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ADAGIO/Rasagiline Study: Has Neuroprotection Been Achieved?

The study, along with previous research, supports a beneficial effect of MAO-B inhibitors on progression of motor disability, if not on the neurobiology of Parkinson disease.

Does rasagiline, a monoamine oxide type B inhibitor, retard the progression of Parkinson disease (PD)? The challenge in this situation is to demonstrate a disease-modifying effect distinct from the drug's clear beneficial effect on motor symptoms. In this study, researchers used a novel delayed-start design in which patients were randomized to receive either rasagiline (1 mg or 2 mg) or placebo for the first 36 weeks, followed by rasagiline for all participants for another 36 weeks. Three endpoints had to be met: slower progression with early rasagiline between 12 and 36 weeks, comparable progression between weeks 48 and 72 (i.e., no "catching up" in the delayed-start group), and a significant between-group difference in motor disability at the end of the study. Of 1176 patients with untreated PD who were randomized, 996 formed the basis for the analysis.

Rasagiline at a dose of 1 mg met all three endpoints, but the effect was not large (1.7 points on the Unified Parkinson's Disease Rating Scale at 72 weeks). Rasagiline at 2 mg failed to meet the same standard. The drug was well tolerated; no tyramine or serotonin effects were reported.

Comment: The findings of this large randomized trial suggest that patients on rasagiline from the start had less disease progression over 18 months. The authors did not examine the drug's effect on survival of nigral neurons, but rasagiline recipients had less motor disability than placebo recipients. The interpretation is uncertain as the 2-mg dose was not successful, and the effect size was small. Longer follow-up of these patients will be instructive.

This outcome, combined with the earlier DATATOP extension (Ann Neurol 2002; 51:604) and the Swedish Parkinson Study Group experience with selegiline (Neurology 2006; 66:1200), shows a beneficial effect of MAO-B inhibitors on progression of motor disability, if not on the neurobiology of disease. In the Swedish study, additional benefits of selegiline seemed to accrue over 5 years. Whether this is a class effect, an effect specific to propargylamine drugs, or simply the impact of earlier intervention remains to be determined. Because rasagiline is costly and its effect size is modest, the search for an effective drug to retard disease progression continues.

— Lewis Sudarsky, MD

Dr. Sudarsky is Director of Movement Disorders, Department of Neurology, Brigham and Women's Hospital, and Associate Professor of Neurology, Harvard Medical School, Boston.

Published in Journal Watch Neurology November 17, 2009

Citation(s):

Olanow CW et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 2009 Sep 24; 361:1268.

• Medline abstract (Free)

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