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RIVASTIGMINE FOR PARKINSON DISEASE DEMENTIA: IS FDA APPROVAL WARRANTED?

Valeo, Tom

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Since 1997, Novartis Pharmaceuticals has been selling rivastigmine tartrate (Exelon) to treat mild to moderate Alzheimer disease, but some neurologists also prescribe the drug off-label to treat dementia in people with Parkinson disease.

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In May, the Food and Drug Administration (FDA) Peripheral and Central Nervous System Drugs Advisory Committee recommended approving rivastigmine for that purpose as well. If approved (and the FDA routinely approves recommendations of advisory committees), the drug would become the only one sanctioned in the United States for the treatment of dementia with Parkinson disease (PD).

In interviews with Neurology Today, experts expressed concerns about the approval, because the committee based their approval on a study (N Engl J Med 2004;351:2509–2518) that found rivastigmine to be only marginally effective in PD.

“The study shows that only 19.8 percent of those who completed the trial had clinically meaningful improvement on rivastigmine, but 14.5 percent of patients on placebo had a similar degree of improvement,” said Stephen Reich, MD, Professor of Neurology at the University of Maryland, and Co-director of Maryland Parkinson's Disease and Movement Disorders Center. “Rivastigmine may help above and beyond placebo about 6 percent of patients treated. It's a modest treatment for the dementia of Parkinson disease.”

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HOW RIVASTIGMINE WORKS

Cholinesterase inhibitors such as rivastigmine work by blocking cholinesterase, which breaks acetylcholine into acetate and choline, making more transmitter available for neural transmission. Since patients with Alzheimer disease and other forms of dementia are thought to lack sufficient acetylcholine in the brain, any drug that increases the amount of the neurotransmitter should help, but not much, say experts.

“Occasionally a patient or caregiver reports there has been meaningful improvement (with cholinesterase inhibitors), but for the most part these drugs don't do the job we had hoped,” said Dr. Reich.

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Like other cholinesterase inhibitors, such as donepezil (Aricept) and galantamine (Razadyne), rivastigmine inhibits acetylcholinesterase (AChE), but it also inhibits butyrylcholinesterase (BuChE), which break down acetylcholine.

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STUDY THAT PROMPTED APPROVAL

“We listened to advisors who said, ‘We think this drug would work well in Parkinson disease dementia,’” said Roger Lane, MD, the Novartis Disease Area Section Head for Dementia and one of the 17 authors of the paper in the New England Journal of Medicine. “It was an unmet medical need, so we set up the study, which was the first prospective, large-scale, placebo-controlled study to show benefits for dementia associated with Parkinson disease.”

The study, known as EXPRESS (EXelon in PaRkinson's disEaSe dementia Study), enrolled 541 patients with mild to moderate dementia that developed at least two years after they were diagnosed with Parkinson disease. Two-thirds received 3 to 12 mg of rivastigmine per day, while one-third received a placebo.

Of the 541, 410 completed the study; the high dropout rate was attributed primarily to nausea and vomiting, the most common side effects. Some patients reported an increase in tremor, but that was slight and did not cause any to drop out.

Patients were assessed at 16 and 24 weeks using two tests to evaluate cognition and overall functioning – the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary measures were obtained from other assessment tools, including the Mini-Mental State Examination, the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the Neuropsychiatric Inventory, Letter Fluency, and the Ten Point Clock-Drawing test.

“The outcomes were better among patients treated with rivastigmine than among those who received placebo,” the authors reported in the NEJM article, “however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer disease.”

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TO MARKET, TO MARKET

Still, no other medications are available to treat Parkinson dementia, which means rivastigmine will undoubtedly find a market. “Rivastigmine is good enough that you can get it on the market and people will use it, and the company will make millions of dollars, but does it really make a difference in a patient's life?” said Stanley Fahn, MD, the H. Houston Merritt Professor of Neurology and Director of the Center for Parkinson's Disease and Other Movement Disorders at Columbia University. “It's certainly not good enough to stop the disease from getting worse. It doesn't change people's lives in a big way, but it's an inch, and you take an inch before you take a foot and then a mile. Every little bit counts when you have no other treatment.”

The market for a drug that treats Parkinson dementia is vast. About 6.3 million people in the world have Parkinson disease; 40 percent have dementia, as well.

