Early Combination Therapy May Benefit Children with Spinal Muscular Atrophy

The availability of multiple disease-modifying therapies (DMTs) for the treatment of spinal muscular atrophy (SMA) has altered the course of disease and prognosis for many individuals living with this condition. Since December 2016, the Food and Drug Administration has approved three DMTs that can improve clinical outcomes and even result in normal motor development with timely treatment, which has been made possible by newborn screening and early diagnosis. Although data about combination therapies are still limited, parents of children with SMA are increasingly expressing interest in the combination of approved DMTs.

A multicenter retrospective review of children with SMA treated at six neuromuscular care centers across the United States showed that the administration of risdiplam after gene transfer therapy led to additional gains in motor, respiratory, and bulbar function. The review included 19 patients, most of whom were clinically diagnosed with type 1 SMA. Fifteen of the children had two copies of the SMN2 gene. The data collected from electronic health records through August 2023 showed that 63% of the children were treated with onasemnogene abeparvovec (OA) followed by risdiplam, while the rest received nusinersen, OA, and then risdiplam. Most of the children included in the case series received OA within 1 month of diagnosis. On average, risdiplam was administered 16 months after OA. The most common reasons cited for the initiation of risdiplam were inadequate improvements or plateaus in gains with previous therapies.

Six patients showed improvements in both respiratory function and dysphagia after receiving risdiplam. Severe dysphagia improved in three children, and mild dysphagia resolved in two children after treatment. One other participant was able to increase the amount of food eaten orally after adding risdiplam. Six children had positive respiratory changes. While one child who did not require breathing assistance after OA began nighttime non-invasive ventilation after adding risdiplam, clinicians attributed this change to disease progression.

The results also showed stability or improvements in motor function in 92% of the participants who were assessed using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders or the Hammersmith Functional Motor Scale – Expanded scores after risdiplam initiation.

No significant adverse events were reported after treatment with risdiplam. All participants continued treatment with the exception of one child, who discontinued risdiplam after 2 months due to a lack of perceived effectiveness.

“I think children with two SMN2 copies should be treated with combination therapy from the start,” said lead author Nancy Kuntz, MD, Professor of Pediatrics and Neurology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois. The author noted that, although the case series included a limited number of children, the findings suggest that patients would benefit from this approach early in the course of their disease.

Future studies may provide more insight into the effects of risdiplam after OA therapy and clarify the risk-benefit profile of this therapeutic sequence, Kuntz said. In the meantime, real-world data about combination therapies may help parents of children with SMA navigate the increasingly complex therapeutic options and make informed decisions about their children’s care.

The findings were presented Tuesday in a poster session at the 2024 MDA Clinical and Scientific Conference in Orlando, Florida