system)
by understanding how this novel protein works in the brain, it may be have triggered the second of three potential US$25 million milestone
possible to target it in people with the disease. payments to Noven Pharmaceuticals. Payment of this milestone was
triggered upon Shire's net sales of Daytrana exceeding US$50 million
The scientists showed that the genetic change that causes in the 12 months preceding 30th June. Under the terms agreed, a third
overproduction of NRG1 type IV is part of a promoter. The research
US$25 million milestone is payable upon Shire's achievement of US$75
revealed that alteration of the promoter in the genetic sequence
million in annual net sales of Daytrana.
linked to schizophrenia resulted in altered amounts of NRG1 type IV.
Daytrana, licensed globally to Shire, was launched in June 2006.
The team now plans to further investigate the role of NRG1 type IV
Payment of the first milestone was triggered upon Shire's net sales of
in brain development and behaviour, plus determine how various
alterations of the NRG1 gene lead to schizophrenia. 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.
Product News Avanir completes sale of FazaClo to Azur
Solvay submits complete responses to Luvox FDA
approvable letters; bifeprunox not approvable Avanir Pharmaceuticals has completed the sale of the currently-
marketed antipsychotic drug, FazaClo (clozapine), to Azur Pharma.
The FDA has accepted for review the submission of the complete Upon closing the transaction, Avanir received an up-front payment
response by Solvay Pharmaceuticals to its approvable letter for Luvox of US$42 million, plus an additional US$1.9 million in working capital
CR (fluvoxamine) extended-release capsules. The NDA for Luvox adjustments.
CR seeks marketing approval for the treatment of obsessions and
compulsions in patients with obsessive-compulsive disorder and for Azur has also assumed Avanir's future earn-out obligations to the prior
the treatment of social anxiety disorder. The PDUFA action date is owner of Alamo Pharmaceuticals, which it acquired in 2006, payable
22nd December. upon the achievement of certain sales milestones. Avanir will finalise
the transfer of FazaClo business operations to Azur in the coming
Furthermore, the FDA has also accepted the submission of the months.
complete response by Solvay to the approvable letter for Luvox
immediate-release tablets, with a PDUFA action date of 21st Avanir believes that the net payments from the sale, plus the cash,
December. In January, Jazz Pharmaceuticals licensed from Solvay the cash equivalents and unrestricted investments in securities, will be
right to market Luvox CR and Luvox in the US. Solvay retains the right sufficient to finance operating expenses through the end of the next
to market both products in other territories around the world. Subject fiscal year, including the initiation of the planned confirmatory Phase
to the receipt of FDA approval, Jazz expects to launch Luvox CR in the III trial of Zenvia (dextromethorphan+quinidine) in patients with
US during the first quarter of 2008. involuntary emotional expression disorder.

Page 20 ©
Espicom Business Intelligence 23rd August 2007
CNS Drug News ANALGESICS/ANAESTHETICS

Analgesics/Anaesthetics
solution formulation. The controlled and sustained PK profile is
R&D Update desirable since ETI-211 is designed to maintain the drug at the local
site of administration, and the PK result is consistent with previously-
Javelin initiates Phase III trial of intranasal ketamine reported sustained pain relief efficacy data.

Javelin Pharmaceuticals has dosed the first patient in a Phase III trial ETI-211 is a proprietary non-liposomal phospholipid gel formulation
that is designed to extend observations in a pilot study of PMI-150 that incorporates the drug in a single-phase depot system. The gel is
(intranasal ketamine) in treating breakthrough pain. capable of delivering the drug for three to seven days with low burst
potential, and is made with existing injectable phospholipids and
Up to 90 patients with breakthrough cancer pain from the US other components that have been used in previous FDA-approved
are planned to be randomised in this multi-centre, double-blind, drug products. Previously-reported results indicated that ETI-211
crossover, placebo-controlled study. Cancer patients with daily outperformed another liposomal anaesthetic depot formulation in
breakthrough pain episodes are eligible for treatment and will receive terms of duration of action in preclinical models.
seven active and three placebo treatments. The primary measure
of efficacy is the sum of the differences from initial pain intensity, as TorreyPines completes enrolment in Phase IIb
measured on a 0-10 scale during the first 60 minutes after dosing. tezampanel trial

Javelin is developing PMI-150 for several intended indications TorreyPines Therapeutics has completed enrolment in its Phase IIb
and anticipates undertaking additional clinical studies aimed at trial of tezampanel for the treatment of acute migraine headache.
broadening the compound's potential indications. The company Tezampanel is an AMPA/kainate receptor antagonist that offers a
believes that PMI-150 is optimised for use as a pain medication non-opioid, non-vascular and non-serotonergic approach to the
and may offer a safe, non-opioid alternative for the treatment of management of pain.
moderate-to-severe pain. Prior randomised, double-blind, placebo-
controlled, Phase II studies of PMI-150 have demonstrated rapid, The double-blind, placebo-controlled, multi-centre trial has reached its
statistically significant relief of moderate-to-severe postoperative and targeted enrolment of 300 patients suffering a single migraine attack,
breakthrough pain. with or without aura. Patients are randomised to one of four arms and
receive a 40, 70 or 100mg single, subcutaneous dose of tezampanel,
The company has begun to assemble an NDA for this product or placebo. The purpose of the trial is to identify a dose, or a range of
candidate for an initial indication as an emergency analgesic for doses, that could be used in a Phase III development programme in
military and civilian use, and plans to submit it to the FDA in 2008. acute migraine. The primary efficacy endpoint is headache pain relief
Clinical efficacy trials to support this initial NDA have been completed. at two hours post-dose. Secondary efficacy endpoints include pain
A later sNDA is planned for the indication of breakthrough cancer free status at two hours, sustained pain relief and sustained pain free
pain. at 24 hours, headache recurrence and relapse. Additional measures
include assessments of functional disability and patient satisfaction,
FDA accepts Acrux' IND for Fentanyl MDTS relief of migraine-associated symptoms (such as nausea, vomiting,
photophobia and phonophobia), as well as various assessments that
Acrux' IND application for Fentanyl MDTS has been accepted by the characterise speed of treatment onset. Safety, tolerability and plasma
FDA, meaning that the company will now proceed with a Phase I pharmacokinetic data will also be evaluated.
trial to test the delivery of fentanyl across the skin using its patented
metered-dose transdermal spray system. Hydra data reveal role of ion channel in pain receptor
activation
The study will commence in the second half of 2007, with the aim of
demonstrating that Acrux' MDTS formulation delivers fentanyl into Data published in the 8th August online issue of PNAS (10.1073/
the bloodstream of healthy volunteers in quantities that are known to pnas.0705924104) have revealed a key role of the transient receptor
be safe and effective in controlling chronic pain. potential ion channel, TRPA1, in the formalin pain model, which is
widely used for evaluating the effects of analgesic compounds in
Encore reports positive preclinical data for ER laboratory animals. These data contradict long-standing views of how
ropivacaine gel formalin induces pain and advance TRPA1 as an attractive target for
analgesic drug development.
Encore Therapeutics has reported data from two preclinical studies
demonstrating that ETI-211, its intradermal extended-release (ER) For a long time, it has been believed that the pain induced in the
ropivacaine gel formulation for postoperative pain management, formalin model was based on generalised tissue damage and
has a markedly-improved safety and pharmacokinetic (PK) profile inflammatory response generated by formalin. The new research
when compared to the currently-marketed ropivacaine solution shows that the acute pain induced by formalin is actually due to
formulation. activation of TRPA1.

