Start Spinal Muscular Atrophy Treatment at Birth?

Oral risdiplam (Evrysdi, Genentech) started in the first 6 weeks of life let most infants with presymptomatic spinal muscular atrophy (SMA) reach motor milestones typical of healthy babies, results of the RAINBOWFISH study showed. 

Infants treated before the development of clinical signs or symptoms of SMA had better functional and survival outcomes at 12 and 24 months than 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,” Richard Finkel, MD, director of the experimental neuroscience program, St. Jude Children’s Research Hospital, Memphis, Tennessee, said in a news release. 

The study was published online on August 13 in The New England Journal of Medicine. 

Altering Disease Trajectory

SMA is a rare and often fatal genetic disease that causes progressive muscle weakness. It affects about 1 in 10,000 babies and is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein, critical for the maintenance and function of motor neurons.

Risdiplam is an orally administered, centrally and peripherally distributed small molecule that increases production of the SMN protein.

As reported by Medscape Medical News, the FDA first approved oral risdiplam in 2020 for SMA in children older than 2 years. A label extension was approved 2 years later to include presymptomatic infants younger than 2 months with SMA, based on data from RAINBOWFISH. 

This new open-label study enrolled infants with genetically diagnosed SMA but no strongly suggestive clinical signs or symptoms. All infants were started on daily oral risdiplam (with the dose adjusted to 0.2 mg/kg of body weight) as early as 16 days of age. 

Of the eight children genetically predisposed to the most severe form of SMA, type 1, seven were able to sit at 12 months and five were able to walk by 24 months. 

Of the 18 children with three or more copies of the SMN2 gene (predicting less severe disease), all could sit by 12 months and walk by 24 months, with most reaching these milestones in timeframes comparable to those in children without SMA. 

The beneficial effects of risdiplam were evident across the spectrum of patients treated, but infants with higher SMN2 copy numbers and baseline ulnar compound muscle action potential (CMAP) amplitudes appeared to have more favorable responses, the researchers noted. 

All 23 infants who completed the 24-month assessment were alive without any respiratory support, and all maintained swallowing and oral feeding abilities.

None of the children experienced any major treatment-related adverse events from daily risdiplam treatment. 

Early Treatment Critical

“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. We are no longer just managing symptoms; we are preserving strength, function and quality of life from the very start,” study investigator Aledie Navas, MD, with Nemours Children’s Hospital, Orlando, Florida, said in the release. 

The researchers are now testing the safety and efficacy of giving risdiplam prenatally, with promising early results reported earlier this year. 

In a linked editorial in The New England Journal of the Medicine, Charlotte Sumner, MD, with the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, noted that risdiplam is one of three approved SMN-inducing treatments for SMA. 

The other two treatments are nusinersen, the intrathecally administered, splice-switching antisense oligonucleotide, and onasemnogene abeparvovec, the adeno-associated virus 9 gene-transfer therapy.

“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 pointed out. 

“Sufficiently early SMA treatment probably not only halts irreversible neurodegeneration but also facilitates normal motor-neuron and muscle development,” Sumner noted. 

The RAINBOWFISH study was supported by F. Hoffman-La Roche. Finkel has worked as a consultant and/or received research grants/contracts from Biogen, F. Hoffman-La Roche, Genentech, Novartis, Sarepta, and others. Navas reported no disclosures. Sumner has worked as a consultant and/or received research grants/contracts from Actio biosciences, argenx, Biogen, Cure SMA, F. Hoffman-La Roche AG, Genentech, and others. Full disclosures for all authors are available in the original article.