STR1VE-EU study shows effectiveness of Onasemnogen Abeparvovec in spinal muscular atrophy

Onasemnogene Abeparvovec gene replacement therapy was effective in helping 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.

Motor neuron dysfunction occurs in infants with SMA1, the most severe postnatal phenotype, due to the biallelic loss of the survival motor neuron 1 gene (SMN1). Typically, the disease is observed by 6 months of age and then can lead to rapid decline in motor function. This can result in death by the age of 2 or sometimes permanent ventilation. Onasemnogene Abeparvovec gene replacement therapy, approved by the U.S. Food and Drug Administration (FDA), is capable of delivering human SMN via a single intravenous infusion and has been used in studies that included infants aged less than 8 months and younger than 6 months , Safety and efficacy shown SMA1 resp.

The aim of the current study was to evaluate the safety and effectiveness of Onasemnogen abeparovec in symptomatic patients under 6 months of age with SMA1 and one or two surviving copies of the motor neuron 2 gene (SMN2).

Continue reading

STR1VE-EU was an open-label, single-arm, multicenter, single-dose study involving infants (n = 33) under 6 months of age with symptomatic spinal muscular atrophy type 1 in 9 hospitals in Italy, the UK and Belgium, and France between 2018 and 2020. All Patients shared the biallelic pathogenic SMN1 deletion of exons 7-8 or point mutations with 1 or 2 copies of the SMN2 gene modifier mutations. The patients received a single intravenous infusion of Onasemnogen Abeparvovec and prophylactic prednisolone (2 mg / kg / day) before and after the infusion. At 18 months, the patients’ functional outcomes were assessed and compared to the data from the Pediatric Neuromuscular Clinical Research (PNCR) database from 23 patients who received no therapy.

The STR1VE and PNCR cohorts averaged 4.1 (range 1.8-6.0) and 28.9 (range 1.9-170.6) months (P = 0.01), 58% of age and 52% were girls who needed onset of symptoms at 1.6 (range 0.0-4.0) and 3.0 (range 0.5-6.0) months (P = 0.0009), 27% and 78% respectively Food intake support (P = 0.0003) or 27% and 52% ventilation support (P = 0.09).

At each visit, 44% of treated patients were able to sit independently for ³10 s, compared to 0% of the PNCR cohort (P <0.0001). Functional independence occurred with a median of 15.9 (interquartile range [IQR], 9.6-18.3) months and another patient achieved functional independence at 18.9 months of age.

Freedom from permanent ventilation support was achieved by 97% of treated patients compared to 26% of the PNCR cohort (P <0.0001). The criteria for viability were met in 30% of the treated infants compared to 0% of the PNCR group (P <0.0001).

In addition, ³1 motor milestones of 82% were achieved, including head control (77%), rolling (58%), and sitting without assistance for 30 seconds (48%). One patient walked alone at the age of 18 months.

The Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP INTEND) mean score increased 6.0 (standard deviation) from baseline [SD], 5.4) points after 1 month and 13.6 (SD, 6.6) points after 6 months. An increased CHOP INTEND score of 40 points was achieved by 73% and by 50 points by 42%.

All but 1 child had ³1 adverse events and 18% were serious. The most common events included fever (67%), hepatotoxicity (55%), upper respiratory tract infections (33%), and increased alanine aminotransferase (27%). There was 1 death caused by hypoxic ischemic brain damage from infection and the death was considered unrelated to the study drug.

This study was constrained by a data collection interruption due to the COVID-19 pandemic, in which some participants were assessed for the final endpoint after 18 months.

The study authors concluded that “… the overall risk-benefit profile for Onasemnogen Abeparvovec for patients with type 1 spinal muscular atrophy remains favorable.”

Disclosure: Several authors stated links to industry. For a full list of the details, see the original article.

reference

Mercuri E., Muntoni F., Baranello G, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile spinal muscular atrophy type 1 (STR1VE-EU): an open, single-arm, multicenter phase 3 study. Lancet Neurol. Published online October 1, 2021. doi: 10.1016 / S1474-4422 (21) 00251-9