No apparent toxicity was shown with the ETI-211 gel at the highest For the combined in vitro and in vivo study, researchers at Hydra
ropivacaine dose used (2,054mg/kg), in contrast to the 54mg/ Biosciences and the University of California, San Francisco, set out to
kg lethal dose for the solution formulation. The PK study showed determine whether TRPA1 activation could account for formalin's
that ETI-211 produced an ER profile lasting for six days and a five- to ability to activate pain receptors. The active component of formalin,
ten-fold reduction in Cmax compared with the currently-marketed formaldehyde, is similar in structure and reactivity to pain-inducing

23rd August 2007 ©


Espicom Business Intelligence Page 21
ANALGESICS/ANAESTHETICS CNS Drug News
irritants found in air pollutants and mustard oil, which are known Additionally, the treatment revealed no toxicity and subjects reported
activators of TRPA1. The scientists found that formalin activated cells no side effects. Low-dose, bi-weekly injections were found to control
expressing human or rat TRPA1, but not those lacking the ion channel. pain in many subjects for periods reaching four years.
These responses in TRPA1-positive cells could be attenuated with
a selective TRPA1 inhibitor identified at Hydra, HC-030031. It was Avigen initiates clinical development of AV411 in the
also found that while sensory neurons isolated from normal mice US
responded to formalin exposure with increased intracellular calcium
ion concentrations, those from TRPA1-deficient mice did not. Rat
Avigen has received approval from the FDA to proceed with the
neurons treated with HC-030031 were similarly resistant to formalin
development of AV411 (ibudilast) in the US. The first Phase I trial for
stimulation.
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
Treatment with HC-030031 also substantially reduced formalin-
mediated pain responses in rats, such as flinching, licking and lifting Phase I and exploratory Phase IIa studies in Australia.
responses. This decrease in pain response was not only apparent
during the early phase (Phase I) of the formalin response, but also This larger US trial is designed to assess the safety and tolerability
persisted in the later phase (Phase II). Phase I is thought to reflect the of AV411, and is also intended to assess the effect of food on the
acute pain response, while Phase II is proposed to be caused by central compound's pharmacokinetics and tolerability. In the study, healthy
sensitisation. Phase I and II formalin responses were also reduced in male and female volunteers will be randomised into cohorts of
mice lacking functional TRPA1, providing further confirmation of the escalating doses of orally-administered, delayed-release AV411
channel's role in pain receptor activation. capsules or placebo. The study may involve the dosing of up to 48
subjects. In parallel, Avigen's Australian Phase IIa trial is expected
Hydra is investigating TRPA1 as part of its Ion Channel Program, a to provide safety and initial efficacy data of AV411 in patients with
research and development effort focused on the TRP family of novel diabetic neuropathic pain and is expected to report by the end of
non-selective cation channels. TRP channels respond to a variety of 2007.
stimuli and may act as multi-modal signal integrators in a number of
tissues, including sensory neurons. Because the members of the TRP AV411 is a first-in-class, orally-bioavailable small molecule that
family have low homology to each other and to other classes of ion suppresses the pro-inflammatory cytokines, interleukin (IL)-1 beta,
channels, Hydra sees significant opportunity for developing drugs that TNF alpha and IL-6, and may upregulate the anti-inflammatory
can potently and selectively target individual TRPs for the treatment of cytokine, IL-10. The compound modulates glial cell function, an
medical conditions such as pain, inflammation, pulmonary disorders, important contributor to chronic pain, as well as opioid dependence
hypertension and renal disease. and withdrawal.

Merck/Neuromed discontinue development of pain Avigen plans to design larger efficacy studies of AV411 in the US for
drug candidate neuropathic pain and other indications, such as opioid withdrawal
and dependence. While ibudilast is approved in Asia at doses of up to
Merck & Co and Neuromed Pharmaceuticals have decided to 30mg/day, Avigen believes that the US Phase I trial will allow further
discontinue development of NMED-160 (also known as MK-6721), a development of the drug at higher doses, which may be optimal for
Phase II N-type calcium channel blocker for the treatment of chronic the neurological applications that the company is pursuing.
pain. A joint research collaboration will continue to evaluate alternate,
earlier-stage therapeutic candidates. Verapamil for cluster headaches linked to heart
problems
While no serious adverse events with MK-6721 were observed in
clinical trials in which up to a 1,600mg single dose was administered, According to research published in the 14th August issue of Neurology
the parties have determined that the compound does not (2007;69:668-675), verapamil, which is increasingly used to prevent
demonstrate the ideal pharmaceutical characteristics considered cluster headaches, can cause heart problems, such as arrhythmia and
necessary to advance it further in development. heart block. The scientists, from the National Hospital for Neurology
and Neurosurgery in the UK and the University of California, San
ReceptoPharm pain study produces positive results Franciso, recommend that those patients taking the drug for cluster
headaches should be closely monitored with frequent ECGs for the
ReceptoPharm (Nutra Pharma) has successfully completed a study potential development of such conditions.
of RPI-78, which is being developed for the treatment of pain. The
continuing pain studies, being conducted in collaboration with The study involved 108 people with an average age of 44 years. The
Soochow University, recently found that RPI-78 was successful in participants started taking verapamil and then had an ECG and
controlling pain with a long duration of effect. an increase in the dosage of the drug every two weeks until the
headaches were stopped or the patient started experiencing side
The latest data demonstrate that RPI-78 was as effective as morphine effects.
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 Arrhythmia was observed in 21 patients (19 per cent) taking the drug.
opioid mechanism. Moreover, the duration of RPI-78's effect was Thirteen (12 per cent) had first-degree heart block at 240 to 960mg/
superior to morphine's. According to ReceptoPharm, it believes day, with one requiring a permanent pacemaker. Four patients had
that the data from this and previous studies may be sufficient to junctional rhythm and one had second-degree heart block. Four
commence a Phase I trial in subjects with severe pain. patients had right bundle branch block.

Clinical studies with early formulations of RPI-78 revealed that the There was bradycardia (heart rate <60 beats per minute) in 39 patients
drug was effective in subjects with pain from terminal cancer, arthritis, (36 per cent), but in only four cases was this severe enough to warrant
headaches and amputations, even where morphine was ineffective. stopping verapamil treatment.

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Espicom Business Intelligence 23rd August 2007
CNS Drug News ANALGESICS/ANAESTHETICS

The investigators noted that 217 people taking the drug were initially endpoint, with results across the 12 weeks of treatment showing both
supposed to take part in the study, but 42 per cent of them did not statistically significant and clinically relevant outcomes for patients
have the ECGs carried out to monitor their heart activity. Many of the with breakthrough pain who were already receiving and were tolerant
patients reported that either they or their local services were reluctant to opioid therapy for their underlying persistent pain.
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 The double-blind, placebo-controlled, variable-dose trial included
cluster headaches, the researchers raised the possibility that some 148 patients. The primary endpoint was the Sum of Pain Intensity
healthcare providers are not aware of the problems that can come Differences from five to 60 minutes, as assessed after 12 weeks
with its use, however, in concluding, the team strongly recommended of treatment. Patients treated with Fentora showed a statistically
ECG monitoring in all patients with cluster headache on verapamil, to significant improvement on the primary endpoint (p<0.0001)
observe for the potential development of atrioventricular block and compared with placebo and the drug was generally well tolerated,
symptomatic bradycardia. with side effects consistent with those in the currently-approved label.

In the future, the scientists believe that the benefit of taking verapamil Fentora is approved only for the management of breakthrough pain
to alleviate the pain of cluster headaches has to be balanced against in patients with cancer who are already receiving and are tolerant to
opioid therapy for their underlying persistent cancer pain. This third
the risk of causing a heart abnormality that could progress into a more
and final controlled study completes Cephalon's Phase III programme
serious problem.
and the company plans to submit these data to the FDA in the fourth
quarter as part of its sNDA.
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
AstraZeneca releases R&D pipeline update
various tradenames, including Verelan, by Elan. The drug has been
For details, see Psychotic Disorders, R&D Update.
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 Product News