But there may be differences in how the dementia is manifest for both diseases, suggesting, experts say, that the drug designed to treat one may not work as well for the other. Parkinson dementia more often resembles Lewy body dementia, Dr. Fahn explained, with Lewy bodies as the pathological hallmark, but Lewy body dementia can occur without Parkinson disease, and can also co-exist with Alzheimer disease, Dr. Fahn said. Lewy body dementia may produce the same symptoms as Alzheimer disease, although hallucinations, usually visual, are more common in the Lewy body condition.

“People with Parkinson dementia don't have as many memory problems,” said Dr. Fahn. “They have more hallucinations and confusion, but they don't start off with a memory deficit.” Like people in the later stages of Alzheimer disease, Parkinson patients often have difficulty with activities controlled by the frontal lobes, such as planning and organizing goal-oriented behavior, he added. They also experience faulty attention, depression, anxiety, and apathy.

Reservation about the differences in dementia for both diseases and the modest effect of rivastigmine has many experts doubting the move to approve the drug. The FDA approval would primarily tap a market filled with desperate patients and their families, they contend.

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Dr. Fahn, for example, called the effort “pure marketing.” “I'm sure the competition is studying the same problem, so Novartis wants to beat the competition,” he said.

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WHY GET FDA APPROVAL?

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But why bother with FDA approval when the drug is widely prescribed off-label? A study published in May (Arch Intern Med 2006;166:1021–1026) reported that about 20 percent of medications are prescribed off-label, about 75 percent lack strong scientific support. Ninety-six percent of off-label psychiatric prescriptions, for example, lacked solid scientific support demonstrating efficacy for the problems they are supposed to treat.

“The ability to prescribe medicines off-label brings more latitude to turn scientific knowledge into innovative clinical practice,” the authors of the study concluded, but “policy makers must begin to consider strategies for mandatory post-approval surveillance that focus on curtailing underevaluated off-label practices that jeopardize patient safety or represent economically wasteful prescribing practices.”

“If you prescribe a drug for an off-label indication, insurance companies and these Medicare prescription plans may tell patients, ‘You have to pay for that yourself,’” said Dr. Fahn. “So getting the drug approved could be a big deal financially.”

Marcia Angell, MD, of the Harvard Medical School, a former Editor of the NEJM and the author of The Truth About the Drug Companies, pointed out that if Novartis can get FDA approval for a new use for rivastigmine, the company would “probably get a three-year extension of exclusive marketing rights, as well as a chance to market the drug more broadly.”

Suspicions about the move to seek approval for rivastigmine were intensified by the fact that of three of the 17 authors of the NEJM study presented to the FDA as evidence of the drug's efficacy were Novartis employees. The remaining 14 received consulting fees, speaking fees, or grant support from the company, though they reported no equity interest in Novartis.

Approval of rivastigmine for treatment of Parkinson dementia is expected as early as July, according to Novartis officials, especially since the drug already has been approved for this use in the European Union, primarily on the basis of the NEJM article. And it will probably become more widely prescribed as a result, even though it produces only modest improvement in a minority of patients.

Like others who spoke to Neurology Today about rivastigmine, Jerome P. Kassirer, MD, of Tufts University School of Medicine, another former NEJM editor and the author of On the Take: How Medicine's Complicity With Big Business Can Endanger Your Health, questioned the approval of a drug that is like other cholinesterase inhibitors, which are not efficacious in forestalling dementia and “have side effects that pretty much preclude their use.” But, he added, “people grasp at straws for any treatment for dementia.”

According to Dr. Reich, providing straws for patients to grasp at may be worth something. “Dementia is one of the most debilitating and challenging problems in the long-term management of PD for which we currently have no effective therapies, other than general supportive measures,” he said. “Even though the benefits of rivastigmine were found to be modest, the study is an important step forward because it demonstrates the feasibility of conducting a rigorous clinical trial for Parkinson dementia. We hope it will stimulate more research and the discovery of more effective therapies.”

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ARTICLE IN BRIEF

✓ Parkinson disease experts expressed concerns about the recommendation that rivastigmine be approved by the FDA for PD-related dementia, because the drug was reported to be only marginally effective for that indication.

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REFERENCES

• Radley DC, Finkelstein SN, Stafford RS. Off-label Prescribing Among Office-Based Physicians. Arch Internal Med 2006;166:1021–1026.

• Aarsland EM, Albanese A, Lane R, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004;351:2509–2518

©2006 American Academy of Neurology

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