Onasemnogene abeparvovec gene replacement therapy effectively helped infants with symptomatic spinal muscular atrophy type 1 (SMA1) achieve at least one episode of independent sitting in a phase 3 clinical trial published in The Lancet Neurology.
Infants with SMA1, the most severe postnatal phenotype, experience motor neuron dysfunction due to the biallelic loss of the survival motor neuron 1 (SMN1) gene. Typically, disease onset is seen at age 6 months and can then progress to a quick decline in motor function. This can lead to death or sometimes permanent ventilation by age 2 years. Onasemnogene abeparvovec gene replacement therapy, approved by the US Food and Drug Administration (FDA), is able to deliver human SMN via a single intravenous infusion and has shown safety and efficacy in trials that evaluated infants younger than 8 months and younger than 6 months with SMA1, respectively.
The objective of the current study was to assess the safety and efficacy of onasemnogene abeparovec for symptomatic patients younger than 6 months with SMA1 and one or two survival motor neuron 2 gene (SMN2) copies.
STR1VE-EU was an open-label, single-dose, single-arm, multicenter trial which recruited infants (n=33) aged younger than 6 months with symptomatic spinal muscular atrophy type 1 at 9 hospitals in Italy, the United Kingdom, Belgium, and France between 2018 and 2020. All patients had the common biallelic pathogenic SMN1 deletion of exons 7-8 or point mutations with 1 or 2 copies of the SMN2 gene modifier mutations. Patients received a 1-time intravenous infusion of onasemnogene abeparvovec and prophylactic prednisolone (2 mg/kg/day) before and after infusion. At 18 months, patients were assessed for functional outcomes which were compared with data from 23 patients who had no therapy from the Pediatric Neuromuscular Clinical Research (PNCR) database.
The STR1VE and PNCR cohorts were aged mean 4.1 (range, 1.8-6.0) and 28.9 (range, 1.9-170.6) months (P =.01), 58% and 52% were girls, symptom onset at 1.6 (range, 0.0-4.0) and 3.0 (range, 0.5-6.0) months (P =.0009), 27% and 78% required feeding support (P =.0003), and 27% and 52% ventilation support (P =.09), respectively.
At any visit, 44% of the treated patients were able to sit independently for ³10 s compared with 0% of the PNCR cohort (P <.0001). Functional independence occurred at a median of 15.9 (interquartile range [IQR], 9.6-18.3) months and an additional patient achieved functional independence at 18.9 months of age.
Freedom from permanent ventilatory support was achieved by 97% of the treated patients compared with 26% of the PNCR cohort (P <.0001). The criteria for ability to thrive were met for 30% of treated infants compared with 0% of the PNCR group (P <.0001).
In addition, ³1 motor milestone was achieved by 82%, including head control (77%), rolling (58%), and sitting without support for 30 seconds (48%). One patient walked alone by age 18 months.
The average Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP INTEND) score increased from baseline by 6.0 (standard deviation [SD], 5.4) points at 1 month and 13.6 (SD, 6.6) points at 6 months. An increased CHOP INTEND score of 40 points was achieved by 73% and 50 points by 42%.
All but 1 child had ³1 adverse event and 18% were serious. Most common events included pyrexia (67%), hepatotoxicity (55%), upper respiratory infection (33%), and increased alanine aminotransferase (27%). There was 1 death caused by hypoxic-ischemic brain damage due to infection and the death was deemed unrelated with the study drug.
This study was limited by disruption to data collection due to the COVID-19 pandemic, in which some participants were evaluated for the final endpoint after 18 months of age.
The study authors concluded “…the overall risk–benefit profile for onasemnogene abeparvovec remains favourable for patients with spinal muscular atrophy type 1.”
Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.
Mercuri E, Muntoni F, Baranello G, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. Published online October 1, 2021. doi:10.1016/S1474-4422(21)00251-9