funds to advance pain therapeutics FDA issues second approvable letter for Trexima
NeurAxon has reported positive data from its Phase I trial assessing
The FDA has issued a second approvable letter for Trexima
the safety and establishing the pharmacokinetic profile of the
(sumatriptan+naproxen), which is being developed by
investigational drug candidate, NXN-188. This first-in-class, dual-action
GlaxoSmithKline and Pozen.
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 The Agency has requested that Pozen further addresses its
CNS neuronal sensitisation. concern, prior to approval, about the potential implications from
one preclinical in vitro chromosomal aberration study (one of four
The double-blind, placebo-controlled, dose-escalation study enrolled standard genotoxicity assays) in which genotoxicity was seen for
healthy volunteers who were randomised to receive single oral the combination of naproxen+sumatriptan, but not with either
doses of either placebo or NXN-188. Nine active drug dose levels component alone. None of the other three standard genotoxicity
were evaluated. Subjects were monitored for adverse events and studies (Ames test, mouse lymphoma TK assay, in vivo mouse
pharmacokinetic parameters. The results indicate that NXN-188 was micronucleus assay) demonstrated any genotoxicity for the
well tolerated, with no drug-related adverse events reported. combination. The companies intend to request a meeting with the
FDA as quickly as possible to discuss the necessary steps to address
Preclinical studies comparing NXN-188 to triptans demonstrated the Agency's concerns.
that the compound has multiple potential advantages over triptan
therapy. These benefits may include increased efficacy, tolerability, In January, Pozen and GSK responded to the Agency's first approvable
safety, treatment window and response rates, plus reduced rebound letter, submitting additional safety data from clinical trials, data
headache. Based on the new results, NeurAxon plans to advance NXN- from GSK's database and additional in vitro preclinical data. In the
188 into a Phase IIa proof-of-concept study in the third quarter of 2007. second approvable letter, no additional information regarding the
cardiovascular safety of Trexima was requested. The companies
In addition... agreed to conduct a prospective study after approval to evaluate the
effects on blood pressure during chronic, intermittent treatment.
NeurAxon, which has generated a portfolio of next-generation pain
therapeutics targeting nNOS, has closed a US$32 million series B Trexima was the proposed brandname for the product candidate
financing, the proceeds of which will be used to accelerate the clinical combining sumatriptan 85mg, as the succinate salt, formulated
development of its product candidates. with RT Technology, and naproxen 500mg in a single tablet. Several
new names are under consideration at the FDA, but pending a
Cephalon to file Fentora sNDA following positive final decision on a new name, the product will still be referred to as
Phase III data Trexima.

Cephalon has reported positive results from a 12-week, Phase III trial The FDA previously determined that Trexima is effective as an acute
of Fentora (fentanyl buccal tablet) [C-II] in patients with breakthrough treatment for migraine headaches. Pozen and GSK will continue to
pain associated with a broad range of chronic non-cancer pain work with the Agency on revisions to the proposed package insert
conditions. The study achieved statistical significance on the primary and tradename.

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ANALGESICS/ANAESTHETICS CNS Drug News
Sativex approved in Canada for cancer pain Anesiva receives FDA approval for Zingo

On 1st August, GW Pharmaceuticals' cannabis-derived pharmaceutical On 16th August, the FDA approved Anesiva's Zingo (lidocaine
therapy, Sativex, was approved in Canada for use as adjunctive hydrochloride monohydrate) powder intradermal injection system,
analgesic treatment in adult patients with advanced cancer who which provides rapid, topical, local analgesia to reduce the pain
experience moderate-to-severe pain during the highest-tolerated associated with venous access procedures, such as intravenous (iv)
dose of strong opioid therapy for persistent background pain. insertions or blood draws, in children aged three to 18 years. Zingo
Administered as a buccal spray, Sativex is composed primarily of is an easy-to-administer, single-use, needlefree system containing
tetrahydrocannabinol and cannabidiol. 0.5mg sterile lidocaine powder.

Data from two pivotal, placebo-controlled, Phase III studies, which


Marketed there by Bayer, Sativex was first indicated in Canada in 2005,
collectively enrolled 1,109 patients across 15 US clinical centres,
as adjunctive treatment for the symptomatic relief of neuropathic pain
demonstrated that Zingo provided statistically significant pain relief in
in multiple sclerosis. Health Canada has approved Sativex for both
children aged three to 18 years undergoing venous access procedures,
indications under the NOC/c policy, which includes a commitment to
such as iv line placements. These data indicated that treatment with
ongoing clinical research. Zingo quickly and effectively reduced pain when given just one to
three minutes prior to the venous access procedure. Zingo was well
The efficacy of Sativex has been demonstrated in a double-blind, tolerated, with the most common adverse reactions being erythema,
placebo-controlled, parallel-group study in patients with cancer pain. petechiae and oedema at the site of administration. Anesiva is now
Participants in the study had advanced cancer and were experiencing studying Zingo in a large Phase III trial in adults. The company will use
pain that was not responding adequately to strong opioid medication the data generated in that trial as the basis for an FDA filing to expand
(eg, morphine). In addition to study medication, all patients remained the label to include adults.
on their existing opioid and other analgesic medication during
the trial. In this study, Sativex achieved a statistically significant Vimpat MAA submitted for DNP
improvement in pain relief, in comparison with placebo. The study
further showed that in patients with advanced cancer who were Schwarz Pharma (UCB) has filed an MAA for Vimpat (lacosamide) as
already taking the strongest available pain treatments, more than therapy for diabetic neuropathic pain (DNP) with the EMEA, which has
four out of ten patients taking Sativex were able to achieve a further been accepted for review. Vimpat, taken as an oral tablet, has been
clinically important reduction in pain. dosed twice daily in clinical trials. Possible tablet strengths range from
50 to 300mg.
In clinical trials, the most frequent side effects with Sativex included
nausea, fatigue, dizziness and application site reactions. These were Vimpat is an anticonvulsant drug of a new generation with a novel
usually mild or moderate in severity and often resolved with down- dual mode of action, acting on CRMP-2 (collapsing response mediator
titration or interruption of treatment. protein-2) and sodium channel slow inactivation. Vimpat has not
shown clinically relevant interactions with other anti-epileptic drugs,
FDA requests more time to review Frova sNDA oral contraceptives or food, neither have oedema or weight gain been
reported during the clinical trial programme. Dizziness and nausea
The FDA has requested an extension of the 19th August review were the most commonly-reported side effects, whereas somnolence
date in order to have more time to review the sNDA for Frova was notably low. An MAA for Vimpat as adjunctive therapy for adult
(frovatriptan) 2.5mg tablets, for the additional indication of short- patients with epilepsy with partial onset seizures was accepted for
term (six days) prevention of menstrual migraine. Vernalis currently review by the EMEA in May. Filing in the US is planned for the fourth
co-promotes Frova with its North American licensing partner, Endo quarter of 2007.
Pharmaceuticals.
Ranbaxy receives FDA approval for generic Norco/
The FDA indicated that it will provide a revised timeline to Endo and Vicodin/Lortab
Vernalis. Until the companies receive further information, they intend
to continue with their existing commercial plan. The FDA has not On 16th August, Ranbaxy Laboratories received FDA approval to
currently requested any additional information or clinical trial data. manufacture and market hydrocodone bitartrate+acetaminophen
tablets in 7.5/750, 10/500, 5/500 and 10/325mg strengths. The
Eslax receives Japanese approval formulations are bioequivalent and have the same therapeutic effect
as that of the reference listed drugs: Norco Tablets 10/325mg (Watson
The Japanese Ministry of Health, Labour and Welfare has approved Pharmaceuticals), Vicodin Tablets 5/500mg and Vicodin ES Tablets
rocuronium bromide, Organon's (Akzo Nobel) neuromuscular- 7.5/750mg (Abbott Laboratories), and Lortab Tablets 10/500mg
blocking agent for use during general anaesthesia, under the (UCB). Ranbaxy's tablets are indicated for the relief of moderate-to-
brandname, Eslax. This muscle relaxant has a fast onset of action moderately severe pain and will be launched in a November time
and is widely used in the US, Canada and many European countries period.
(marketed under the brandnames, Zemuron/Esmeron).

