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FDA APPROVES DONEPEZIL FOR SEVERE DEMENTIA – EXPERTS QUESTION WHY

Cajigal, Stephanie

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In October, the FDA approved the use of the drug donepezil (Aricept) for patients with severe Alzheimer disease (AD). While more treatment options are usually good news, experts are divided over whether the drug is worth the added effort and cost for patients and families.

The FDA had already approved the drug – a cholinesterase inhibitor – for mild to moderate dementia in 1996, but donepezil is only the second drug after the glutamate modulator memantine (Namenda) approved for severe dementia. The agency's decision was based on the results of two clinical trials submitted by the drug's sponsors, Eisai and Pfizer. Together, the studies showed that patients with severe dementia on donepezil performed better on cognitive functions, such as memory, language, orientation, and attention, compared to placebo.

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SWEDISH NURSING HOME STUDY

One study, published in the April issue of The Lancet (367(9527):1057–1065), followed 248 Swedish nursing home patients with severe dementia for six months. Patients were assigned donepezil at 5 mg per day for 30 days, then up to 10 mg per day thereafter, or placebo. Ninety-five patients assigned donepezil and 99 patients assigned placebo completed the study. Primary outcomes were measured using the severe impairment battery (SIB) and the modified Alzheimer's Disease Cooperative Study activities of daily living inventory for severe Alzheimer's disease (ADCS-ADL-severe).

The SIB measures the severity of cognitive dysfunction in advanced AD in terms of memory, language, orientation, attention, praxis, visuospatial construction, ability to name people and objects, and social interaction. The ADCS-ADL-Severe is a 19-item scale used to measure basic activities of daily living, such as eating and bathing, and complex abilities, such as opening water taps and switching on lights, with scores ranging from zero to 54. The study defined severe dementia as a Mini-Mental State Examination score of 1 to 10. At six months, the donepezil-treated group had higher SIB scores by a mean of 5.7 points (p = 0.008) and higher ADCS-ADL-severe scores by a mean of 1.7 points (p=0.03) compared to placebo. The differences were statistically significant.

The second study was conducted in Japan and included 325 patients with severe dementia who were randomized to receive either 5 mg or 10 mg of donepezil a day, or a placebo, for six months. Improvement was measured using the SIB and the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). On the SIB scale, patients on 10 mg improved by a mean of 4.7 points, patients who received 5 mg improved by a mean of 2.5 points, while the placebo group showed a decline of 4.2 points. At both dose levels, the difference between the treatment groups and placebo was statistically significant compared to placebo in the SIB, but not on the CIBIC-Plus.

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The Japanese study is yet to be published but the results were presented in July at the International Conference on Alzheimer's Disease and Related Disorders.

“It's fair to say that these drugs aren't cures or miraculous treatments,” Russell Katz, MD, Director of the FDA Division of Neurological Products, said in a phone interview. “The average response both on the cognitive and global functioning measures is relatively small, there is no denying that.” But the agency's standard for approving Alzheimer disease drugs, he explained, is that drug sponsors show evidence of a statistically significant difference on both a cognitive measure and a global functioning measure. That difference does not have to be of a particular magnitude, he said.

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STUDY LIMITATIONS

Experts said there were several shortcomings in the studies, however. For one, though the Swedish study was designed to test the drug in patients with severe AD who had limited previous exposure to cholinesterase inhibitors, it did not address the question of whether the drug is worth continuing in patients once the dementia becomes severe.

David Knopman, MD, a neurologist at the Mayo Clinic Alzheimer's Disease Research Center in Rochester, MN, told Neurology Today he is skeptical of the drug's value for patients with severe AD. He said that judging from his own clinical experience, starting patients on cholinesterase inhibitors once they are already severely demented usually does not improve their quality of life. He also pointed out that the Swedish nursing home study did not find that the drug had a significant effect on behavior.

In any case, most neurologists have been prescribing the drug to severe Alzheimer patients off label for years, he said. “I am an advocate of using the drug in patients with mild to moderate disease. It's my view that they should stay on it until they reach the stage of needing 24-hour assistance. At that point, I would say that the drug has no value. It's just one more thing to bother the patient with.” And at about $150 a month, the price of the drug can also be a burden, he added.

