Treatment response to Aricept® (donepezil hydrochloride) not predicted by Apolipoprotein E4 genotype or gender

July 10, 2000

WASHINGTON, D.C. 11 July, 2000 -- Aricept® (donepezil hydrochloride) demonstrated beneficial effects on cognition and global function over the course of one year in a double-blind, placebo-controlled, multinational study in patients with mild to moderate Alzheimer's disease (AD). In this study, treatment response was not predicted by Apolipoprotein E4 (ApoE4) genotype and/or gender, according to data presented today at the World Alzheimer Congress in Washington D.C.

ApoE is a lipoprotein that carries cholesterol in the blood. The exact role the ApoE4 allele plays in the pathogenesis of AD or in the memory decline of cognitively impaired elderly is unclear presently. Furthermore, much of the evidence concerning a correlation between ApoE4 copy number and the pathological features of AD (e.g. neuronal plaque density and the appearance of neurofibrillary tangles) is contradictory. It has been suggested that patients carrying an ApoE4 allele may have a more severe cholinergic deficit than those who do not.

"The reports of associations between ApoE4 genotype, gender and response to cholinesterase inhibitor therapy in AD patients are conflicting. In this recently completed study, a secondary analysis showed that the treatment response to ARICEPT®, a cholinesterase inhibitor, was not predicted by ApoE4 genotype and/or gender in patients with mild to moderate AD," says Hilkka Soininen, M.D., Ph.D., University of Kuopio, Kuopio, Finland.

This one-year multinational, double-blind, placebo-controlled study enrolled 286 patients with mild to moderate AD from 28 sites in five Northern European countries (Denmark, Finland, Norway, Sweden and The Netherlands). Patients were randomized to receive either ARICEPT® (n=142; 5 mg/day for 28 days, and then 10 mg/day) or placebo (n=144) for one year. The mean age of the patients enrolled in the study was 72.5 (range: 49-88 years).

Outcomes measures included evaluation of global function (the Gottfries-Brane-Steen [GBS] scale) and cognition (the Mini-Mental State Examination [MMSE]). In addition, ApoE genotype was determined from patients' plasma samples. Of the 285 plasma samples available, ApoE4 allele was present in 196 (69%) patients.

Patients receiving ARICEPT® (donepezil hydrochloride) showed statistically significant differences in their global functioning compared to patients receiving placebo at Week 52 (observed cases p=0.014). Patients taking ARICEPT® also maintained their cognition at or near baseline over the course of one year while cognition in the group receiving placebo declined.

Furthermore, a three-way analysis of covariance (ANCOVA) revealed no significant interaction between the effect of treatment with ARICEPT® on the patient's global function and cognition as measured by the GBS and MMSE scales, ApoE4 genotype and/or gender at Week 52 (p=0.7503 and p=0.6839, respectively).

"The findings from this study suggest that ApoE4 genotype and/or gender do not necessarily predict an AD patient's response to ARICEPT® treatment," said Dr. Soininen.

In this trial, 66.9 percent of ARICEPT®- and 67.4 percent of placebo-treated patients completed the study with 7 percent of ARICEPT®-treated and 6.3 percent of placebo-treated patients discontinuing due to adverse events. Adverse events that occurred in at least 5 percent of the ARICEPT® group and twice the rate of the placebo group were vertigo (ARICEPT® 8 percent, placebo 2 percent), asthenia (ARICEPT® 8 percent, placebo 4 percent) and syncope (ARICEPT® 6 percent, placebo 3 percent).
Background Information
AD, which is a progressive and degenerative brain disorder, impairs cognition and the ability to perform such daily living activities as handling money, using the telephone, grooming, etc. Approximately 15 million people suffer from AD worldwide.

ARICEPT® is indicated for the symptomatic treatment of mild to moderate Alzheimer's dementia. ARICEPT® is well-tolerated, with a low incidence of side effects, offers convenient once-daily dosing and can be taken with or without food. ARICEPT® is clinically effective at the starting dose of 5-mg/day and the dose can be escalated to 10-mg/day after four to six weeks if clinically indicated.

ARICEPT® is well tolerated but may not be for everyone. Some people may experience nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue or loss of appetite. In studies, these effects were usually mild and temporary. Some people taking ARICEPT® may experience fainting. People at risk for ulcers should tell their doctors because their condition may get worse.

ARICEPT® is available by prescription in more than 44 countries. In November 1994, Eisai Co., Ltd. and Pfizer Inc announced the formation of a strategic alliance for the promotion of ARICEPT® and development of new treatments for Alzheimer's disease and other cognitive disorders. ARICEPT® is the lead compound in this alliance. First launched in the United States in February 1997, ARICEPT® has been well-received in the Alzheimer's disease community with more than 314 million days of patient use worldwide and over one million people initiating treatment.

Eisai Ltd. and Pfizer Inc are committed to a collaboration dedicated to advances in Alzheimer's therapy.

Full prescribing information is available upon request from Diane DiBello of Porter Novelli or Celeste Torello of Pfizer Inc (see contact information above).

ARICEPT® is a registered trademark of Eisai Co., Ltd. News Source: Eisai Ltd. and Pfizer Inc

Porter Novelli

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