Nippon Organon is preparing to introduce the drug in the course of Agreement News
this year. Eslax' rapid onset of action allows almost all patients to be
intubated within approximately one minute of its administration. Ono obtains Japanese rights to CNS 7056
Additionally, it will come in a ready-to-use solution and no active
metabolites with the drug have been identified in clinical trials, to Ono Pharmaceutical has obtained the exclusive rights in Japan to
date, which further contributes to safety and ease of continuous develop and commercialise CeNeS Pharmaceuticals' CNS 7056, a
infusion. benzodiazepine that is being developed as a general anaesthetic and

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CNS Drug News ANTI-EPILEPTICS

short-acting sedative. Under the terms agreed, Ono will pay up-front collaboration. Pfizer will fund all aspects of the collaboration, including
and milestone payments based on development stage, as well as the research and preclinical development efforts at Icagen, in addition
royalties on sales of CNS 7056. to having exclusive worldwide rights to commercialise products that
result from the partnership. Pfizer will make an equity investment in
CNS 7056 is a short-acting general anaesthetic and sedative that Icagen in connection with the collaboration.
acts on GABA-A receptors. Preclinical studies demonstrate that
after intravenous administration, the compound rapidly induces The ion channel targets included in the collaboration are important
deep sedation that is maintained during continuous administration. in the generation of electrical signals in nerve fibres that mediate the
Importantly, the sedative effects rapidly disappear after cessation initiation, transmission and sensation of pain. In preclinical studies,
of administration. The rapid offset of effect of the compound is due compounds identified by Icagen have demonstrated efficacy in pain
to its metabolism by esterase enzymes that are widely distributed models. Icagen has also established a broad portfolio of intellectual
throughout the body. It is therefore anticipated that CNS 7056 property in this area, covering multiple promising compounds
could be clinically developed as a sedative agent for the induction targeting sodium channels.
and maintenance of anaesthesia, plus as a sedative for mechanical
ventilation in the intensive care unit. Under the terms of the agreement, Pfizer will provide US$38
million in committed funding to Icagen over the first two years of
CeNeS plans to start a Phase I study in the US in the first half of 2008, the collaboration, including an initial up-front licence fee of US$12
while Ono expects to start a Phase I study in Japan as early as the million, up to US$15 million through an equity commitment, plus R&D
second half of 2008. funding. The equity commitment comprises an initial investment in
Icagen common stock in the amount of US$5 million at fair market
Paladin signs licensing agreement for Glide Pharma's value on the effective date of the agreement and an equity put option,
Glide SDI exercisable by Icagen, to sell to Pfizer at market value up to US$10
million of common stock, subject to certain terms and conditions,
Paladin Labs has entered into an exclusive licence and distribution at any time during the first 18 months following the signing of the
agreement to develop and market Glide Pharmaceutical Technologies' agreement. Additionally, Icagen is eligible to receive US$359 million in
(Glide Pharma) innovative Glide SDI (solid-dose injector) needlefree research, development, regulatory and commercialisation milestones
drug-delivery products in Canada. Under the terms agreed, Paladin for each product. Icagen is also eligible to receive tiered royalties,
will assume responsibility for local clinical trials, registration, against which the commercialisation milestones are creditable,
marketing, sales and distribution of at least three of Glide Pharma's depending upon sales achieved.
pipeline products, which include needlefree versions of sumatriptan
for the treatment of migraine and fentanyl for breakthrough pain. EKR acquires US rights to Pacira's DepoDur

The companies expect the first product under this agreement to be EKR Therapeutics has acquired exclusive US marketing and distribution
filed for Canadian regulatory approval in 2009. Further terms were not rights to DepoDur (morphine extended-release liposome injection)
disclosed. from Pacira Pharmaceuticals, which will continue to manufacture the
product. DepoDur, which utilises DepoFoam technology, is the only
Icagen/Pfizer enter pact for pain and related disorders extended-release opioid that is approved by the FDA for epidural use.

Icagen has entered into a worldwide collaboration and licensing A single injection of DepoDur into the lumbar epidural space may
agreement with Pfizer for the discovery, development and provide pain relief for up to 48 hours following major surgery without
commercialisation of compounds that modulate three specific the restrictions and potential complications associated with an in-
sodium ion channels as new potential treatments for pain and related dwelling epidural catheter.
disorders. Under the terms agreed, the companies will combine
resources to identify compounds that target these three ion channels ProStrakan enters agreements with Orexo and LG
in a global research and development collaboration. The companies
will form a joint research committee to monitor and oversee the For details, see Drugs Used in Nausea & Vertigo, Agreement News.

ANTI-EPILEPTICS
The primary endpoint of RESTORE 1 is a change in total partial seizure
R&D Update frequency per four weeks from baseline to the double-blind period
(titration phase and maintenance phase). For EMEA review, the
Valeant completes enrolment in first retigabine Phase primary endpoint is the proportion of responders, where a responder
III epilepsy study is defined as a patient experiencing a reduction of at least 50 per
cent in total partial seizure frequency per four weeks from baseline
Valeant Pharmaceuticals International has completed enrolment in to double-blind period. A total of 306 patients have been enrolled
the first retigabine pivotal study, RESTORE (Retigabine Efficacy and into RESTORE 1, which is being conducted at 49 sites across the US,
Safety Trials for Partial Onset Epilepsy) 1. The RESTORE trials are two Argentina, Mexico, Brazil and Canada, and Valeant anticipates the
large, randomised, double-blind, placebo-controlled, multi-centre, study's completion in the first quarter of 2008.
parallel-group, pivotal Phase III studies that will evaluate the safety
and efficacy of retigabine, a first-in-class neuronal potassium channel RESTORE 2, the second pivotal trial in the programme, is targeted to
opener, in patients with refractory partial onset seizures who are enrol 510 patients and is being conducted in 72 sites across Europe,
receiving one, two or three concomitant anti-epileptic drugs. Israel, Australia, South Africa and the US, with full enrolment expected

23rd August 2007 ©


Espicom Business Intelligence Page 25
EATING DISORDERS / DRUGS USED IN NAUSEA & VERTIGO CNS Drug News
in the autumn. At the completion of these trials, retigabine will have epilepsy who are currently on stable doses of oral carbamazepine. The
been studied in more than 1,500 subjects, including more than 1,100 sequential, open-label, 65-day study has already accepted more than
patients with epilepsy. More than 350 of these patients will have taken 40 patients and plans to enrol 96 in total.
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 Product News
directly from the RESTORE programme.
FDA approves Cerebyx generics
Ovation initiates clinical trial of iv carbamazepine
On 6th August, the FDA approved the first generic versions of Pfizer's
Ovation Pharmaceuticals has expanded its CNS development Cerebyx (fosphenytoin), with the following companies' applications
pipeline with the initiation of a pivotal clinical trial to support an having been cleared: Abraxis BioScience, Apotex, Baxter, Bedford
NDA for intravenous (iv) carbamazepine in adult patients with (Ben Venue Laboratories [Boehringer Ingelheim]), Hospira, Teva
epilepsy. To date, there have been no iv options for patients that are Pharmaceutical Industries, Wockhardt and IV Therapeutics.
therapeutically equivalent to oral carbamazepine when replacement
therapy is required. Cerebyx is used for the control of generalised convulsive status
epilepticus, as well as the prevention and treatment of seizures
As the first and only injectable form of the widely-used oral anti- occurring during neurosurgery. It can also be substituted, short-term,
epileptic drug, carbamazepine, the product is an important alternative for oral phenytoin. Abraxis has confirmed that it expects to commence
for patients with epilepsy who may be hospitalised or otherwise marketing its fosphenytoin sodium injection 100mg/2mL and 500mg/
temporarily unable to take oral carbamazepine. The trial is designed 10mL vials, which are preservative- and latex-free, during August.
to evaluate the bioequivalence of the iv doses with oral doses, as
well as assess the safety, tolerability and pharmacokinetics of iv In addition, GeneraMedix has launched its preservative-free
carbamazepine relative to orally-administered carbamazepine. Fifteen fosphenytoin sodium injection, 50mg phenytoin sodium equivalent/
investigative sites around the US have begun recruiting patients with mL in 2 and 10mL vials in the US.

Eating Disorders
in otherwise healthy obese volunteers. The presentation included
R&D Update 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
Interim Phase I trodusquemine data presented sequential dose groups. The PK profiles, thus far, show a predictable
pattern, with minimal between-subject variability and linearity across
At the IBC's 12th Annual World Congress on Drug Discovery & the range of doses studied. To date, no serious adverse events have
Development of Innovative Therapeutics, held from 6th to 8th August, been reported. It was emphasised that further study is needed to
in Boston, MA, Genaera presented interim data from the first Phase I establish dose-limiting toxicity and proof-of-concept in humans.
study of trodusquemine (MSI-1436) for the treatment of obesity.
Trodusquemine is the first drug candidate that acts both centrally and
The presentation summarised the design of the double-blind, peripherally to selectively inhibit the established, validated target,
randomised, placebo-controlled, single ascending-dose study to protein tyrosine phosphatase-1B (PTP-1B). By inhibiting PTP-1B, the
evaluate the safety and pharmacokinetics (PKs) of trodusquemine drug is expected to decrease appetite and normalise blood glucose.

