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Cognitive Improvements Seen in Patients Treated With Memantine and Donepezil

HONOLULU, April 4 /PRNewswire-FirstCall/ -- Forest Laboratories, Inc. (NYSE:FRX) announced today that researchers have presented results from the first U.S. clinical trial evaluating a combination therapy for moderate-to-severe Alzheimer's disease at the American Academy of Neurology (AAN) Annual Meeting in Honolulu, Hawaii. These results were previously presented at a closed meeting of neurology, psychiatry and pharmacology experts in December, 2002. In the landmark study of more than 400 patients, memantine combined with donepezil (Aricept(R)*) demonstrated improvement in patients' cognition relative to baseline and as compared to the donepezil/placebo arm of the trial. Separately, researchers presented results demonstrating memantine's long-term efficacy when used as a single agent. These results have been previously presented to the scientific community and are the result of an open-label extension phase of a memantine study published in the current issue of the New England Journal of Medicine. Both the combination data and the long-term, monotherapy data were presented at the American Academy of Neurology (AAN) Annual Meeting in Honolulu, Hawaii.

Memantine Used In Combination Improves Cognition Relative to Baseline
The six-month, Phase III, randomized, placebo-controlled study involved 402 patients with moderate-to-severe Alzheimer's disease at 37 U.S. sites. The combination study was designed to compare a treatment regimen of memantine, an investigational drug, and donepezil, a widely used acetylcholinesterase inhibitor, to a combination of donepezil and placebo. Researchers reported that patients treated with memantine and donepezil illustrated a sustained improvement in cognitive function over baseline as measured by the Severe Impairment Battery (SIB). By comparison, cognitive function for patients on donepezil and placebo declined relative to their baseline status. The difference between the two treatment groups was statistically significant (p = 0.001) with patients in the memantine/donepezil group performing significantly better than those in the placebo/donepezil group.

Patients taking the combination therapy also showed significantly less decline in activities of daily living (p = 0.028) according to the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, modified for severe dementia (ADCS-ADLsev). A significant difference in global status in favor of the patients treated with memantine/donepezil, compared to placebo/donepezil, was also demonstrated on the Clinician's Interview-Based Impressions of Change-Plus (CIBIC-Plus) (p = 0.027). In addition, a significantly greater percent of patients in the memantine/donepezil group (85% vs 75%) completed the study compared to the placebo/donepezil group (p = 0.011). In general, the incidence of treatment-emergent adverse events was similar in patients treated with memantine/donepezil and the placebo/donepezil combination.

"The results of this memantine combination therapy study point the way towards a new standard of care in the treatment of moderate-to-severe Alzheimer's disease," said Martin Farlow, M.D., a lead investigator on the study and Professor of Neurology at the Indiana University School of Medicine. "The findings are encouraging since they suggest memantine's mechanism of action, which is unique and different from cholinesterase inhibitors, will really let us attack the disease on another front. Clearly, in this study, memantine provided additional cognitive and functional benefits in patients already taking donepezil. This is the first successful combination drug trial for Alzheimer's, and it is truly an exciting advance for patients and their loved ones."

Study Supports Memantine Use Long Term
In a separate presentation today at AAN, researchers presented the follow-up extension study to data published yesterday in the New England Journal of Medicine. Frederick A. Schmitt, Ph.D., Professor of Neurology at the University of Kentucky, and colleagues concluded that memantine provides long-term meaningful clinical benefit for patients with moderate-to-severe Alzheimer's disease. One hundred and seventy-five patients who completed a 28-week, placebo-controlled, double-blind study were given open-label memantine treatment for an additional 24 weeks. Patients who switched to memantine from the earlier study's placebo arm improved relative to the projected rate of continued decline. In addition, benefits for patients who remained on memantine appeared to be sustained throughout the 52-week study period relative to the projected rate of decline. Efficacy parameters used in this six-month extension study included well-established cognitive and global functioning assessment scales, including the CIBIC-Plus, ADCS-ADLsev and SIB.

"The data presented today are significant on several levels," said Lawrence S. Olanoff, M.D., Ph.D., Executive Vice President, Forest Laboratories. "The combination study potentially provides the Alzheimer's community with a new paradigm to treat moderate-to-severe Alzheimer's disease. To date, the acetylcholinesterase inhibitors have been the only approved option available. The combination study suggests that memantine can provide additional benefits to patients already on these therapies. The extension study, along with the data published in the New England Journal of Medicine, demonstrates that memantine may also have a role as monotherapy in a patient population that is currently without an approved treatment."

A Distinct Mechanism of Action
Memantine is the first of a new class of medications for Alzheimer's disease with a mechanism of action distinct from currently available drugs. Memantine is a moderate-affinity NMDA (N-methyl-D-aspartate) receptor antagonist. It is thought that overexcitation of NMDA receptors by the neurotransmitter glutamate may play a role in Alzheimer's disease since glutamate plays an integral role in the neural pathways associated with learning and memory. The excitotoxicity produced by abnormal levels of glutamate is thought to be responsible for neuronal cell dysfunction and the eventual cell death observed in Alzheimer's disease. Memantine is thought to selectively block the excitotoxic effects associated with abnormal transmission of glutamate, while allowing for the physiological transmission associated with normal cell functioning.

Additional placebo-controlled trials evaluating memantine as monotherapy and combination therapy are ongoing in patients with mild-to-moderate and moderate-to-severe Alzheimer's disease. Results from these investigations are expected to become available later in 2003.

Forest Laboratories announced on January 30, 2003 that the company's New Drug Application (NDA) for memantine as a treatment for moderate-to-severe Alzheimer's disease was accepted for filing by the U.S. Food and Drug Administration (FDA). Forest anticipates receiving an action letter from the FDA regarding this submission by the end of 2003.

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