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Dealing with dementia

New medicines that treat AD, rather than merely delay its symptoms, are not far away

Dementia is a major public health issue that is on the increase because of the so-called 'demographic time bomb' of increasing life expectancy.

Alzheimer's disease (AD) is the most common form of dementia, but current AD treatments can only temporarily slow the disease's progression rather than prevent or treat it.

There are more than five million people with dementia in Europe and 18 million worldwide - a figure that is predicted to top 34 million by 2025 - according to the UK Alzheimer's Society. A huge market opportunity exists for new drugs that can tackle AD's root causes.

The mainstay of current AD treatment is the acetylcholinesterase inhibitor class of drugs, including Eisai's Aricept (donepezil) and Novartis' Exelon (rivastigmine), which are used in the early stages of the disease. Treatment with these drugs is typically followed by Forest Laboratories' glutamate antagonist, Namenda (memantine), when the disease reaches an advanced stage.

Aricept and Exelon act by preventing the breakdown of a neurotransmitter, acetylcholine, the levels of which are significantly reduced in patients with AD. Namenda, launched more recently than the others, in 2002, protects brain cells from further damage by blocking the release of the neurotransmitter glutamate, present in excessive amounts in sufferers' brains.

According to Thomson Pharma, the top drugs in the AD market - Aricept, Reminyl (gelantamine hydrobromide), Namenda and Exelon - generated Ä2.59bn ($3.37bn) in global sales in 2005, and this figure is predicted to rise to Ä3.69bn ($4.67bn) by 2010. Unfortunately, however, these drugs do not work in all patients and only improve memory, or delay its loss, for a short time.

So what developments are taking place in the pharmaceutical industry, and what can we expect to see make an impact on the market soon?

First across the line
A new therapy in late-stage development is Myriad Genetics' Flurizan (the R-enantiomer of flurbiprofen), which lowers brain levels of the protein amyloid-beta 42, and modulates signal transduction through nuclear factor kappa B.

Amyloid-beta is a very important target for AD because the protein forms the dense amyloid plaques in the brain which are a key characteristic of the disease. A European and US phase III trial began enrolling the first of 800 patients with mild AD in summer 2006, and results are expected towards the end of this year.

In the US, a second, 1,600-patient trial completed recruitment in August 2006. Phase II trials of Flurizan have yielded some promising results and the drug is targeted for a US launch in 2010.

Voyager Pharmaceuticals and DURECT have a candidate in phase III studies in the US and Australia which adopts another novel approach. Memryte is a biodegradable implant formulation of leuprolide, a gonadotrophin-releasing hormone agonist. The drug reduces the excessive levels of leuteinising hormone found in the brains of AD patients, which is postulated to drive the disease process.

In October 2006, a phase III trial ended early to assess the drug's efficacy in the 600 patients who had received treatment.

Phase II results reported in January 2006 showed that the drug stabilised disease in the higher-dose group. The ADAS-Cog scores in these patients, a measure of cognitive abilities, declined by 0.18 points compared with 3.30 points in patients receiving placebo plus acetylcholinesterase inhibitors, and the mean ADCS-ADL score decline was 0.54 and 6.85, respectively.

A promising late-stage candidate is Neurochem's Alzhemed (tramiprosate). This drug works by mimicking and binding to glycosaminoglycan (GAG), which promotes the formation of the amyloid-beta plaques. In Europe, a 930-patient phase III trial is nearly complete, after Neurochem got the go-ahead to continue from the study's Data Safety Monitoring Board in November 2006.

A North American phase III trial in 1,052 patients is also scheduled to be completed soon. If results are positive, Alzhemed could be the first disease-modifying AD treatment to reach the market. Analysts predict sales of Ä153.9m ($200m) in the US in 2010, assuming a 2009 launch.

However, while Alzhemed's mechanism of action seems rational, there is a question mark over whether it offers any advantage over targeting amyloid-beta directly via a monoclonal antibody, especially given that little efficacy data has been published to date.

Monoclonal antibodies for treating AD are an area of considerable interest, which is reflected by Thomson Pharma's data. Following closely behind Alzhemed, several other companies are developing antibody therapies, many of which target the amyloid-beta protein.

