Onasemnogene abeparvovec gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): Global pivotal phase 3 study program (STR1VE-US, STR1VE-EU, STR1VE-AP)

Abstract

SMA1 is a rapidly progressing neurologic disease caused by loss of function of the survival motor neuron 1 gene (SMN1). Onasemnogene abeparvovec (AVXS-101), a one-time, intravenous, investigational GRT treats the genetic root cause of SMA and is designed for immediate, sustained neuronal SMN expression. In a phase 1/2a study, AVXS-101 demonstrated exceptional improvements in survival and motor function. We report data from the global phase 3 STR1VE program evaluating AVXS-101 in the United States (US; NCT03306277), European Union (EU; 2017-000266-29/NCT03461289), and Asia Pacific (AP; NCT03837184). The STR1VE trials are multicenter, open-label, single-arm studies in symptomatic SMA1 patients <6 months (biallelic SMN1 deletion/mutations, 1–2 SMN2 copies). Primary outcomes: independent sitting ≥10 (EU, AP) or ≥30 s (US) at 18 months; event-free survival (no death/permanent ventilation) at 14 months (US only; secondary outcome in EU, AP). Secondary/exploratory outcomes: independence of ventilator support; motor function improvements (Bayley-III, CHOP INTEND). US enrollment is complete (N = 22). As of 8 March 2019, survival was improved compared with natural history among patients who could have reached 13.6 months of age at datacut; 11/22 patients (median age at datacut: 14.4 months) achieved sitting without support for ≥30 seconds; 21/22 patients have achieved a CHOP INTEND score ≥40 points (maximum 64). As of 24 April 2019, 27 patients have been enrolled in STR1VE-EU (30 planned). STR1VE-AP is currently enrolling patients (6 planned). Updated data (pooled) will be presented. In STR1VE, AVXS-101 has demonstrated significant therapeutic benefit in prolonging survival and improving motor function in symptomatic infants with SMA1.