Long-term Safety of Onasemnogene Abeparvovec in Spinal Muscular Atrophy

The back of a baby boy
Study researchers sought to assess the safety of onasemnogene abeparvovec for the treatment of infants with spinal muscular atrophy.

In infants with spinal muscular atrophy type 1, treatment with a single dose of onasemnogene abeparvovec provides a continued monitorable and manageable safety profiles up to 6.2 years after treatment administration, according to results of an ongoing study published in JAMA Neurology.

In a previous 2-year, open-label, phase 1 study (START), onasemnogene abeparvovec, a single intravenous infusion of a recombinant adeno-associated virus serotype 9 vector-based gene therapy, provided longer survival and improved motor function in patients with spinal muscular atrophy compared with historical controls.

In the extension of the START trial, a team of investigators conducted an ongoing, observational, long-term follow-up study (START LTFU; ClinicalTrials.gov Identifier: NCT03421977) to determine the long-term safety and durability of response in infants who completed phase 1 of the START study. The study researchers measured safety profiles and aimed to determine developmental milestones achieved in the START phase 1 trial, if these milestones were maintained, and if any new milestones presented in this patient population. The primary outcome measured the incidence of serious adverse events.

Of the 15 patients who were in the original START analysis, 13 (median age, 38.9 months; 7 girls) were included in the analysis; 3 patients had been treated with a low dose (6.7 × 1013 vg/kg) and 10 patients were treated with a therapeutic dose (1.1 × 1014 vg/kg). There was an overall median time of 5.2 years since dosing; 5.9 years for the low-dose arm and 4.8 years for the therapeutic arm.

Serious adverse events were reported in 8 of the patients but none resulted in study discontinuation or patient mortality. Acute respiratory failure (n=4), pneumonia (n=4), dehydration (n=3), respiratory distress (n=2), and bronchiolitis (n=2) were the most common serious adverse events.

A total of 4 patients in the therapeutic-dose arm required noninvasive ventilatory support before baseline. All 10 patients in the therapeutic-dose arm were alive and did not require permanent ventilation. They also maintained all previously developed motor milestones, while 2 patients also developed the milestone “standing with assistance” without the use of concomitant nusinersen.

The 3 patients in the low-dose cohort also remained alive; only 2 of the 3 patients were free of permanent ventilation.

This study was limited by its relatively small sample size and by the ongoing COVID-19 pandemic which caused disruptions to members of the patient population.

“Anticipated results from completed and ongoing phase 3 and 4 studies will further confirm the efficacy and safety of onasemnogene abeparvovec,” wrote the study researchers. They concluded that “current evidence demonstrates that onasemnogene abeparvovec continues to have a favorable benefit-risk profile for the treatment of pediatric patients with [spinal muscular atrophy].”

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Mendell JR, Al-Zaidy SA, Lehman KJ, et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. Published online May 17, 2021. doi:10.1001/jamaneurol.2021.1272