Treatment with onasemnogene abeparvovec gene therapy for spinal muscular atrophy (SMA) type 1 was associated with less need for nutritional support or nighttime ventilation compared to recommended first-line nusinersen, new data showed.

Those treated with gene therapy also had lower rates of unsatisfactory clinical responses (UCRs), a composite of death, treatment change due to inadequate response, initiation of feeding support, and/or failure to achieve independent sitting.

However, differences between groups in these outcomes were not significant and motor outcomes were similar with both treatments. Still, as the first comparison of the two disease-modifying therapies, the study offers important information, researchers noted.

“These exploratory findings, while not statistically conclusive, support further investigation and suggest the consideration of gene therapy as a preferred first-line option in this population,” lead author Juliette Ropars, MD, PhD, Reference Center for Neuromuscular Disorders, Pediatric Department, Brest University Hospital, Brest, France, and colleagues wrote.

The results were published online on October 8 in JAMA Network Open.

Filling the Gap

Nusinersen, an antisense oligonucleotide, was approved by the FDA in 2016 as the first treatment for SMA. The US approval for onasemnogene abeparvovec gene therapy followed in 2019.

Previous research demonstrated both therapies were associated with improved motor function and survival without the need for permanent ventilation. However, less was known about their comparative effectiveness on bulbar and respiratory functions.

To fill the gap, investigators used data from the French SMA Registry from September 2016 to July 2024 to identify 88 children with genetically confirmed untreated SMA1. All were unable to sit up independently, had two or three copies of the SMN2 gene, and were younger than 9 months for types 1a and 1b or less than 12 months for type 1c.

Investigators matched 24 children from this cohort 1:1 based on sex (five girls in each group), age at treatment (mean, 6.1 months), type of SMA1, and pretreatment baseline motor function, and feeding and ventilatory status. 

Treatment was started within 6 months of diagnosis and follow-up was at least 24 months.

Three patients, one in the gene therapy group and two receiving nusinersen, died within the first year of treatment from respiratory complications. None of the deaths were attributed to these therapies.

Gene Therapy vs Nusinersen

At the 2-year follow-up, surviving patients receiving nusinersen were more likely than surviving gene therapy treated-patients to need nutritional support (50% vs 9%) and nocturnal ventilation (80% vs 45%).

Two of the children in the gene therapy group were weaned off nocturnal ventilation; none in the nusinersen group improved.

UCR rates were higher in the nusinersen group (8 of 12 children) compared to the gene therapy group (3 of 12 children).

Two of the 11 surviving patients treated with gene therapy received an add-on therapy because of insufficient motor improvement: one received risdiplam 3 years after gene therapy and the other received nusinersen 2 years after gene therapy.

In the nusinersen group, five of the 10 surviving patients switched to risdiplam after a median treatment duration of 38 months (range, 23-69 months), four because of bulbar deterioration or lack of motor improvement and one due to injection difficulties.

“The more frequent UCR in the nusinersen group highlights the challenges of achieving sustained efficacy in some patients,” the researchers noted.

The differences in nutritional support, ventilation, and UCR outcomes could be caused by lower bioavailability of nusinersen in brainstem motor nuclei, as previously hypothesized.

Differences in motor outcomes, measured by the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders assessment, were not statistically different between groups.

“Although exploratory and based on small numbers, such differences are relevant in guiding early treatment decisions and anticipating long-term needs in SMA1 care,” researchers wrote.

Important Distinctions

Researchers said the 13% mortality rate in the study was higher than previous reports in the literature for either gene therapy (8% vs 1.7%) or nusinersen (17% vs 5%). The researchers hypothesized that the current participants could have had more severe disease at baseline, or it could be due to a longer follow-up time.

Study limitations included the potential for residual confounding, even with the exact matching between treatment groups. Treatment initiation occurred in different calendar periods because nusinersen was available before the gene therapy. In addition, statistical power was limited given the small study population.

“Despite the small sample size, our study offers valuable insights into the comparative outcomes of these therapies in routine clinical practice, highlighting both their transformative potential and important distinctions in clinical outcomes,” the researchers wrote.

With the growing number of SMA newborn screening programs, more direct comparison studies will be needed to guide treatment decisions, they added. This includes evaluating and treating presymptomatic children.

The registry is supported by an unrestricted grant from Biogen, Roche, and Novartis. Ropars reported receiving honoraria for presentations and/or travel support from Novartis, Roche, and Biogen and participating on advisory boards of Novartis, Roche, Pfizer, and Italfarmaco.