By Peter Berger, Alzheimer's Weekly
Week of December 23 - December 30, 2007

LEXINGTON, Mass. - EPIX Pharmaceuticals announced compelling results from a two-week clinical trial of its novel new drug in patients with Alzheimer's. The medication is currently called PRX-03140, and it is in Phase 2a clinical trials, which is about midway along the typical testing process.

People taking the new medication were monitored by the standard Alzheimer's performance exam used in clinical trials, called the "ADAS-cog Test." The test examines a person's performance in such areas as memory, orientation, attention, reasoning, and language. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater impairment. The name stands for "Alzheimer's Disease Assessment Scale cognitive subscale."

The results show that patients receiving 150 milligrams of PRX-03140 orally once daily without any other medication achieved a mean 5.7 point improvement on the ADAS-cog test, while people taking placebos experienced a typical 0.2 point worsening. Patients on a lower 50 milligram dose of PRX-03140 showed a 1.1 point improvement on the ADAS-cog.

"The responses observed in this clinical trial over a short duration are promising, and clearly indicate that PRX-03140 is worthy of further study over a longer period and in a larger patient population," stated Paul Solomon, Ph.D., Professor, Department of Psychology and Program in the Neurosciences, Williams College, and the Clinical Director of the Memory Clinic in Bennington, Vermont. "Our patients are always in need of safe and effective treatments for Alzheimer's disease, and I am very encouraged by these data."

After reviewing these data, Serge Gauthier, M.D., Director of the Alzheimer's Disease Research Unit at McGill University, stated, "There is such an urgent and undeniable need for additional safe and effective treatments for Alzheimer's patients. Findings like these data are not only encouraging and compelling - they appear to represent a step forward in our ability to understand and combat the effects of Alzheimer's. I look forward to the next clinical trial of PRX-03140 as the development of this drug could be an important advance toward effective Alzheimer's treatment."

As for side-effects, PRX-03140 appeared to be well tolerated alone and in combination with donepezil (Aricept(R)) with no serious drug-related adverse events. The results show that patients on PRX-03140 alone achieved a statistically significant improvement in ADAS-cog; ADAS-cog changes when the medicine was taken in combination with Aricept were not statistically significant.

The results are impressive when one sees noticeable results in two weeks, compared with the medicines available today by prescription, where significant improvements in ADAS-cog measures are not typically observed in less than 12 weeks of therapy. "We had several responses of note in this trial," stated Marvin Kalafer, M.D., Principal Investigator at The Clinical Trial Center in Jenkintown, Pennsylvania. "The compelling efficacy and tolerability data observed in this two-week trial are indicative of a profile that would be highly differentiated in the category."

In pre-clinical models, PRX-03140 has been shown to have a novel mechanism of action that differentiates it from current Alzheimer's therapies. This oral drug selectively activates the 5-HT4 receptor in the brain. Activation of 5-HT4 not only stimulates the production and release of acetylcholine, which may improve cognitive symptoms of Alzheimer's, but also stimulates the alpha secretase pathway, potentially slowing down the progression of the disease. PRX-03140 has the potential to be the first Alzheimer's medicine involving the 5-HT4 agonist for the treatment of Alzheimer's disease.

Michael G. Kauffman, M.D., Ph.D., chief executive officer of EPIX Pharmaceuticals stated, "We are very excited by the measurable impact on memory and cognition, achieved in such a short period of time, in a trial that was designed primarily to assess safety and tolerability. While we recognize that this is a two-week study on a relatively small population of patients, these statistically significant results, as well as the anecdotal reports we have received from study investigators and patients' families since the trial concluded, support our belief that PRX-03140 has the potential to improve memory and cognition. We look forward to initiating a larger Phase 2b clinical trial early next year to further explore the potential of PRX-03140."

Technical Information: Trial Design and Results

This Phase 2a clinical trial was conducted across 17 U.S. sites and included 80 patients who were treated for two weeks. Patients were studied on PRX-03140 alone (across three dose arms of 10 patients each: 50 mg once-daily, 150 mg once-daily and placebo) or in a placebo-controlled combination with 10 mg donepezil (Aricept(R)) (across five dose arms of 10 patients each: PRX-03140 at 5, 25, 50, 100 and 200 mg with donepezil (Aricept(R))10 mg once-daily). Primary endpoints were safety, tolerability and assessment of quantitative electroencephalograms (qEEG). A battery of cognitive measures, including ADAS-cog assessment, and pharmacokinetic evaluations were measured as secondary endpoints.

Key trial findings include:

PRX-03140 is part of EPIX's worldwide, multi-target strategic collaboration with GlaxoSmithKline to discover, develop and market novel medicines targeting four G-protein coupled receptors (GPCR) for the treatment of a variety of diseases, including Alzheimer's disease. EPIX is responsible for discovery and development of products in the collaboration, including PRX-03140, through to clinical proof of concept, at which point GSK has an exclusive option to license each product for further development and commercialization on a worldwide basis.

About PRX-03140

PRX-03140 is a novel, oral investigational drug candidate for Alzheimer's disease. It is selective for the 5-HT4 receptor in the brain and is believed to stimulate both acetylcholine production/release - which enables symptomatic improvement in Alzheimer's patients - and the alpha-secretase pathway - which slows Alzheimer's disease progression. In three Phase 1 trials and this Phase 2a trial, with more than 180 patients and healthy subjects, PRX-03140 has been well-tolerated. In a 14-day Phase 1b clinical trial, treatment with PRX-03140 resulted in changes in brain wave activity in Alzheimer's patients that are consistent with those seen in clinical trials with currently approved drugs for Alzheimer's disease. In preclinical studies, PRX-03140 has shown to improve cognitive function through increasing levels of acetylcholine, soluble amyloid precursor protein (sAPP) and brain-derived neurotrophic factor (BDNF) in regions of the brain known to be important for memory.

About EPIX

EPIX Pharmaceuticals is a biopharmaceutical company focused on discovering and developing novel therapeutics through the use of its proprietary and highly efficient in silico drug discovery platform. The company has a pipeline of internally-discovered drug candidates currently in clinical development to treat diseases of the central nervous system and lung conditions. EPIX also has collaborations with leading organizations, including GlaxoSmithKline, Amgen, Cystic Fibrosis Foundation Therapeutics and Bayer Schering Pharma AG, Germany.

More information:

EPIX Pharmaceuticals website

Aricept(R) website

Source:

Epix Pharmaceutical press release.

Byline:

Reviewed by Dr. B. Ancselovicz, Geriatrician

Edited by Peter Berger, Editor

Copyright:

© 2007 Alzheimer's Weekly LLC. All Rights Reserved.