Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis (RAP-ALS study)

Abstract In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells (Tregs), and autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Rapamycin has never been tested in ALS patients. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in Tregs from baseline to treatment end, was not attained. Of the secondary outcomes, rapamycin decreased mRNA relative expression of pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. Rapamycin, in combination with riluzole, was well tolerated and provided reassuring safety findings. Based on immunological effects, plasma concentration stability and safety, rapamycin 1 mg/m2/day resulted the best dosage in this study, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.