Drugs used in Nausea & Vertigo


per cent of the company. The JV will initially trade as ProStrakan AB
Agreement News from its offices in Malmo, Sweden. ProStrakan has entered into an
exclusive supply agreement with the JV for the commercialisation of
ProStrakan enters agreements with Orexo and LG 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
Orexo has entered into a joint-venture (JV) agreement with ProStrakan similarly shared.
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 In addition...
companies' portfolio, which will include currently-marketed and future
products, such as Sancuso (granisetron), ProStrakan's transdermal LG Life Sciences has signed an exclusive distribution agreement for
patch for the prevention of chemotherapy-induced nausea and Sancuso. Under the terms agreed, ProStrakan will receive up-front and
vomiting (CINV), plus Rapinyl (fentanyl), Orexo's patented product for milestone payments, subject to the achievement of certain approvals
the treatment of cancer breakthrough pain, to which ProStrakan holds and sales targets, of up to US$6 million. ProStrakan will exclusively
European distribution rights. ProStrakan's existing Swedish affiliate, supply Sancuso to LG and receive an undisclosed royalty rate on sales
ProStrakan AB, will be used as the JV company. Orexo is investing £1.3 generated by LG in South Korea. ProStrakan submitted an NDA to the
million (SKr 17.9 million), through a directed share issue, to acquire 50 FDA in June and an MAA across Europe in July. Following approval in

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CNS Drug News GENERAL DEVELOPMENT NEWS

the US, LG will seek approval for Sancuso in South Korea. ProStrakan's Under the terms agreed, Par gains exclusive North American rights
transdermal patch delivers granisetron, an established 5-HT3 receptor to Zensana and will have primary responsibility for the compound's
antagonist that treats CINV, steadily into the bloodstream without development, all regulatory filings with the FDA, and sales and
the need for injection or having to swallow pills. ProStrakan reported marketing. Hana will receive an initial payment of US$5 million
positive results from the pivotal Phase III programme on Sancuso in through the sale of common stock at a share price of US$2, a 25
patients undergoing multi-day chemotherapy in December 2006. per cent premium. Hana may also receive up to US$45 million in
development and commercialisation milestone payments. Following
Par granted North American rights to Zensana Zensana's approval, Hana will be eligible to receive royalty payments
on sales exceeding specified levels.
Par Pharmaceutical Companies has entered into an exclusive
licensing agreement with Hana Biosciences for the development Simultaneous to this sublicence, NovaDel and Hana have amended
and commercialisation of Zensana (ondansetron) Oral Spray (OS) in their licence agreement for Zensana in North America. The key
North America. Hana licensed exclusive US and Canadian rights to the financial provisions of the agreement remain unchanged, with
product from NovaDel Pharma in October 2004. Zensana is the first 5- NovaDel expecting to receive a milestone payment upon approval
HT3 antagonist to deliver ondansetron, an anti-emetic therapy used in and royalties ranging from 15 to 25 per cent of net sales upon
the prevention of nausea and vomiting as a result of chemotherapy, successful commercialisation of the drug. Par and NovaDel anticipate
radiation and surgery, in an OS formulation. collaborating on the development of a formulation of Zensana.

General Development News


Eisai updates clinical progress
R&D Update
Eisai has released an update on its progress with clinical studies since
Lexicon's LX-6171 completes Phase I trials April. It confirmed that:

LX-6171, an oral drug candidate for cognitive disorders, has successfully • a Phase III trial has been initiated with the Alzheimer's disease
completed Phase I trials. According to Lexicon Pharmaceuticals, therapy, Aricept (donepezil), for a sustained-release formulation
the safety and exposure profile that was observed in this phase of the product, which was originally approved as a tablet
encourages it to proceed with further development and the company formulation;
anticipates progressing the compound into Phase II trials. • the Dainippon Sumitomo Pharma-originated product, Zonegran
(zonisamide), which is currently indicated for adjunctive therapy
The recently-completed Phase Ib trial of LX-6171 was designed as a in the treatment of adult patients with partial seizures, has
randomised, double-blind, placebo-controlled, multiple ascending- entered a Phase III trial for epilepsy monotherapy in Europe; and
dose study to evaluate safety, tolerability and pharmacokinetics over • a Phase II study with E2007, a compound that selectively
seven days of dosing in normal, healthy young (age 18-50 years) and antagonises the AMPA-type glutamate receptor, has been
elderly (age 65-80 years) volunteers. LX-6171 was well tolerated at all initiated for neuropathic pain in the US.
dose levels and showed good systemic exposure. Over the seven-day
trial, no dose-limiting toxicities were observed and exposure levels For details of a further Aricept study and a judicial review affecting its
supported a once-daily dosing regimen.
use in the UK, see Neurodegenerative Disorders, Alzheimer's Disease -
R&D Update and Product News, respectively.
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 Neuren sets out plans for Hamilton acquisition
disease, schizophrenia or vascular dementia. Its target, a membrane
protein that is expressed exclusively in the CNS, was identified through Neuren Pharmaceuticals is looking to acquire Hamilton
Lexicon's Genome 5000 programme through the study of mouse Pharmaceuticals in a transaction that is expected to position the
knockouts that showed enhanced learning and memory. LX-6171 company as a key player in the CNS field, specialising in the cognitive
is a potent oral inhibitor of its target and reproduces these effects in and psychological effects of CNS injury. Hamilton's shareholders have
animal models. unanimously approved the transaction, while Neuren has yet to seek
shareholder approval. A definitive legal agreement is being prepared.
LX-6171 is being developed under a product development
collaboration with Symphony Capital Partners and its co-investors. Through the acquisition, Neuren will obtain a Phase IIb compound,
Under the terms of the arrangement, US$45 million was provided to Motiva, which is from the acetam class of compounds and being
Symphony Icon, a newly-created company established to fund and developed for psychological and cognitive disorders resulting
accelerate development of Lexicon's first three product candidates from stroke, traumatic brain injury, and Alzheimer's and Parkinson's
and to hold the licence to the intellectual property. An additional diseases. Exclusive rights to develop and commercialise Motiva
US$15 million of equity capital was provided directly to Lexicon for intellectual property in the US and EU were licensed to Hamilton by
general corporate purposes. Daiichi Pharmaceutical (now Daiichi Sankyo) in 2004. The compound
already has proven clinical safety and efficacy in 1,700 patients.
Lexicon expects to receive full audited results of its Phase I trials in the
third quarter of 2007 and anticipates filing with European regulatory Neuren will not be retaining any Hamilton management and no
authorities for approval of its Phase II plans in the fourth quarter. cash payment will be made for the acquisition. The company will
Pending regulatory approval, the company plans to initiate Phase II acquire 100 per cent of Hamilton in exchange for US$4.4 million in
trials in the first quarter of 2008. 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 year from internal research and development, starting in 2011. While
contingent Motiva-related milestones, such as successful completion the total number of Phase I compounds has declined since 2006, the
of Phase II, initiation of a Phase III pivotal study, first filing of an NDA majority of Pfizer's Phase I starts are targeted for the second half of
or equivalent and first approval of an NDA or equivalent. The three 2007.
major venture capital investors from Hamilton, Vivo Ventures, CNF
Investments and Index Ventures, will become shareholders in Neuren The pipeline includes 17 potential treatments for pain and
through the transaction, and upon closing, Vivo Ventures and CNF will inflammation, as well as 17 for neurological disorders. The update also
invest US$3 million in the company. includes 85 new molecular entities, plus 14 potential new indications
or enhancements for medicines, including Lyrica (pregabalin) and
Motiva has been studied in two randomised clinical trials, which Geodon (ziprasidone).
showed clinically and statistically significant efficacy of the drug, and
in 2006, a third trial in post-stroke patients was suspended due to poor The updated pipeline shows eight candidates for pain, with an
contract research organisation execution. Motiva's FDA-approved IND additional nine in the related area of inflammation. Data from a Phase
remains open and there are sufficient quantities of the compound II trial of S,S-reboxetine, a selective norepinephrine reuptake inhibitor,
available to complete a Phase II trial. In 2008, Neuren intends to in patients with fibromyalgia, are encouraging. Phase II trials have
conduct a larger Phase II trial of Motiva, with a broader range of progressed as monotherapy or in combination with pregabalin for
endpoints and tighter patient attributes. The company will thereby post-herpetic neuralgia and a Phase II trial is being planned for painful
be conducting one Phase III trial and three Phase II trials in 2008, all diabetic neuropathy.
focusing on cognitive and psychological effects of acute CNS injury,
with results expected by early 2009. 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-
CCK finding offers potential for mood disorder and dose trial in OA, plus initiate studies in other settings of pain, during
epilepsy therapies 2007. A Phase II trial recently started to compare PF-592379 with
oxycodone in severe OA pain.
Researchers at the University of California, Irvine have discovered a
novel molecular switch that powerfully modulates nerve cell activity, Pfizer has received approval for Lyrica's fibromyalgia indication, which
which offers the potential for new mood disorder and epilepsy is an important line extension in the US. The product is currently in
treatments. Phase III testing for epilepsy monotherapy and generalised anxiety
disorder (GAD) in the US, as well as Phase II for restless legs syndrome.
For this research, which was published in the 5th August online issue Additionally, Geodon is in Phase II for adjunctive bipolar depression
of Nature Neuroscience (10.1038/nn1952), the scientists investigated and Phase III for bipolar relapse prevention (for forecasts of Geodon's
the role of the natural substance, cholecystokinin (CCK), in modulating future sales, see In Focus).
communication between cells in the brain. CCK is one of the most
abundant peptides in the brain and is linked to psychiatric disorders Pfizer is continuing with work on alpha-2-delta compounds for
such as anxiety, depression and schizophrenia. patients with neurological disorders and is proceeding with broad
confirmatory development of PD-332334, which is in Phase II studies
The study looked at the hippocampus, damage or alterations to which for the treatment of GAD. Pfizer scientists continue to believe that
can cause cognitive disorders, epilepsy and mental illness. Using molecules with this mechanism of action are potentially important
electrophysiological measurements, the researchers showed that CCK new therapies for the treatment of illnesses such as insomnia and
functions in the brain as an extremely specific switch with a highly- vasomotor symptoms. The company also has several new approaches
unusual dual action. On the one hand, CCK enhances the synthesis to the treatment of Alzheimer's disease in ongoing Phase II trials.
and release of natural endocannabinoid substances from a particular
class of nerve cells known to modulate neuronal excitability in brain Research offers hope for new antisense drug class
circuits critical for cognition and mood, while on the other hand, CCK
robustly increases electrical activity in a different class of nerve cells According to research published in the 14th August issue of Neurology
that play critical roles in learning and memory. (2007;69:699-700), a new type of treatment significantly reduces the
severity of muscle weakness in myasthenia gravis (MG), giving hope
According to the investigators, by linking CCK actions to for a new class of antisense drugs to treat neurological disorders.
endocannabinoids, the study provides novel possibilities for the future
development of therapies for a number of neurological diseases. The The drug, oral EN101 antisense, inhibits the production of
link between CCK and cannabinoids can now be further investigated acetylcholine esterase, an important enzyme in the function of
to determine how its modulation by either pharmacological or genetic neuromuscular junctions. This is the first time that the scientists from
means alters excitability in the hippocampus. the Hadassah Hebrew University Medical Center in Israel have been
able to show that antisense is effective and safe when taken orally for
Pfizer set to triple its Phase III portfolio by 2009 a neurological disease.

