Eleven Deaths during ARICEPT Trial Raises Concern over FDA Application to Permit Wider Use of the Drug

By Steve DiJoseph

An article in the October, 2005, issue of Worst Pills Best Pills Newsletter from the consumer watchdog group, Public Citizen, reported that three Alzheimer’s drugs had been found to be of “questionable “ value in a study published in the British Medical Journal (BMJ) (August 5, 2005).

Those drugs were donepezil (<"http://www.yourlawyer.com/topics/overview/aricept">ARICEPT), rivastigmine (EXELON), and galantamine (REMINYL). The conclusion reached by Public Citizen was that the study “adds additional evidence to support our long-standing listing of these drugs as DO NOT USE because of their questionable effectiveness.”

Donepezil, rivastigmine, and galantamine are known as cholinesterase inhibitors and inhibit the enzyme that breaks down acetylcholine, a brain transmitter. A deficiency of acetylcholine has been thought to play a role in Alzheimer’s disease.

The BMJ review identified 22 published studies that tested the use of these three drugs in the treatment of Alzheimer’s disease. No study found anything more than a minimal benefit with respect to any of the drugs when compared to a placebo.

As a result, the authors concluded: “Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer’s disease is questionable.”

The authors also found that “donepezil, rivastigmine, and galantamine caused a broad spectrum of adverse events — nausea, vomiting, diarrhea, and weight loss were the most common.”

Public Citizen has been a critic of ARICEPT since as far back as 1997 and noted that the three drugs accounted for over $861 million in sales in 2004 not because “evidence of either the effectiveness or safety of these drugs, but is rather a testament to the marketing skills of the drug industry, aimed at consumers and prescribers.”

The group concluded that the “very successful strategy to sell Alzheimer’s disease drugs is based on hope, fear, and guilt: hope that one of these drugs might ‘work,’ fear that if one of these drugs is not started quickly all will be lost, and guilt if family members have not made the decision to ‘fight’ the disease with these expensive, minimally effective drugs.”

As is often the case with prescription medications that have been approved for a specific or limited purpose, however, a manufacturer will seek to gain approval for one or more additional uses that will significantly boost the revenue generated by a particular drug.

That was the case with ARICEPT (marketed jointly by Pfizer, Inc. and Eisai Co.) when testing began in connection with an application to have the drug approved for the treatment of vascular dementia, a widespread form of cognitive decline that results from narrowing and blockage of arteries that supply blood to the brain

The test, however, raised some serious concerns about both the effectiveness and the safety of ARICEPT.

Although the Phase 3 clinical trial found ARICEPT was no better than a placebo in improving the overall functioning of patients with vascular dementia, Eisai claims that the drug did improve cognitive function.

Critics, who believe the drug is also not effective in the treatment of Alzheimer’s, were even more concerned over the fact that 11 (of 648) patients given ARICEPT once a day for 24 weeks, died. None of the 326 patients who took a placebo died.

Such a major discrepancy in mortality rates between two test groups is statistically significant and is therefore unlikely to be a chance occurrence.

Eisai claims that the deaths do not change the risk profile of the drug. Pfizer has not taken a position on the issue.

Nevertheless, some experts see the results as a “red flag” that should raise some concern as to the approval of the application now before the FDA to expand the use of ARICEPT.  The drug is currently approved for vascular dementia in six smaller markets. U.S. approval, however, who significantly, boost

The trial was limited to patients with vascular dementia and no prior diagnosis of Alzheimer’s disease. Most of the subjects had a history of stroke or heart disease and were also taking medications for their cardiovascular problems.

Since there had been a combined 2% incidence of death in the placebo groups from two previous vascular dementia tests, and given the overall age and health problems of the subjects in this trial, Eisai had not expected the absence of deaths in the placebo group.

Eisai claims the 1.7% incidence of death in this ARICEPT group was similar to that in prior trials. In those trials, however, the difference between placebo and ARICEPT deaths had not been statistically significant.

Although the ARICEPT group in the latest test showed a statistically significant improvement in cognitive function when compared to those taking placebos, the ARICEPT group showed no significant benefit with respect to “global function,” another primary measure of the trial.

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