Background Spinal Muscular Atrophy type 1 (SMA1) is a rapidly progressing disease resulting in death/permanent ventilation by 2 years of age. In ENDEAR, ∼10% of patients died/required permanent ventilation within 2 months after therapy initiation; 39% died/required permanent ventilation by 6 months. This may reflect a non-immediate therapeutic impact related to loading dose schedule. This study explored the rapidity of therapeutic effect of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy (phase 1 study) relative to nusinersen (phase 3 study, ENDEAR).

Methods SMA1 patients were treated with a one-time intravenous AVXS-101 injection (NCT02122952; cohort 2; N=12; 24 months follow-up). Outcomes were event-free survival (EFS, no death/permanent ventilation [AVXS-101: ≥16 hours ventilation/day for >2 weeks; ENDEAR: tracheostomy or ≥16 hours ventilation/day for >21 days]) and motor function improvements (CHOP-INTEND).

Results All patients treated with AVXS-101 survived event-free 24 months post-dose, while 49/80 nusinersen patients showed EFS. Rapid increases in CHOP-INTEND of 9.8 and 15.4 points were observed at 1- and 3-months post–AVXS-101 dose (nusinersen: ≤5-point increase at 2 months after initiation).

Conclusions AVXS-101 appears to improve survival and induce more rapid motor function improvements relative to nusinersen, consistent with rapid restoration of survival motor neuron expression in motor neurons with a single dose.