Background: SMA1 is caused by functional loss of SMN1, and typically results in death/permanent ventilation by 2 years if untreated. Onasemnogene abeparvovec-xioi (formerly AVXS-101), a one-time, AAV9-based, intravenous gene therapy, addresses the genetic root cause of SMA and is designed for sustained SMN protein expression in neurons.
Objective: Assess preliminary data from the phase 3 STR1VE (NCT03306277) study evaluating efficacy/safety of onasemnogene abeparvovec in SMA1 patients (pts).
Methods: STR1VE is a multicenter, open-label, single-arm, single-dose study in symptomatic SMA1 pts aged <6 months (biallelic SMN1 mutations, 1–2 SMN2 copies [1–2xSMN2]) conducted in the United States. Outcomes: independent sitting ≥30 seconds at 18 months, survival (no death/permanent ventilation) at 14 months, and motor function improvements (Bayley-III, CHOP INTEND). Safety outcomes: unanticipated treatment-related toxicity of grade ≥3 based on CTCAE.
Results: As of 31 May 2019, enrollment is complete (N=22; 2xSMN2; 10 male, 12 female). Mean age (range) at dosing: 3.7 (0.5–5.9) months. Of 19 pts who could have reached age 13.6 months at data cutoff, 17 (89.5%) were surviving without permanent ventilation (death unrelated to treatment, n=1; respiratory endpoint prior to withdrawal of consent, n=1) compared with 25% survival in untreated natural history. Mean (range) baseline CHOP INTEND score was 32 (18–52) and increased 6.9, 11.7, and 14.3 points at months 1, 3, and 5, respectively. 11/22 (50%) pts sat independently ≥30 sec (mean of 8.2 months post-treatment); 5/6 (83%) pts ≥18 months old sat independently ≥30 sec (co-primary endpoint). As of 8 March 2019, treatment-emergent adverse events of special interest were transient and not associated with any sequelae.
Conclusions: Interim data from the ongoing STR1VE study suggest that a one-time intravenous dose of onasemnogene abeparvovec provides benefit in pts with SMA1. Updated data from STR1VE will be presented.