Further to its recent pipeline update, Pfizer has confirmed that it now For the study, 16 people with MG were given daily doses of oral EN101
has 99 programmes in development, with 38 in Phase I, 47 in Phase II, antisense for four days and monitored for one month. Four of the
11 in Phase III and three in registration, awaiting action from regulatory people later took the drug for one month.
authorities. Since December 2006, three compounds have entered
Phase III, 14 have entered Phase II and seven have entered Phase I, The study found that oral antisense reduced disease severity by an
while a total of 13 programmes were discontinued. The company average of 46 per cent, with patients experiencing improvements
reiterated that the number of Phase II programmes reflects continued in both muscle function and swallowing time, as well as the
progress towards its target of tripling its Phase III portfolio by 2009. disappearance of a drooping eyelid. Side effects reported during the
It is also targeting having a steady stream of four new medicines per study were dryness of the eyes and mouth.

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CNS Drug News GENERAL DEVELOPMENT NEWS

It is hoped that this discovery may have implications beyond MG. and psychiatric disorders a safer and potentially more efficacious
Further study is needed to investigate whether oral antisense may treatment option. Neurocrine intends to initiate clinical studies after
become another mode of therapy in neuromuscular disease. The submitting an IND application in the first half of 2008.
researchers noted that these preliminary results should be evaluated
with caution since this was an open-label study. Further research is BrainStorm restructures agreement with Ramot
under way to investigate the effects of this drug over a longer period
of time. BrainStorm Cell Therapeutics has reached a restructured research
and licence agreement with Ramot at Tel Aviv University with respect
Editor's note: EN101 (now known as Monarsen) was awarded orphan to payment obligations for its technology licence, plus the Double U
drug status by the FDA and is in development by Ester Neurosciences, Fund, a lender to the company, has also come to an agreement over
which supported the current study. funds owed to it by BrainStorm. The waiver and release from Ramot
ensures that BrainStorm's technology licence is securely held by the
Noven completes JDS acquisition company.

Noven Pharmaceuticals has completed its acquisition of JDS BrainStorm holds rights to develop and commercialise NurOwn
Pharmaceuticals, a specialty pharmaceutical company that currently patent-pending technology, which allows for the differentiation
markets two branded prescription psychiatry products in the US: of bone marrow-derived stem cells (SCs) into functional neurons
Lithobid (lithium carbonate) for bipolar disorder (BPD) and Pexeva and astrocytes, as demonstrated in animal models, through the
(paroxetine) for depression, panic disorder, obsessive-compulsive licensing agreement with Ramot. For details of preclinical testing with
disorder and generalised anxiety disorder. The company also has BrainStorm's human bone marrow-derived mesenchymal SCs, see
a pending NDA for Stavzor (valproic acid softgel) in BPD, migraine Neurodegenerative Disorders, Parkinson's Disease - R&D Update.
and epilepsy, as well as a product in Phase III trials, Lithium QD
(once-daily lithium) for BPD. JDS' non-hormonal product, Mesafem Valeant's candidate selection triggers payment to
(low-dose paroxetine mesylate), which is entering Phase III Ardea
development for vasomotor symptoms associated with menopause,
is also complementary with Noven's expertise in women's health. Ardea Biosciences has received the first milestone payment of
The purchase price for the acquisition was US$125 million cash paid at US$0.5 million from Valeant Pharmaceuticals International under
closing on 14th August, plus the assumption of approximately US$10 the companies' December 2006 collaboration. Valeant's selection
million in net non-contingent liabilities. 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-
Product News generation compounds to treat serious diseases. The companies
agreed to collaborate exclusively to design a series of compounds to
FDA approves first generic Dantrium injection treat neurological disorders.

