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.
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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.
Reference
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
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Long-term Safety of Onasemnogene Abeparvovec in Spinal Muscular Atrophy - Neurology Advisor
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