The value of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy for spinal muscular atrophy type 1

Abstract

Spinal muscular atrophy type 1 (SMA1) is a rapidly progressing neurologic disease caused by biallelic survival motor neuron 1 gene (SMN1) deletion/mutation. This study highlights the value of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy for SMA1. Twelve SMA1 patients were treated with a one-time intravenous AVXS-101 infusion (NCT02122952; Cohort 2; therapeutic dose) and assessed for event-free survival (absence of death/permanent ventilation), pulmonary/nutritional interventions, swallowing, hospitalizations, CHOP INTEND, and safety, for 2 years. By study end, all patients survived event free; 7 did not need daily non-invasive ventilation. Eleven patients had stable or improved swallowing, demonstrated by the ability to feed orally; 6 fed exclusively by mouth; 11 could speak. Patients experienced a mean of 2.1 (0–7.6) hospitalizations per year (natural history: 4.2 per year) and 1.4 (0–4.8) respiratory hospitalizations per year. The mean (range) proportion of time hospitalized and length of stay were 4.4% (0–18.3%) and 6.7 (3–12.1) days (natural history: 13 days). Rapid increases in CHOP INTEND of 9.8 (standard deviation [SD]=3.9) and 15.4 (SD=6.4) points at 1- and 3-months post-dose, were observed. Eleven patients sat unassisted; 2 crawled, pulled to a stand, stood, and walked. No motor milestones were lost in the long-term follow-up study (NCT03421977). Adverse events included elevated serum aminotransferase levels, which were attenuated by prednisolone. A one-time AVXS-101 infusion improved survival and motor function, likely due to continuous SMN expression. The reduced healthcare utilization in treated infants could decrease cost; alleviate patient, caregiver, and societal burden; and improve quality of life.