On 25th July, the FDA approved US WorldMeds' dantrolene injection The authoritative online
20mg/vial, which is the first therapeutically-equivalent injectable business resource for
version of Procter & Gamble's Dantrium. Used in the treatment of everyone involved in
spasticity in stroke, multiple sclerosis, cerebral palsy and spinal cord
injury, P&G's product was first approved in 1979.
this high growth area,
providing:
• Company Analysis
Agreement News Regularly updated and detailed analysis of 135
leading companies’ strategy, research, products
Neurocrine in-licenses valnoctamide isomers from
Yissum and agreements
• R&D and Product Developments
Neurocrine Biosciences has entered into an exclusive worldwide R&D and product developments in all major
licensing agreement for the development and commercialisation of cancer areas.
valnoctamide stereoisomers with Yissum Research Development of
the Hebrew University of Jerusalem in Israel. Valnoctamide and its • Market Statistics
individual stereoisomers have been shown to be active in a number Demography, disease
of preclinical models and have the potential to treat epilepsy, bipolar incidence and cause of
disorder (BPD) and neuropathic pain. The parent compound is a
uniform combination of four valnoctamide stereoisomers that was
death for 20 markets.
marketed as an anxiolytic in several European countries. • Latest News
Track over 2,000
While from the same chemical class as valproate, which is currently companies and
approved for use in the treatment of epilepsy, migraine prophylaxis
and BPD, in preclinical studies completed, to date, this stereoisomer organisations involved
of valnoctamide has not been associated with the safety concerns with cancer drugs.
(ie, teratogenicity and hepatotoxicity) of valproate and its related For full details about this report’s content, pricing and availability go to:

www.espicom.com/cio
analogues. The clinical development of one of the stereoisomers of
valnoctamide is intended to offer patients suffering from neurological

23rd August 2007 ©


Espicom Business Intelligence Page 29
COMPANY INDEX CNS Drug News

COMPANY INDEX
Abbott.............................................................................................................................................4, 23, 24 Medistem Laboratories......................................................................................................................18
Abraxis BioScience...............................................................................................................................26 Medtronic..................................................................................................................................................14
Accentia Biopharmaceuticals......................................................................................................... 11 Merck & Co...........................................................................................................................................3, 22
Acrux............................................................................................................................................................21 Merck KGaA.............................................................................................................................................. 17
Akzo Nobel.......................................................................................................................................... 4, 24 Merck Sharp & Dohme..........................................................................................................................3
Alnylam Pharmaceuticals.................................................................................................................14 Merz................................................................................................................................................................1
Alphapharm............................................................................................................................................. 17 Montréal Neurological Institute....................................................................................................10
ALZA...............................................................................................................................................................4 National Hospital for Neurology and Neurosurgery..........................................................22
Anesiva.......................................................................................................................................................24 National Institute of Mental Health.............................................................................. 16, 18, 20
Apotex........................................................................................................................................................26 National Institutes of Health.........................................................................................6, 12, 14, 20
Applied NeuroSolutions.......................................................................................................................9 Navinta.......................................................................................................................................................14
Ardea Biosciences.................................................................................................................................29 NeurAxon..................................................................................................................................................23
AstraZeneca..................................................................................................................................4, 17, 23 Neuren Pharmaceuticals...................................................................................................................27
Avanir Pharmaceuticals.....................................................................................................................20 Neurocrine Biosciences.....................................................................................................................29
Avigen.........................................................................................................................................................22 Neuromed Pharmaceuticals...........................................................................................................22
Azur Pharma............................................................................................................................................20 NovaDel Pharma...................................................................................................................................27
Baxter..........................................................................................................................................................26 Novartis........................................................................................................................................1, 4, 6, 15
Bayer....................................................................................................................................................... 4, 24 Noven Pharmaceuticals..............................................................................................................20, 29
Bayer Schering Pharma.........................................................................................................................4 Nutra Pharma..........................................................................................................................................22
Bayhill Therapeutics............................................................................................................................10 Ohio State University.......................................................................................................................... 11
Ben Venue Laboratories....................................................................................................................26 Ono Pharmaceutical............................................................................................................................24
Boehringer Ingelheim........................................................................................................................26 Opexa Therapeutics............................................................................................................................ 11
BrainStorm Cell Therapeutics....................................................................................................6, 29 Orexo....................................................................................................................................................25, 26
Bristol-Myers Squibb..............................................................................................................................4 Organon................................................................................................................................................ 4, 24
Cambridge Laboratories...................................................................................................................14 Orion...............................................................................................................................................................6
CeNeS Pharmaceuticals.....................................................................................................................24 Otsuka............................................................................................................................................................4
Cephalon............................................................................................................................................18, 23 Ovation Pharmaceuticals..................................................................................................................26
Chelsea Therapeutics..........................................................................................................................15 Pacira Pharmaceuticals......................................................................................................................25
Chiesi Farmaceutici..............................................................................................................................13 Paladin Labs......................................................................................................................................15, 25
Chugai Pharmaceutical......................................................................................................................16 Par Pharmaceutical Companies....................................................................................................27
Clinical Data...........................................................................................................................................3, 4 Pfizer...........................................................................................................................1, 4, 6, 9, 25, 26, 28
Cytokine PharmaSciences................................................................................................................ 11 Pozen...........................................................................................................................................................23
Daiichi Sankyo........................................................................................................................................27 Prana Biotechnology..............................................................................................................................8
Dainippon Sumitomo Pharma........................................................................................... 5, 15, 27 Procter & Gamble..................................................................................................................................29
DOV Pharmaceutical...........................................................................................................................16 ProStrakan..................................................................................................................................25, 26, 27
Ecole Polytechnique Fédérale de Lausanne........................................................................... 12 QRxPharma..............................................................................................................................................14
Eden Biodesign......................................................................................................................................10 Ranbaxy Laboratories.........................................................................................................................24
Eisai.................................................................................................................................................1, 6, 9, 27 ReceptoPharm........................................................................................................................................22
EKR Therapeutics..................................................................................................................................25 Roche...................................................................................................................................................... 5, 16
Elan...............................................................................................................................................................23 Samaritan Pharmaceuticals................................................................................................................8
Eli Lilly.................................................................................................................................................4, 9, 19 sanofi-aventis..................................................................................................................................... 4, 16
Emory University.................................................................................................................................5, 8 Santhera Pharmaceuticals................................................................................................................14
Encore Therapeutics............................................................................................................................21 Schwarz Pharma....................................................................................................................................24
Endo Pharmaceuticals........................................................................................................................24 Shanghai Jiao Tong University..........................................................................................................3
EPIX Pharmaceuticals..........................................................................................................................10 Shire................................................................................................................................................. 1, 15, 20
Ester Neurosciences.............................................................................................................................29 Sirtris Pharmaceuticals................................................................................................................12, 15
Forest Laboratories...................................................................................................................1, 16, 17 Socratech......................................................................................................................................................8
Genaera......................................................................................................................................................26 Solvay..............................................................................................................................................5, 16, 20
GeneraMedix...........................................................................................................................................26 Soochow University.............................................................................................................................22
Georgetown University........................................................................................................................8 Symphony Capital Partners.............................................................................................................27
GlaxoSmithKline........................................................................................................................4, 10, 23 Takeda.........................................................................................................................................................14
Glide Pharma...........................................................................................................................................25 Tel Aviv University............................................................................................................................5, 29
GW Pharmaceuticals...........................................................................................................................24 Teva Pharmaceutical Industries.....................................................................................................26
Hadassah Hebrew University Medical Center.......................................................................28 Tikvah Therapeutics.....................................................................................................................13, 14
Hamilton Pharmaceuticals...............................................................................................................27 Tokyo Institute of Psychiatry...........................................................................................................15
Hana Biosciences...................................................................................................................................27 TorreyPines Therapeutics.................................................................................................................21
Hebrew University of Jerusalem...................................................................................................29 Translational Genomics Research Institute............................................................................. 11
Heinrich-Heine University...................................................................................................................8 UCB...............................................................................................................................................................24
Hospira.......................................................................................................................................................26 University College London.................................................................................................................3
Hydra Biosciences.................................................................................................................................21 University of Alabama........................................................................................................................14
Icagen..........................................................................................................................................................25 University of Birmingham................................................................................................................10
Intellect Neurosciences......................................................................................................................10 University of California................................................................................................. 12, 21, 22, 28
IV Therapeutics.......................................................................................................................................26 University of Central Florida...............................................................................................................6
Janssen-Cilag..................................................................................................................................... 4, 19 University of Edinburgh........................................................................................................................3
Janssen Pharmaceutica........................................................................................................................1 University of Georgia........................................................................................................................5, 8
Javelin Pharmaceuticals....................................................................................................................21 University of Glasgow............................................................................................................................3
Jazz Pharmaceuticals...................................................................................................................16, 20 University of Mainz..................................................................................................................................8
JDS Pharmaceuticals...........................................................................................................................29 University of North Carolina...............................................................................................................4
Johns Hopkins..................................................................................................................................11, 17 University of Oxford.......................................................................................................................3, 20
Johns Hopkins University................................................................................................................. 11 University of Rochester.........................................................................................................................7
Johnson & Johnson.....................................................................................................................1, 4, 19 University of Wisconsin-Madison................................................................................................. 12
Karolinska Institutet................................................................................................................................6 US WorldMeds........................................................................................................................................29
KineMed.....................................................................................................................................................13 Valeant Pharmaceuticals International....................................................................... 16, 25, 29
Knoll.............................................................................................................................................................23 Vernalis.......................................................................................................................................................24
Lexicon Pharmaceuticals............................................................................................................. 5, 27 Watson Pharmaceuticals...................................................................................................................24
LG Life Sciences......................................................................................................................................26 Wockhardt................................................................................................................................................26
Lundbeck..............................................................................................................................1, 4, 5, 16, 17 Wyeth..................................................................................................................................................... 5, 20
Medical Research Council Technology......................................................................................10 Yissum Research Development.....................................................................................................29
MedImmune............................................................................................................................................ 17

