Donepezil (Eisai/Pfizer’s Aricept) () is the market leader in the treatment of Alzheimer’s disease. This drug was first launched in the United States in 1997 and is now available in all the major markets. Donepezil is approved for mild to moderate Alzheimer’s disease, and Eisai and Pfizer will attempt to expand the approval of donepezil to include moderate to severe Alzheimer’s disease and mild cognitive impairment (MCI); the drug is currently in Phase III clinical trials for moderate to severe Alzheimer’s disease, and a Phase IV study for MCI was completed in September 2004. Efforts to expand approval of donepezil to vascular dementia suffered a setback in July 2003 when Eisai received a letter from the FDA labeling donepezil as unapprovable for this indication because of insufficient data.
Donepezil’s availability in the different cortical regions of patients with mild to moderate Alzheimer’s disease is similar to that of rivastigmine, although with a greater proportion of acetylcholinesterase inhibition in the frontal cortex of patients than in the temporal and parietal regions (). Unlike galantamine and rivastigmine, donepezil has a single mechanism of action: inhibiting acetylcholinesterase. Thus far, donepezil’s single-mechanism approach does not appear to be a significant clinical disadvantage compared with the other acetylcholinesterase inhibitors (AChEIs).
As with other acetylcholinesterase inhibitors, only a minority of patients experience cognitive improvement with donepezil over placebo. A 30-week, placebo-controlled, double-blind trial consisting of 818 patients with mild to moderately severe Alzheimer’s disease (MMSE scores, 10-26) found that approximately 25% of patients taking donepezil at 10 mg per day demonstrated significant improvement in cognitive function over placebo beginning at week 6 and continuing until study end (). Patients were assessed with both a cognitive performance test, the Alzheimer’s disease Assessment Scale-cognitive subscale (ADAS-cog), and a global evaluation test, the Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC-plus). However modest, these data suggest that donepezil treatment can delay the cognitive decline associated with Alzheimer’s disease.
Donepezil’s effect on cognition was confirmed by an independent, long-term study (). In contrast to industrγ-sponsored studies such as the one by A. Burns and colleagues, the study by C. Courtney and others enrolled “typical Alzheimer’s disease patients” who were referred from memory clinics and were diagnosed with or without comorbid cerebrovascular disease. In this three-year study, 565 Alzheimer’s disease patients were randomly assigned to receive placebo or donepezil (5 or 10 mg/day). At study end, MMSE scores for donepezil-treated patients were significantly improved over placebo for the first two years, although treatment did not ultimately delay the progression to severe dementia. These data support the conclusion that donepezil is a symptomatic treatment and not a disease-modifying agent.
A 24-week study demonstrated the effects of donepezil on cognitive improvement in “earlγ-stage” (very mild or mild) Alzheimer’s disease (); 153 patients (MMSE scores, 21-26) were randomly assigned to receive donepezil (5mg for the first six weeks, 10 mg thereafter) or placebo. The primary efficacy measure was the modified ADAS-cog total score. By study end, donepezil-treated patients showed significant cognitive improvement over placebo at weeks 12 and 24. At least 70% of donepezil-treated patients experienced no cognitive decline as measured by ADAS-cog versus 47% of those who received placebo during the 24 weeks of treatment, a difference that was statistically significant. MMSE scores, a secondary end point, significantly improved with donepezil as early as week six, and improvements remained statistically significant when compared with placebo through study end. These data support early initiation of treatment in Alzheimer’s disease in an effort to preserve cognitive function early in the course of the disease.