Monoclonal antibodies
The most advanced of the monoclonal antibodies for AD is Wyeth and Elan's bapineuzumab, which is poised to begin phase III studies by mid-2007, assuming positive phase II trial results. A 16-week, 30-patient phase I study has already shown an impressive improvement in cognitive function from a single dose of 1.5mg/kg, and analysts predict a 2010 launch and Ä769.5m plus ($1bn plus) sales potential in the US.

Wyeth and Elan are also investigating AAB-002, a follow-on amyloid-beta-targeting monoclonal antibody that is expected to enter clinical studies soon.

Other AD antibody therapies targeting amyloid-beta include Eli Lilly & Co's M-266, which is in phase II studies, while in phase I trials are Roche's R-1450 and Rinat Neuroscience's RN-1219. Preclinical programmes are underway at Abiogen and Takeda.

Interest in this area is also sufficiently high to generate licensing deals: in December 2006, Intellect Neuroscience licensed the rights to two amyloid-beta-specific, humanised monoclonal antibodies from Immuno-Biological Laboratories. They are designed to provide passive immunisation and promote amyloid-beta clearance from the brain.

Tried and tested
Some companies have opted to focus their drug development efforts against known targets, developing improved formulations of existing drugs or investigating compounds with similar mechanisms of action to Namenda, Exelon and Aricept.

Forest Laboratories is developing an NMDA receptor antagonist, neramexane, as an extension to its successful Namenda franchise. The drug is claimed to be more selective and require less frequent dosing than Namenda, for which market exclusivity expires late 2008. Neramexane, while not promising a dramatic new approach to AD, may help to improve patient compliance.

In a similar vein, Pfizer has a new acetylcholinesterase inhibitor in phase III development, and Eisai is developing a liquid formulation of Aricept. Furthermore, Novartis filed an application for European approval of a transdermal formulation of Exelon in November 2006, which is currently under review by the European Medicines Agency.

New vaccines
Clive Ballard, director of research at the Alzheimer's Society, recently told the media that there has been tremendous interest in developing an AD vaccine, but warned that side effects could be an issue.

An early attempt by Elan to create an AD vaccine failed in 2002 when patients in a phase IIa trial developed severe brain inflammation. The programme, AN-1792, was abandoned and the adverse reactions put down to the vaccine eliciting inappropriate T cell activation.

However, Thomson Pharma's data reveals that although still in their infancy, there are around 12 AD vaccines in preclinical and clinical development, so this field has the potential to make a big impact on the market if such side effects can be avoided.

One of the two most advanced
programmes is Elan and Wyeth's ACC-001, which consists of a peptide fragment of amyloid-beta conjugated to a CRM carrier protein. Phase I trials of the vaccine are complete, and phase II trials are scheduled to begin shortly. The other vaccine in phase I studies is Cytos and Novartis' CAD-106, an injectable amyloid-beta-modulating therapeutic vaccine based on Cytos' Immunodrug technology. A clinical trial was underway in Sweden by July 2005, and results are scheduled to be reported this year. Also of note is an amyloid-beta vaccine from Merck that is set to follow ACC-001 into phase I trials in the near future, and DNAVEC's intranasal vaccine based on a Sendai virus vector encoding the amyloid-beta gene.

Stem cell therapy
Much hope is resting on stem cell therapies for neurodegenerative diseases and media interest has been high. While stem cell therapies are still at an early stage of development, one promising example is ReNeuron's ReN-004 neural stem cell therapy for both Alzheimer's and Parkinson's diseases. Preclinical work on the candidate is still underway, and the company is seeking collaborative funding.

In January 2007, data were reported showing that ReN-004 cell lines survive well in vivo. The company plans to seek fast track approval for the therapy.

AD research is on the cusp of delivering some innovative new therapies that may finally begin to treat the disease, instead of merely delaying the inevitable decline into dementia which causes so much distress to sufferers and their carers.

The next 10 years will likely see a variety of drugs focused on modifying amyloid-beta, including antibody treatments and even AD vaccines, with stem cell therapies also on the horizon. With AD incidence set to rise as populations age, any therapies which are able to modify the disease will generate significant revenue.

The Author
Sarah Harrop is an editor in the Drug Information News team at Thomson Scientific. This article is based on data taken from the Thomson Pharma database (www.thomsonpharma.com)

8th March 2007

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