Objective: SPR1NT (NCT03505099) was a multicenter, open-label, Phase III study to evaluate the safety and efficacy of onasemnogene abeparvovec in presymptomatic patients with spinal muscular atrophy (SMA) and three copies of the survival motor neuron 2 (SMN2) gene.
Background: SMA causes loss of motor and respiratory function because of SMN1 deletion/mutation. Copies of SMN2 modify disease severity. A range of phenotypes may occur with three SMN2 copies, and approximately 85% of patients develop symptoms in infancy and are unable to walk independently without intervention.
Methods: Presymptomatic patients who were expected to develop SMA (biallelic SMN1 deletions, three SMN2 copies) received a one-time intravenous infusion of onasemnogene abeparvovec and were assessed through 24 months. Primary outcome was standing unassisted for ?3 seconds by 24 months of age. Secondary outcome was independent walking by 24 months. Safety outcomes included incidence of adverse events (AEs)/serious AEs (SAEs). Primary and secondary outcomes were compared with a cohort from the Pediatric Neuromuscular Clinical Research (PNCR) natural history data set.
Results: Fifteen patients were enrolled, and all completed the study. Primary and secondary endpoints were statistically significant compared with the PNCR cohort (p<0.001). All patients were alive, and none used ventilatory or feeding tube support at any time. All 15 patients achieved the ability to stand alone (14 within the WHO-MGRS developmental window). Fourteen patients also walked alone (11 within the WHO-MGRS developmental window). All patients had AEs. Eight patients (53%) had at least one treatment-related AE, and three patients had SAEs. No SAEs were considered treatment-related by the investigator.
Conclusions: Onasemnogene abeparvovec was efficacious and well-tolerated for presymptomatic SMA patients with three SMN2 copies. All patients survived, and none used ventilatory or feeding tube support. All achieved the ability to stand alone, most within the normal developmental window. No new safety signals were identified.