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Ampakine Study of Mild Cognitive Impairment Fails to Meet Primary Endpoint

Irvine, CA, (February 17, 2004) Cortex Pharmaceuticals, Inc. (AMEX: COR) and Les Laboratoires Servier jointly announced that the cross national MCI study with a fixed dose of CX516 versus placebo failed to meet the study's primary endpoint, improvements in the 15- item word list delayed recall. However, a subset review of the patients with the worst baseline memory impairment (the worst 25% of the patient population), showed substantial improvement with CX516 versus placebo on the 15- item word list delayed recall test. In part, since MCI covers a broad range of memory impairment, including patients who demonstrate very little impairment to those with substantial impairment, it was much more difficult to get statistical improvements after just one month of treatment. A review of the safety data showed a significant difference in patient withdrawals in the active treatment group, primarily due to gastrointestinal side effects, when compared to the placebo group. While there were a substantial number of adverse events in the active treatment group, there were no treatment-related serious adverse events in either the placebo or CX516 groups.

"Both Servier and Cortex are naturally disappointed by the results, but for CX516, with a half-life of less than one hour and very low potency, the primary endpoint for this study proved to be a very tough hurdle,"stated Roger G. Stoll, Ph.D., Chairman, President and Chief Executive Officer of Cortex. This opinion was reinforced by Laurent Perret, M.D., Ph.D., President and Executive Director of Research and Development at Les Laboratoires Servier. "Neither Cortex nor Servier view this as an indication that the AMPAKINE® technology is flawed." Both companies have a large number of compounds with much greater potency and longer pharmacokinetic half-lives, which will be more appropriate for clinical development than CX516. Both companies are proceeding diligently with the clinical development of two other AMPAKINE® drugs, CX717 from Cortex and S-18986 from Servier. Both companies renewed their R&D collaboration during January 2004. Another licensee of Cortex, Organon NV, is proceeding with Phase II trials using another drug from Cortex’s laboratories, Org-24448, for schizophrenia.

Dr. Stoll explained that data based on a recently completed primate study by Dr. Sam Deadwyler, Professor and Vice Chairman of the Department of Physiology and Pharmacology at Wake Forest School of Medicine, suggests that CX516 did not show any significant activity in their primate behavioral model until the dose exceeded 20 mg/Kg. The MCI study was conducted at doses of approximately 12 mg/Kg. In a primate sleep deprivation study (to be published), Dr. Deadwyler required doses of 40 mg/Kg of CX516 to maximize short-term memory recall in a delayed match to sample task. This new primate data may suggest that at least three or four doses of 2000 mg of CX516, rather than the 900 mg dose administered to the MCI patients, would have been necessary for a significant improvement. Similarly, a recent clinical study that tested the ability of CX516 to reverse the effects of sleep deprivation in young healthy adult male volunteers, performed at the Medical University of South Carolina by Dr. Mark George, found no significant effects on sleep deprivation at doses below 30 mg/Kg. However, in another soon-to-be published preclinical study by Dr. Deadwyler, it would appear that with CX717, a single dose of 0.5 to 1.5 mg/Kg may be sufficient to produce an optimal response on short term memory, which would be roughly 75-100 mg per day in an elderly patient, most likely as a single dose. Meanwhile, Cortex has accelerated its development of CX717 and will be initiating clinical development of this compound beginning in the second quarter of 2004. In addition, Servier is continuing its clinical development of S-18986 and should be in Phase II by the end of this year.

About the Study
This double-blind, placebo-controlled study was the first cross-national clinical trial to evaluate the efficacy and safety of AMPAKINE CX516 in patients with MCI. There were a total of 9 investigative sites in the United States and 22 sites across France, Belgium, United Kingdom, Sweden and the Netherlands, making a total of 31 sites. One hundred seventy-five patients meeting entry criteria for MCI were randomized to receive CX516 (n = 84) or placebo (n = 91). The primary outcome measure was the change, between week four and baseline, in the number of words recalled from a 15-item list approximately 20 to 30 minutes (delayed recall) after the patients practiced learning the list.

Cortex has overall responsibility for the conduct of the trial, which was designed by a joint Cortex and Servier clinical team, in consultation with an International Scientific Advisory Committee (ISAC). A separate independent data safety monitoring board, commissioned by Cortex, monitored the safety aspects of this study in a blinded fashion for severe adverse events. The diagnostic procedures, as well as the primary and secondary outcome measures, were agreed upon by the ISAC composed of neurological experts and a prominent statistician from academic institutions in the United States and Europe. The ISAC also agreed upon the medical assessment of the study results at a recent meeting in Paris.

The majority of the study costs were funded by Servier. Initial funding was provided for by the Institute for the Study of Aging, a non-profit foundation supported by the Estee Lauder Trust. The Institute for the Study of Aging catalyzes and funds the discovery and development of new therapies to prevent and treat cognitive aging and Alzheimer's disease.

Source: Cortex Pharmaceuticals, Inc.

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