- The first prenatal treatment for spinal muscular atrophy showed promise in a single case report.
- Risdiplam was given to the mother during pregnancy and to the child after birth.
- More than 2 years later, the child shows no features of the disease.
The first prenatal therapy for spinal muscular atrophy (SMA) showed promising results, a case report indicated.
More than 2 years after the child was born, no identifiable features of SMA have been observed, reported Richard Finkel, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and colleagues in a correspondence to the New England Journal of Medicine.
The child was treated in utero with risdiplam (Evrysdi), which is approved to treat SMA in pediatric and adult patients, and continues to receive the oral drug daily.
SMA is caused by reduced levels of survival motor neuron (SMN) protein due to deletions or mutations of the SMN1 gene. A nearly identical gene, SMN2, produces low levels of functional SMN protein.
Risdiplam is an SMN2 pre-mRNA splicing modifier designed to increase and sustain SMN protein levels centrally and peripherally. It’s one of three drugs approved for SMA, the others being nusinersen (Spinraza) and onasemnogene abeparvovec (Zolgensma).
In the St. Jude’s case, the child was at risk for type 1 SMA, a severe form of the disease, due to family history and was tested for SMA through amniocentesis. Testing showed no copies of SMN1 and two copies of SMN2, which is predictive of type 1 SMA. If not treated, type 1 SMA results in progressive muscle weakness that leads to death.
Widespread newborn screening for SMA has been in place across the U.S. since 2018, and all 50 states now screen for it. Though newborn screening has helped infants with SMA be treated earlier and have better motor outcomes, it may not be enough for some children.
“Even with newborn screening and identification of babies with SMA shortly after birth, and with prompt initiation of one of the three FDA-approved drugs for SMA, it is now apparent that a substantial proportion of these babies — mainly those with the genotype predictive of type 1 SMA — lag behind in their motor development and, in some cases, have limitations in feeding and respiratory status,” Finkel told MedPage Today.
“This observation, along with neuropathological data to indicate that the neurodegenerative process in SMA begins in utero, generated the idea of starting treatment in utero,” he said.
“The overarching goal in this first case study was to demonstrate feasibility of prenatal therapy with one of these drugs, generate safety data, and gather biomarker and clinical data that might give a hint of improved efficacy when compared to initiation of treatment postnatally,” he added.
In this single-patient case approved by the FDA, researchers administered risdiplam orally to the mother at 5 mg/day during the last 6 weeks of pregnancy. The mother was monitored weekly for drug-related side effects and the fetus was monitored for growth, activity, and anatomical development through ultrasonography.
Risdiplam was subsequently administered orally to the infant 8 days after birth and has been continued daily to the present time (at 30 months of age in February 2025).
The infant appeared normal at birth but was identified postnatally to have a heart murmur due to a ventricular septal defect, which resolved.
The infant has optic nerve hypoplasia and a brainstem asymmetry, with related delays in vision and overall development. Risdiplam prescribing information states the drug may cause fetal harm in pregnancy, but the abnormalities in this case were considered to have occurred early in fetal development, before risdiplam exposure.
No features of SMA, including hypotonia, weakness, areflexia, or fasciculation, have emerged to date, Finkel and colleagues said. Motor function, muscle ultrasonographic, and electrophysiological studies have been performed every 6 months and have shown normal peripheral nerve and muscle development for the child’s age.
The case study may generate further discussion in the SMA community about whether prenatal treatment should be pursued further in formal clinical trials, Finkel observed.
“I get one or two inquiries a month of similar cases, so this is not so rare,” he said. “It may offer another option for some babies that could optimize the response to treatment during a time of high motor neuron vulnerability.”
Disclosures
This study was sponsored by St. Jude Children’s Research Hospital. F. Hoffmann-La Roche provided scientific advice, advised on the safety of prenatal exposure, and supplied risdiplam at no cost as an investigational product.
Finkel reported relationships with Biogen, F. Hoffmann-La Roche, Genentech, Ionis, Novartis, Scholar Rock, and Elsevier Publishing, and holds several patents.
Several co-authors were employees of F. Hoffmann-La Roche. No other conflicts of interest were reported.
Primary Source
New England Journal of Medicine
Source Reference: Finkel RS, et al “Risdiplam for prenatal therapy of spinal muscular atrophy” N Engl J Med 2025; DOI: 10.1056/NEJMc2300802.
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