Safety and efficacy of intravenous onasemnogene abeparvovec gene therapy in patients with spinal muscular atrophy type 1: interim analysis from LT-001, a long-term follow-up study of patients from the START study

Background LT-001 evaluated long-term safety/efficacy of onasemnogene abeparvovec (OA) for spinal muscular atrophy (SMA) patients from START (N = 15; NCT02122952). Methods Reported is an interim analysis (5-year totalling up to 10-years post-dose) of long-term follow-up data from START (phase 1, open-label, single-arm, dose-escalation; 2-year follow-up [Nationwide Children's Hospital, Columbus, Ohio] [first patient dosed: May 5, 2014]). Patients (symptomatic SMA type 1, biallelic SMN1 mutations/deletions, two SMN2 copies; full analysis set) received single intravenous OA dose (low [6·7 × 10 13 vg/kg] or proposed therapeutic dose [equivalent to 1·1 × 10 14 vg/kg]). Safety (primary outcome) and efficacy (alive and independent of permanent ventilatory support [ post hoc ]) were assessed (NCT03421977 [September 21, 2017–September 17, 2018]). Findings The LT-001 study was initiated on September 21, 2017, and the last patient was enrolled on September 17, 2018. As of July 1, 2024, 13 START patients enrolled in LT-001 (n = 3/13, low-dose; n=10/13, therapeutic-dose). Mean (SD); min–max age at dosing was 6·3 (0·7); 5·8–7·1 months (low-dose) and 2·8 (1·5); 0·9–5·6 months (therapeutic-dose). Mean (SD); min–max follow-up duration was 9·9 (0·2); 9·8–10·1 years (low-dose) and 8·3 (1·1); 6·8–9·6 years (therapeutic-dose). Most patients (≥70%) received nusinersen/risdiplam post-dosing. Serious adverse events (n = 11/13; 85%) were most frequently acute respiratory failure, dehydration, and pneumonia (none led to study discontinuation or death). Six adverse events (AEs) of special interest (n = 4/13; 31%) included transient thrombocytopenia, cardiac AEs, and new incidence of neurologic disorders (unrelated to treatment). All (n = 13/13) were alive at last visit (n = 5 therapeutic-dose) or data cutoff (n = 8 ongoing). The majority (n = 12/13) were free of permanent ventilation. Interpretation OA demonstrated a favourable benefit–risk profile and efficacy up to 10 years for START/LT-001 patients, though there are limitations (descriptive analyses, small population, add-on therapy, lack of comparator). Further long-term research may build on phase 3/4 study findings with OA for SMA patients.