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Abstract
Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.
Acknowledgements
The authors would like to thank the patients and their caregivers. We are grateful for their participation in this trial.
Funding provided in part by an investigator initiated grant from TEVA Pharmaceuticals (Yunxia Wang), a grant from Project ALS, and an and an Institutional Clinical and Translational Science award (NIH/NCATS Grant #UL1TR000001). Work on this project was supported by the University of Kansas Medical Center. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Biomarker studies were partly supported by the University of Kansas Alzheimer's Disease Center (P30AG035982). TEVA Pharmaceuticals performed a medical accuracy review of this manuscript.
Work by JS was supported by the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translation Research (KL2TR000119). TEVA Pharmaceuticals performed a medical accuracy review of this manuscript.
Western ALS Study Group
Contributors: Y. Wang, R.J. Barohn, R.H. Swerdlow, M.M. Dimachkie, A. McVey, Arthur Dick, Z. Macchi, M. Walsh & L. Herbelin (University of Kansas Medical Center); J. Katz, R. Miller, D. Moore, D. Forshew & M. Engel (California Pacific Medical Center); D. Saperstein, T. Levine & N. Hank (Phoenix Neurological Associates); D. Walk & S. Rolandelli (University of Minnesota); A. Swenson, J. Sieren & H. Olalde (University of Iowa Health Care); J.A. Fernandes, P. Thaisetthawatkul, C. Cowardin (University of Nebraska); E. Simpson, S. Halton, L. Lay (The Methodist Hospital System); L. McCluskey, L.B. Elman, K. Almasy (University of Pennsylvania); T. Bertorini, M. Barrett-Adair, C. Benzel (University of Tennessee); A. Genge, K. Salmon, A. Zaloum (McGill University); C. Jackson (University of Texas Health Science Center).
Declaration of interest: All sources of funding for this study are mentioned in the Acknowledgements section. The authors report no conflicts of interest and alone are responsible for the content and writing of the paper.