Donepezil’s effects on functional decline are controversial. Functional decline, a common feature of Alzheimer’s disease, is characterized by loss of the ability to perform activities of daily living (ADLs). One outcome of this decline is a growing caregiver burden; as a result, the patient often is moved to a nursing home. A 54-week, placebo-controlled, double-blind study of 431 Alzheimer’s disease patients with mild to moderate Alzheimer’s disease showed that while detectable disease progression continued over the study, donepezil extended the median time to functional decline by five months compared with placebo (median function decline occurred at 357 days in treated patients as compared with 208 days for placebo) (). At study end, 56% of placebo-treated patients versus 41% of donepezil-treated patients experienced clinically significant functional decline from baseline. Secondary end points included functional and cognitive assessments as measured by the Alzheimer’s disease Functional Assessment and Change Scale (Alzheimer’s disease-FACS), the MMSE, and Clinical Dementia Rating scale (CDR scale). These secondary measures tended toward better cognitive and functional scores in favor of donepezil-treated patients but failed to reach overall statistical significance.
Unlike the industrγ-sponsored studies that used refined selection criteria when enrolling patients, the long-term independent study by C. Courtney and colleagues found that donepezil treatment failed to significantly delay progression of disability when compared with placebo, as measured by the loss of 2 out of 4 basic ADLs or 6 out of 11 instrumental ADLs on the Bristol Activities of Daily Living Scale (BADLS) (). By study end, 55% of donepezil-treated patients experienced progression of disability, versus 53% placebo-treated patients.
Data supporting donepezil’s impact on neuropsychiatric behavioral problems (e.g., delusions, hallucinations, apathy) associated with Alzheimer’s disease are also controversial (). In a double-blind, randomized, placebo-controlled study, 134 patients with mild to moderate Alzheimer’s disease (MMSE scores, 10-27) and a Neuropsychiatric Inventory (NPI) total score of> 11 points were titrated to 10 mg/day of donepezil over 12 weeks and then randomly assigned to receive donepezil or placebo for an additional 12 weeks. The primary end point of this study was the NPI total score. At study end, NPI scores for donepezil-treated patients were significantly improved over the NPI scores for patients receiving placebo. Other data, however, suggest the opposite. In the long-term study by C. Courtney and others, donepezil did not significantly improve behavioral symptoms at any time point, as measured by the NPI ().
Donepezil’s benefits may extend to more severe forms of the disease for which it is not yet approved — to date, only memantine (Merz’s Axura, Lundbeck’s Ebixa, Forest’s Namenda) is approved in moderate to severe Alzheimer’s disease. A double-blind study involving patients with moderate to severe Alzheimer’s disease (MMSE scores, 5-17) reported that donepezil improved the global function, cognition, behavior, and ADLs in these patients (). This multicenter study randomly assigned 290 patients with moderate to severe Alzheimer’s disease to donepezil or placebo and followed them for 24 weeks. The primary end point of the study was global function of the patients, assessed using the CIBIC-plus test. At week 24, 63% of donepezil-treated patients were rated as “improved” or “no change, ” compared with 42% for placebo. Secondary measures included cognition, measured using the standardized MMSE; disability, using the Disability Assessment for Dementia (DAD); and behavior, using the NPI. Patients treated with donepezil showed statistically significant improvement in the area of cognition and were stabilized in functional measures. For patients’ behavior, the total NPI score for treated patients was improved over that of placebo, although changes were not significant at every time point. Donepezil was tested in Phase III trials in the United States and Europe for the treatment of severe Alzheimer’s disease and in Phase II studies in Japan. The results of these studies presumably supported Eisai’s filing of a supplemental NDA in February 2006. Filings in Europe are expected to follow.
Donepezil is generally associated with mild and transitory side effects, which are mostly cholinergic side effects, including diarrhea (10% in treated patients versus 5% for placebo recipients), nausea (11% versus 6%), vomiting (5% versus 3%), and anorexia (4% versus 2%); these side effects are the main reason for patient withdrawal from clinical trials, according to the drug’s label. Other adverse effects include headache, insomnia, fatigue, and muscle cramps (). The incidence of side effects can be reduced by adjusting the titration of donepezil. For example, if titration to 10 mg/day lasts just one week, 19% of patients experience nausea, 15% suffer diarrhea, and 14% are troubled by insomnia. If the titration period is extended to six weeks, however, these rates fall to 6%, 9%, and 6%, respectively — close to those for the 5mg/day dosage or placebo (data from the drug’s package insert).