A multi-center screening trial of rasagiline in patients with ALS: Possible mitochondrial biomarker target engagement

Zachary Macchi^a,Yunxia Wang^a,Dan Moore^b,Jonathan Katz^b,David Saperstein^c,David Walk^d,Ericka Simpson^e,Angela Genge^f,Tulio Bertorini^g,J. Americo Fernandes^h,Andrea Swensonⁱ,Lauren Elman^j,Mazen Dimachkie^a,Laura Herbelin^a,Joann Miller^a,Jianghua Lu^a,Heather Wilkins^a,Russell H. Swerdlow^a,Jeffrey Statland^a,Richard Barohn^a*& the Western ALS (WALS) Rasagiline Study Group^k

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.