Early Treatment with Risdiplam Provides Significant Benefit for Infants with Spinal Muscular Atrophy

Early Treatment with Risdiplam Provides Significant Benefit for Infants with Spinal Muscular Atrophy

A majority of infants with presymptomatic spinal muscular atrophy (SMA) treated with risdiplam achieved important motor milestones after 12 months of treatment without experiencing significant adverse events, according to data from the RAINBOWFISH trial presented at the 2024 MDA Clinical and Scientific Conference in Orlando, Florida.

In infants with SMA, motor neuron degeneration caused by a deficiency of survival motor neuron (SMN) protein begins before the onset of symptoms. Previous clinical studies have shown that the early initiation of treatment can improve response to disease-modifying therapies and outcomes in individuals with SMA (Motyl AAL and Gillingwater TH; Cell Rep Med 2022; 3:100725). Risdiplam, an oral SMN2 pre-mRNA splicing modifier that increases and sustains functional SMN protein levels, has been approved for the treatment of SMA in more than 100 countries. RAINBOWFISH is an ongoing, single-arm, multicenter study that was designed to assess the safety and efficacy of risdiplam in infants with genetically diagnosed, presymptomatic SMA.

“Presymptomatic is a broad term,” said lead author Richard Finkel, MD, a pediatric neurologist at St. Jude Children’s Research Hospital in Memphis, Tennessee. “I think today we would look at the criteria and say that this probably included some babies who were early symptomatic. But, at the time, it made sense [to call them presymptomatic].”

The study enrolled 26 infants who received their first dose of risdiplam between 16 and 41 days after birth. Of those who had two copies of the SMN2 gene and baseline ulnar compound muscle action potential (CMAP) amplitude ≥1.5 mV, 80% met the primary endpoint of sitting without support for at least 5 seconds by month 12. Moreover, seven of the eight infants with two SMN2 copies were able to sit without support for at least 30 seconds, including all three children with a lower CMAP amplitude (<1.5 mV). The analysis showed that 92% of the enrolled infants were able to sit without support by 12 months and many were able to stand and walk.

“There is a limitation here because we did not say they were sitting or standing or walking until we could confirm it in the clinic,” Finkel explained. “Sometimes they might have started it one or two months before, but it did not count until we could actually observe it. We did not use video confirmation like some of the other studies. This was very conservative.”

All infants were alive 12 months after treatment initiation and none required permanent ventilation. No major adverse events (AEs) were reported, allowing for continuation of treatment in all participants. The authors noted that the most common AEs, including teething, pyrexia, gastroenteritis, eczema, constipation, and diarrhea, were more reflective of the age of the infants rather than the underlying SMA. Most AEs were not considered treatment-related and resolved over time. Only one participant met the criteria for the development of clinically manifested SMA at 12 months.

“The really important point is that the infants did well with their bulbar function,” Finkel said. “All 26 were swallowing, feeding, had no abnormal speech and no [need for] ventilation. It wasn’t just the motor function that improved.”   

The author noted that findings from the RAINBOWFISH trial were instrumental in the approval of a label extension for risdiplam to include the treatment of children with SMA younger than 2 months.