Evotec completes Phase I component for Alzheimer's drug

By Wai Lang Chu

- Last updated on GMT

Evotec has announced the successful completion of the single
ascending dose component of its phase I trial for its
subtype-specific NMDA receptor antagonist drug candidate for the
treatment of Alzheimer's disease.

EVT 101 is being developed for the treatment of Alzheimer's disease and is a highly potent and selective antagonist of NR2B subunit containing NMDA receptors.

Studies over the last 15 years have indicated a potential for NMDA receptor antagonists in the treatment of these diseases. However, the clinical development of non-selective antagonists has been limited by unfavourable side effects, such as hallucinations.

Apart from their normal physiological role in nerve-to-nerve cell communication NMDA receptors are important players in certain pathological disease states such as Alzheimer's disease, Parkinson's disease, neuropathic pain and epilepsy.

Drug researcher shave theorised that NMDA receptor over-activation is reduced in these conditions with an "antagonist," disease symptoms are reduced.

The study in 48 young healthy subjects of whom 36 received EVT 101 showed that EVT 101 was well absorbed, achieving good exposure levels, was well tolerated with no significant adverse events and had a good pharmacokinetic profile consistent with once or twice daily oral dosing.

Evotec expects to publish final results of the complete Phase I trials for EVT 101 in Q3 2006.

This result is significant given the unfavourable side-effect profile of non-selective NMDA antagonists. So much so that the clinical development of non-selective NMDA receptor antagonists has been hampered by this low therapeutic window

Nevertheless, memantine, a relatively low affinity, non-selective NMDA receptor blocker has been recently approved in both the US and Europe for the treatment of moderate-to-severe Alzheimer's disease.

Compounds selectively targeting NR2B subunit-containing receptors retain many of the beneficial effects of earlier non-selective compounds but have much improved side effect profiles.

Separating side effects from beneficial effects by selectively targeting the NR2B-subunit allows higher dosing and hence the potential to increase efficacy of the drug.

"Alzheimer's disease, Parkinson's disease and neuropathic pain remain major unmet medical needs with only limited treatment options currently available,"​ said Dr John Kemp, Executive Vice President R&D Pharmaceuticals Division at Evotec.

EVT 101 is the only publicly described orally active NR2B subtype selective antagonist to have entered clinical testing and, as such, represents a new opportunity to deliver novel therapeutic approaches through significant inhibition of this importantNMDA receptor system.

The class of drugs most commonly used to treat and prolong the symptoms of AD is called acetylcholinesterase inhibitors (AchI).

This market has been dominated by Pfizer's Aricept (donepezil), which holds over 50 per cent of the global market. Novartis's Exelon and Ortho-McNeil's Razadyne/Reminyl (galantamine) share the remainder.

The worldwide Alzheimer's disease therapeutics market is estimated to grow 11 per cent each year from $1.79 billion in 2004 to approximately $3.05 billion in 2009 and during this time AchIs will continue to dominate the market.

However, beyond this, their sales will suffer because of the expiry of their patents and the launch of new and combination products, such as the NMDA receptor antagonist recently launched by Forest's Namenda, and the availability of cutting edge disease-modifying therapies.

Related topics Preclinical Research

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