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Earlier Dose of Rasagiline Shown More Effective than Delayed Treatment for Parkinson Disease

ARTICLE IN BRIEF

Parkinson disease patients who delayed taking 1 mg of rasagiline worsened more quickly than those who started taking medication at the start.

SALT LAKE CITY—Early-stage Parkinson disease (PD) patients who started taking 1 mg rasagiline (Azilect) daily at the start of an 18-month trial had significantly slower functional decline — as measured by scores on the United Parkinson's Disease Rating Scale (UPDRS) — than those who started treatment nine months later.

This possibly neuroprotective effect appears promising, said the lead ADAGIO study investigator C. Warren Olanow, MD, professor of neurology and neuroscience at Mount Sinai School of Medicine and the chairman of the neurology department.

Dr. Olanow, who is also a paid consultant for the study sponsor Teva Pharmaceuticals, Inc., of Israel, discussed the findings here in September at the annual meeting of the American Neurological Association. [ADAGIO stands for Attenuation of Disease progression with Azilect.]

STUDY DESIGN, FINDINGS

The study was the first to use the delayed start design prospectively in an effort to find a neuroprotective therapy, he said.

The 1,178 patients were randomized to receive 1 mg or 2 mg rasagiline at the start, or they took a placebo for the first 36 weeks, and then switched to 1 mg or 2 mg rasagaline for the next nine months. None of the patients were taking dopamine drugs. The patients were evaluated periodically with the UPDRS scale, which measures the severity of mood, speech, hygiene, tremor, gait, and activities of daily living.

By the end of 72 weeks, patients who delayed taking the 1 mg of rasagiline worsened more quickly than those who started taking medication at the start. The early start group went down 2 points in the UPDRS scale, while the group that started the therapy later had a 3.7-point decline (p = 0.025).

Dr. Olanow acknowledged that the results could have been the result of an early symptomatic treatment that helped some compensatory mechanism. He said it was also possible that there was a “maladaptive compensatory reaction that happens with placebo” but is prevented with earlier use of rasagiline.

“Finally, could it be simply a cumulative symptomatic effect which hasn't caught up after nine months after introduction of the drug?” Dr. Olanow asked. He answered that it was “probably unlikely.”

Both the 1 mg and 2 mg doses were found to be safe and well-tolerated. One patient in the 1 mg group had a melanoma at 18 weeks, but no other melanomas were noted, Dr. Olanow said. Eighty-four percent of the patients who began the lengthy study completed it.

Patients who started with the 2 mg rasagiline showed more benefit than those taking placebo; at the end of the first 36 weeks, their scores on the UPDRS scale had become only slightly worse. But by the end of 72 weeks, those who started the 2 mg dose earlier had the same UPDRS scores as those who started taking it later.

Explaining the results, Dr. Olanow said: “It could be that 2 mg has greater symptomatic effects that simply mask any protective benefit at the early time point we looked. And you may need a little more severity in order to unmask any benefit.”

EXPERTS COMMENT

David Charles, MD, an associate professor of neurology at the Vanderbilt University School of Medicine, praised the breadth of the study.

“The message from this was real exciting — a potential, disease-modifying neuroprotective,” said Dr. Charles, who was not involved with the study. “If it proves to be true, it would be the first medication shown to have changed the disease progression. So — very exciting.”

He also praised the methodology. “The delayed start, for all of its problems, is the best we have right now to test anything that could potentially be disease-modifying,” he said.

Dr. Kathleen Shannon, MD, an associate professor of neurological sciences at the Rush University Medical Center in Chicago, cautioned that it's difficult to comment on the study without first reviewing a peer-reviewed manuscript.

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DR. WARREN OLANOW said rasagalines possibly neuroprotective effect appears promising for Parkinson disease patients.

But based on the study as presented, she said there are “too many variables” to say that it's evidence that the drug actually slows down the progression of Parkinson. The differences in the drug's effects on the early- and late-start groups could just be a matter of a difference in treating symptoms, she said.

The disease had progressed further in the late-start group, so it might just be that the symptomatic effect of rasagiline on those patients was less prominent, and not anything more dramatic than that.

She also suggested that there might be a complex symptomatic effect that might cause the late-starters to catch up to the early-starters eventually.

“The delayed start method appears to be the recent darling of the neuroprotection set, but absent a gold standard measure of disease severity it is difficult to feel comfortable that meeting these primary outcomes is evidence for modification of disease progression,” Dr. Shannon wrote in an e-mail to Neurology Today.

The lack of results in the 2 mg group is also cause for pause, she said. “This failure to show a dose-response pattern seems important to me and I wouldn't be so anxious to explain it away,” she wrote. “I think a healthy dose of skepticism goes a long way here, since this is a very expensive medicine.”

Dr. Olanow said there will be a lot more discussion about rasagiline and its potential in helping stunt Parkinson disease. “Clearly, it is crucial to know if early treatment will not only retard a delay in UPDRS but will retard a delay in gait dysfunction, in cognitive impairment, and other areas,” he said.