Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by deteriorating muscle strength and typically results in morbidity due to respiratory muscle weakness within 3-5 years. Terminal complement activation has been implicated in the ‘hallmark’ death of upper and lower motor neurons in ALS. Given the unmet need for highly efficacious ALS treatments and the favorable benefit-risk profile of the anti-C5 antibody ravulizumab in other complement-mediated neurological diseases , we proceeded directly to a Phase 3 clinical trial to evaluate the efficacy and safety of ravulizumab in ALS.
Objectives: CHAMPION-ALS (NCT04248465) was a global, double-blind, placebo-controlled, Phase 3 trial. Adults diagnosed with ALS who had received meningococcal vaccination were randomized 2:1 to receive either ravulizumab or placebo for 50 weeks. The primary efficacy endpoint was change from baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score at Week 50, as assessed through the Combined Assessment of Function and Survival (CAFS). Secondary endpoints included a range of functional and PK/PD measures. Safety assessments focused on rates of treatment-emergent adverse events (TEAEs).
Results: In total, 255 participants received ravulizumab and 127 received placebo. Demographics and baseline characteristics were well balanced between groups. The trial was terminated for futility following a pre-planned interim analysis when 33% of participants had completed the week 26 visit. Fifteen ravulizumab-treated participants and five participants receiving placebo completed the Week 50 visit. The primary analysis showed no significant difference in treatment effect between groups [CAFS LS mean ranks difference estimate (SE): 5.5(10.8); 95% CI: −15.7, 26.6; p=0.61]. Additionally, there were no observed differences in key efficacy-related secondary outcome measures and no notable differences in TEAE rates between treatment groups.
Conclusions: There were no differences in the functional decline rate or survival amongst participants treated with ravulizumab compared with placebo. No new ravulizumab safety signals were identified.