Page 30 ©
Espicom Business Intelligence 23rd August 2007
CNS Drug News COMPOUND INDEX

COMPOUND INDEX
Abilify.............................................................................................................................................................4 Motiva..................................................................................................................................................27, 28
AC-5216................................................................................................................................................15, 17 MSI-1436.....................................................................................................................................................26
acetaminophen.....................................................................................................................................24 N-desmethylclozapine..........................................................................................................................5
ACP-103.........................................................................................................................................................5 Namenda......................................................................................................................................................1
agalsidase alpha....................................................................................................................................15 naproxen...................................................................................................................................................23
Akatinol.........................................................................................................................................................1 NBI-18.............................................................................................................................................................7
amisulpride.................................................................................................................................................4 Nipolet...........................................................................................................................................................4
Amoban.....................................................................................................................................................16 Nitoman.....................................................................................................................................................14
Aricept....................................................................................................................................1, 6, 9, 10, 27 NMED-160.................................................................................................................................................22
asenapine.....................................................................................................................................................4 Norco...........................................................................................................................................................24
AV411...........................................................................................................................................................22 NXN-188.....................................................................................................................................................23
Axura..............................................................................................................................................................1 olanzapine........................................................................................................................................... 4, 19
AZD9272....................................................................................................................................................18 ondansetron............................................................................................................................................27
BHT-3009...................................................................................................................................................10 paliperidone...............................................................................................................................................4
bifeprunox....................................................................................................................................5, 16, 20 paroxetine.................................................................................................................................................29
blonanserin.................................................................................................................................................5 PBT2................................................................................................................................................................8
cannabidiol..............................................................................................................................................24 PD-332334.................................................................................................................................................28
carbamazepine......................................................................................................................................26 perphenazine.............................................................................................................................................4
carbidopa.....................................................................................................................................................6 Pexeva.........................................................................................................................................................29
Celexa..........................................................................................................................................................16 PF-4383119................................................................................................................................................28
Cerebyx......................................................................................................................................................26 PF-592379..................................................................................................................................................28
chlorpromazine........................................................................................................................................4 phenserine..............................................................................................................................................6, 7
citalopram.................................................................................................................................................16 PMI-150.......................................................................................................................................................21
clozapine..........................................................................................................................................4, 5, 20 pregabalin.................................................................................................................................................28
Clozaril...........................................................................................................................................................4 Provigil........................................................................................................................................................18
CNS 7056.............................................................................................................................................24, 25 PRX-03140.................................................................................................................................................10
cyclophosphamide.............................................................................................................................. 11 quetiapine.............................................................................................................................................4, 17
Dantrium...................................................................................................................................................29 quinidine...................................................................................................................................................20
dantrolene................................................................................................................................................29 Rapinyl........................................................................................................................................................26
Daytrana....................................................................................................................................................20 Razadyne......................................................................................................................................................1
DepoDur....................................................................................................................................................25 reboxetine.................................................................................................................................................28
dextromethorphan..............................................................................................................................20 Reminyl..........................................................................................................................................................1
donepezil....................................................................................................................................1, 6, 9, 27 Replagal.....................................................................................................................................................15
DOV 21,947........................................................................................................................................16, 17 resveratrol..........................................................................................................................................12, 15
droxidopa..................................................................................................................................................15 retigabine...........................................................................................................................................25, 26
E2007...........................................................................................................................................................27 Revimmune.............................................................................................................................................. 11
Ebixa................................................................................................................................................................1 Risperdal............................................................................................................................................... 4, 19
Elaprase......................................................................................................................................................15 risperidone.......................................................................................................................................... 4, 19
EN101................................................................................................................................................... 28, 29 rivastigmine................................................................................................................................................1
entacapone.................................................................................................................................................6 rocuronium bromide..........................................................................................................................24
escitalopram............................................................................................................................................ 17 ropivacaine...............................................................................................................................................21
Eslax..............................................................................................................................................................24 RPI-78...........................................................................................................................................................22
Esmeron.....................................................................................................................................................24 Sancuso...............................................................................................................................................26, 27
ETI-211.........................................................................................................................................................21 Sativex.........................................................................................................................................................24
Exelon.............................................................................................................................................................1 Seroquel..........................................................................................................................................4, 17, 18
FazaClo.......................................................................................................................................................20 SNT-MC17..................................................................................................................................................14
fentanyl................................................................................................................................21, 23, 25, 26 sodium oxybate.....................................................................................................................................16
Fentanyl MDTS.......................................................................................................................................21 sodium phenylbutyrate.............................................................................................................13, 14
Fentora.......................................................................................................................................................23 Solian..............................................................................................................................................................4
fluvoxamine.............................................................................................................................................20 SRT501..................................................................................................................................................12, 15
fosphenytoin...........................................................................................................................................26 Stalevo...........................................................................................................................................................6
Frova............................................................................................................................................................24 Stavzor........................................................................................................................................................29
frovatriptan..............................................................................................................................................24 sumatriptan...................................................................................................................................... 23, 25
galantamine................................................................................................................................................1 tetrabenazine...................................................................................................................................13, 14
Geodon.................................................................................................................................................4, 28 tetrahydrocannabinol........................................................................................................................24
granisetron........................................................................................................................................26, 27 tezampanel..............................................................................................................................................21
Haldol.............................................................................................................................................................4 Thorazine......................................................................................................................................................4
haloperidol..................................................................................................................................................4 Tovaxin........................................................................................................................................................ 11
HC-030031................................................................................................................................................22 Trexima.......................................................................................................................................................23
hydrocodone...........................................................................................................................................24 Trilafon...........................................................................................................................................................4
ibudilast......................................................................................................................................................22 trodusquemine......................................................................................................................................26
idebenone................................................................................................................................................14 valnoctamide..........................................................................................................................................29
idursulfase.................................................................................................................................................15 valproic acid.............................................................................................................................................29
Invega.............................................................................................................................................................4 verapamil........................................................................................................................................... 22, 23
ketamine....................................................................................................................................................21 Verelan........................................................................................................................................................23
KM-801.......................................................................................................................................................13 Vicodin........................................................................................................................................................24
lacosamide...............................................................................................................................................24 Vimpat........................................................................................................................................................24
levodopa.......................................................................................................................................................6 vOX2:Fc.......................................................................................................................................................10
Lexapro....................................................................................................................................................... 17 Xenazina.............................................................................................................................................13, 14
lidocaine....................................................................................................................................................24 Xenazine....................................................................................................................................................14
lithium carbonate.................................................................................................................................29 Xyrem..........................................................................................................................................................16
Lithobid......................................................................................................................................................29 Zeldox............................................................................................................................................................4
Lortab..........................................................................................................................................................24 Zemuron....................................................................................................................................................24
Luvox....................................................................................................................................................16, 20 Zensana......................................................................................................................................................27
LX-6171.................................................................................................................................................. 5, 27 Zenvia..........................................................................................................................................................20
Lyrica............................................................................................................................................................28 Zingo............................................................................................................................................................24
memantine..................................................................................................................................................1 ziprasidone..........................................................................................................................................4, 28
Mesafem....................................................................................................................................................29 Zonegran...................................................................................................................................................27
methylphenidate..................................................................................................................................20 zonisamide...............................................................................................................................................27
MK-6721.....................................................................................................................................................22 zopiclone...................................................................................................................................................16
modafinil............................................................................................................................................18, 19 zotepine........................................................................................................................................................4
Monarsen..................................................................................................................................................29 Zyprexa.................................................................................................................................................. 4, 19
morphine...................................................................................................................................22, 24, 25

23rd August 2007 ©


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