Dr. Knopman advised, however, that neurologists monitor patients for cognitive decline after taking them off the drug, especially those whose condition is not severe enough to necessitate them to be placed in a nursing home. “There have been instances where I've [taken patients who are still at home off donepezil] and I've regretted doing it because in some I did observe a worsening that was fairly dramatic.”

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A BUILT-IN BIAS?

But Rachel Doody, MD, PhD, Effie Marie Cain Chair in Alzheimer's Disease Research at Baylor College of Medicine in Houston, TX, said many physicians have a built-in bias against treating severe AD. They think these patients have no function or cognition, and that the drugs prolong life in this state but do not improve quality of life, she said.

Dr. Doody co-authored a 2001 study in Neurology suggesting that donepezil benefits patients with mild to moderate dementia. The study, which was funded by Eisai and Pfizer, found that over one year donepezil was associated with a 38 percent reduction in cognitive decline compared with placebo (57:481–488). It did not measure quality of life.

“Even patients with very severe AD have retained some cognition and function – sometimes quite a lot,” she said. “There is evidence that treatment helps patients retain these abilities longer. It helps people to live better within their natural lifespan.”

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LITTLE DATA ON QUALITY OF LIFE

But even if donepezil is effective in slowing down cognitive decline in severe AD patients, are the effects worth the cost of the drug?

The only way to answer that question is through more studies, said Lon Schneider, MD, Professor of Psychiatry, Neurology, and Gerontology at the University of Southern California. “Missing from these studies and from most other cholinesterase inhibitor studies are outcomes that measure health-related quality of life so we can better assess whether the drug is worthwhile,” he said.

He too was concerned by the fact that the Swedish nursing home study did not find that donepezil had a significant effect on behavior; and that two unpublished trials in outpatients with severe AD also showed no effect on behavior or activities of daily living. Those studies were presented at the International Conference on Alzheimer's Disease and Related Disorders.

“Many patients with severe AD in nursing homes have major and troublesome behavioral problems that outweigh the cognitive problems,” he said. “They're delusional, they're aggressive, they misperceive. And these medications seem not to help that, despite what the company may advertise.”

But Dr. Doody countered that determining the value of AD treatments is difficult because the benefits are accrued over many years and most controlled clinical trials last only up to one year. She said most of her patient's families think donepezil is worth the price.

Indeed, findings on the cost-effectiveness of donepezil have varied depending on the endpoints measured. One 2004 study found that treating patients with moderate to severe dementia with donepezil reduced costs because it prompted less use of residential care by patients and caregivers spending less time assisting patients with activities of daily living (Neurology 2004;63:644–650).

But another study that same year determined that donepezil provided only marginal improvement in cognition for those with mild or moderate dementia, and was not cost-effective because it did not slow time to institutionalization or disability (Lancet 363:2105–2115). The study did not consider quality-of-life improvements in its calculation. To further complicate things, the first study was sponsored by a drug company (Pfizer) while the second was funded by a health care payer (the UK National Health Service), which would potentially have an interest in negative study outcomes as a way to justify not providing coverage of the drug.

Regardless of the drug's cost-benefit ratio, experts agreed that the FDA was justified in approving the drug for severely demented patients.

“They [FDA] are not obligated or responsible by law for determining best medical practices,” Dr. Knopman said. “They are charged with determining whether the drug is safe or effective by the guidelines they've laid out. The sponsors of Aricept proved these two points.”

And while the drug may be far from a cure-all, it may be worth the effort for a select group of patients, Dr. Katz said. In the Swedish study, for example, some patients showed much greater benefits than others. “We don't think that the average person will have a miraculous response to this treatment but we would expect that in many people the drug would have an effect.”

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REFERENCES

• Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomized double-blind trial. Lancet 2004;363:2105–2115.

• Feldman H, Gauthier S, Hecker J, et al. Economic evaluation of donepezil in moderate to severe Alzheimer disease. Neurology 2004;63:644–650.

• Moss RC, Doody RS, Morris MD, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001;57:481–488.

• Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006;367(9527):1057–1065.

• Wilkinson D, Doody R, Helme R, et al. Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology 2003;26(4):479–486.

©2006 American Academy of Neurology

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