OBJECTIVES: Spinal muscular atrophy type 1 (SMA1) is a rapidly progressing, debilitating neurodegenerative disease resulting from bi-allelic survival motor neuron 1 (SMN1) deletion/mutation. This cross-study comparison describes the impact of onasemnogene abeparvovec (AVXS-101) on survival, motor milestone achievement, and time to treatment effect in SMA1 patients contrasted with response to nusinersen and untreated patients in natural history studies.

METHODS: SMA1 patients (two SMN2 copies) were treated with AVXS-101 (CL-101; NCT02122952; cohort 2; N=12) or nusinersen (ENDEAR; NCT02193074; N=80). Event-free survival (EFS, composite endpoint of time to death or permanent ventilation), motor milestone achievement, nutritional/ventilatory support, and CHOP INTEND (CL-101, ≥20 months; ENDEAR, ≥14 months of age) were contrasted with natural history studies (14 months of age): Pediatric Neuromuscular Clinical Research network (PNCR; N=23) and NN101 (NCT01736553; N=16).

RESULTS: The proportion of patients achieving EFS at ≥14 months was 30% in PNCR, 50% in NN101, 66% in nusinersen-treated patients (ENDEAR), and 100% in AVXS-101-treated patients (CL-101). No patient in either natural history study achieved motor milestones. In nusinersen-treated patients, 8% sat independently and 1% stood; 92% of AVXS-101-treated patients sat unassisted, 17% stood with assistance, and 17% walked independently. Whereas 70% of PNCR study patients received nutritional support, 86% of AVXS-101-treated patients who were independent of nutritional support at baseline continued to eat exclusively by mouth; 92% spoke or had stable/improved swallowing function. AVXS-101 led to rapid increases in mean changes in CHOP INTEND scores from baseline, particularly in the first few months after dosing (9.8- and 14.9-point increase at 1- and 2-months post-dose, respectively; CL-101) versus the ≤5-point increase at 2-months post-dose with nusinersen (ENDEAR).

CONCLUSIONS: A one-time intravenous infusion of AVXS-101 as assessed in CL-101 improved survival, motor milestone achievement, and reduced ventilatory/nutritional support with rapid treatment effects relative to nusinersen in the ENDEAR study and in contrast to natural history.