Introduction and Objective Onasemnogene abeparvovec (formerly AVXS-101) is designed to address the genetic root cause of spinal muscular atrophy type 1 (SMA1). In the phase 1 trial (START; NCT02122952), patients who received a one-time (proposed therapeutic dose) infusion (n=12) demonstrated significantly improved outcomes versus untreated natural history. Here, we evaluate long-term safety in patients previously treated in START and long-term efficacy in patients from both Cohorts. START patients could electively enroll into a LTFU study (NCT03421977).

Methods Primary objective: long-term safety. Patients have annual visits (5 years) followed by annual phone contact (additional 10 years). Assessments include medical history/record review, physical examination, clinical laboratory evaluation, pulmonary assessments, and milestone maintenance.

Results As of 31 Dec 2019, 13 patients (low dose, n=3; therapeutic dose, n=10) were enrolled. The oldest patients were aged 6.2 (low dose) and 5.6 (therapeutic dose) years. All patients who received the therapeutic dose have survived and are free of permanent ventilation (mean [range] age at last data cut: 4.8 [4.3–5.6] years; mean [range] time since dosing: 4.5 [4.1–5.2] years). These patients have either maintained all previously attained milestones or gained new milestones; 2 patients have newly achieved standing with assistance while not receiving concomitant survival motor neuron 2 protein (SMN2) upregulating therapy at any point. Of the 10 enrolled patients who received therapeutic dose, 6 did not require regular, daily respiratory support more than 4 years after dosing. Additionally, 6 have never received concomitant SMN2 upregulating therapy. No new treatment-related adverse events (AEs) were reported. Onasemnogene abeparvovec has been associated with transient, manageable, and subacute AEs. During LTFU, no AEs of special interest have been reported to date, specifically none associated with liver enzyme elevations, haematology values, new malignancies or autoimmune disorders. Serious AEs were reported in 8/13 (61.5%) patients; however, no serious AEs were considered related to treatment or lead to study discontinuation supporting a favorable risk–benefit profile.

Conclusions Onasemnogene abeparvovec shows a favorable risk–benefit profile, and continues to demonstrate efficacy with new milestone developments.