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Combination of Memantine, Donepezil More Effective Than Donepezil Alone

NEW YORK, Jan. 20 /PRNewswire-FirstCall/ -- Forest Laboratories, Inc. (NYSE:FRX) announced today that a study published in the current issue of the Journal of the American Medical Association (JAMA) concludes that combining Namenda(TM) (memantine HCl) with a stable dose of donepezil, a commonly prescribed Alzheimer's drug, provides greater cognitive, functional, global, and behavioral benefits to people with moderate to severe Alzheimer's disease than treatment with donepezil alone. The results of this study mark the first time that positive results have been observed when using a combination of two drugs for the treatment of Alzheimer's disease. While the results of this trial have been previously presented at major medical meetings around the world, their publication in JAMA represents the first time these results have been published in a peer-reviewed journal.

Namenda, now available in the United States, is the first and only medication approved to treat the moderate to severe stages of Alzheimer's disease. All other approved treatments, including donepezil, belong to a class of drugs called acetylcholinesterase inhibitors (AChEI) that are indicated for patients in the mild to moderate stages of Alzheimer's. Because Namenda has a unique mechanism of action that is different from the acetylcholinesterase inhibitors, the availability of Namenda makes its use in combination with donepezil a possibility for the treatment of moderate to severe Alzheimer's disease.

"The study published today is a source of excitement and hope for the Alzheimer's community," said study lead investigator Pierre Tariot, M.D., Professor of Psychiatry, Medicine and Neurology at the University of Rochester. "The results clearly show that patients with moderate to severe Alzheimer's disease treated with the combination of Namenda and donepezil perform better on measures of intellectual and daily functioning compared to those patients taking donepezil and a sugar pill."

Study Design
This ground-breaking, six-month study included 404 patients at 37 sites and was the first prospective, double-blind, placebo-controlled, Phase III trial to evaluate the benefits of dual therapy with Namenda and donepezil in patients with moderate to severe Alzheimer's disease. All patients were treated with donepezil for a minimum of six months and were required to receive a stable dose of donepezil for at least three months in order to enter the study. Patients were then randomized to receive donepezil plus 20mg per day of Namenda, or donepezil and placebo. The study was designed to measure cognition and function as primary outcomes, while global status and behavioral symptoms were measured as secondary endpoints.

Positive Results Seen In All Measures: Cognition, Global Status, Function, and Behavior
Patients receiving the combination of Namenda and donepezil experienced an improvement in cognition relative to baseline while patients receiving donepezil and placebo declined relative to their baseline status. The difference between these two groups was statistically significant (p=0.001). Cognition was measured via the Severe Impairment Battery (SIB). This test, designed especially for people with moderate to severe dementia, enables researchers to gather direct performance-based data related to a wide variety of tasks, such as writing simple words or using a cup and spoon.

Researchers also observed significantly less decline in activities of daily living (p=0.028) as assessed by the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, modified for severe dementia (ADCS-ADLsev). The findings suggest that people on the combination of Namenda and donepezil may be able to perform basic activities necessary for independence and personal care -- such as dressing and bathing to a greater extent than patients taking donepezil alone. Patients treated with Namenda/donepezil also performed better in an assessment of global status, based on the Clinician's Interview-Based Impressions of Change-Plus (CIBIC- Plus) compared to the study's control group (p=0.03). According to the Neuropsychiatric Inventory (NPI), a scale used to assess behavioral effects, patients treated with Namenda/donepezil exhibited fewer behavioral disturbances, with less severity as compared to patients treated with donepezil alone (p=0.002).

"The study is especially significant because it is the first placebo-controlled trial to show efficacy in patients with moderate to severe Alzheimer's disease when treatments with different mechanisms of action are used together," said Lawrence S. Olanoff, M.D., Ph.D., Executive Vice President, Forest Laboratories. "Additionally, patients treated with Namenda and donepezil performed significantly better than patients on donepezil alone with respect to cognition and daily functioning. While Namenda's efficacy as a monotherapy has been demonstrated by other large-scale studies, this study supports its clinical utility when used in combination with the acetylcholinesterase inhibitor, donepezil."

In general, the incidence of treatment-emergent adverse events was similar in patients treated with Namenda/donepezil and the placebo/donepezil combination. A significantly greater percent of patients in the Namenda/donepezil group (85 percent vs. 75 percent) completed the study compared to the placebo/donepezil group (p=0.011).

About Namenda
Namenda (memantine HCl), approved on October 16, 2003, by the U.S. Food and Drug Administration, is indicated for the treatment of moderate to severe Alzheimer's disease. Namenda is the first of a new class of medications, called NMDA (N-methyl-D-aspartate)-receptor antagonists, to treat Alzheimer's disease with a mechanism of action distinct from other currently available drugs. Namenda is administered orally at a recommended dose of 10mg twice daily following a four-week titration.

In all clinical trials, Namenda has been safe and well tolerated. Namenda is contraindicated in patients with known hypersensitivity to memantine HCl or to any excipients used in the formulation. The most common adverse events reported with Namenda vs. placebo (> or = 5% and higher than placebo) were dizziness, confusion, headache, and constipation. In patients with severe renal impairment the use of Namenda has not been systematically evaluated and is not recommended.

Namenda is available in pharmacies in both a 4 week Titration Pak and 5mg and 10mg tablets. Interested parties can get more information on Namenda and obtain the prescribing information by logging on to www.Namenda.com or by calling 1-877-2-NAMENDA (1-877-262-6363).

Namenda's Mechanism of Action
Namenda is a low to moderate affinity NMDA-receptor antagonist. It is thought that overexcitation of NMDA receptors by the neurotransmitter glutamate may play a role in Alzheimer's disease. 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 observed in Alzheimer's disease. Namenda 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.

Alzheimer's Disease
Alzheimer's is a progressive disease of the brain and it is the most common type of dementia. The term dementia is used to describe the progressive loss of cognitive, intellectual, or functional abilities. Published reports project that by 2010 more than 5.1 million people in the United States will have Alzheimer's disease. Currently, all Alzheimer's medications approved in the United States other than Namenda belong to a class of agents called acetylcholinesterase inhibitors, which are indicated for patients with mild to moderate symptoms of the disease. The progressive nature of Alzheimer's disease means that most patients who suffer from it will move through all the stages, including the moderate to severe stages. Namenda will be of use to patients from the time their disease has reached the moderate stage through progression into and throughout the severe stages.

Source: Forest Laboratories, Inc.

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