Oral risdiplam (Evrysdi, Genentech) administered within the first six weeks of life has enabled most infants with presymptomatic spinal muscular atrophy (SMA) to achieve motor milestones typical of healthy babies, according to the RAINBOWFISH study. The findings, published in The New England Journal of Medicine, highlight the potential of early intervention in altering the disease trajectory.
Infants treated before the onset of clinical signs or symptoms of SMA demonstrated significantly better functional and survival outcomes at 12 and 24 months compared to untreated infants in natural history studies. “The impact of giving risdiplam soon after birth is quite dramatic. By age 2, we saw most of the children who we had treated were walking and in good general health,” said Dr. Richard Finkel, director of the experimental neuroscience program at St. Jude Children’s Research Hospital, Memphis, Tennessee.
Understanding Spinal Muscular Atrophy and Risdiplam
SMA is a rare and often fatal genetic disease characterized by progressive muscle weakness. It affects approximately 1 in 10,000 babies and is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which is crucial for the maintenance and function of motor neurons. Risdiplam, an orally administered small molecule, increases the production of the SMN protein, offering a new avenue for treatment.
The U.S. Food and Drug Administration (FDA) first approved oral risdiplam in 2020 for children older than two years with SMA. In 2022, the approval was extended to include presymptomatic infants younger than two months, based on data from the RAINBOWFISH study.
RAINBOWFISH Study: Key Findings
The open-label study enrolled infants genetically diagnosed with SMA but without significant clinical signs or symptoms. These infants began daily oral risdiplam treatment as early as 16 days old, with doses adjusted to 0.2 mg/kg of body weight.
Among the eight children predisposed to the most severe form of SMA, type 1, seven were able to sit by 12 months, and five could walk by 24 months. Of the 18 children with three or more copies of the SMN2 gene, all could sit by 12 months and walk by 24 months, with most achieving these milestones within typical timeframes for children without SMA.
All 23 infants who completed the 24-month assessment were alive without respiratory support, maintaining swallowing and oral feeding abilities, and none experienced major treatment-related adverse events.
The Importance of Early Treatment
Dr. Aledie Navas from Nemours Children’s Hospital in Orlando, Florida, emphasized the transformative potential of early treatment, stating, “For families facing a diagnosis of SMA, the results of this study offer real hope. Treating children before symptoms appear — when they are still developing normally — can change the entire trajectory of the disease.”
Researchers are now exploring the safety and efficacy of administering risdiplam prenatally, with promising early results reported earlier this year. This proactive approach could further enhance outcomes for those at risk of SMA.
Comparative Treatments and Future Directions
In a related editorial, Dr. Charlotte Sumner from Johns Hopkins University School of Medicine noted that risdiplam is one of three approved SMN-inducing treatments for SMA, alongside nusinersen and onasemnogene abeparvovec. “All three drugs are substantially more effective when started before symptom onset, which has prompted neonatal screening programs for SMA in many countries to hasten treatment initiation,” Sumner explained.
She further highlighted that early treatment could not only halt irreversible neurodegeneration but also facilitate normal motor-neuron and muscle development, offering a brighter future for affected infants.
The RAINBOWFISH study was supported by F. Hoffman-La Roche. Dr. Finkel has collaborated with various pharmaceutical companies, while Dr. Navas reported no disclosures. Full author disclosures are available in the original article.
As research continues, the medical community remains hopeful that these advancements will lead to improved quality of life for those affected by SMA, underscoring the critical role of early diagnosis and intervention.
