Early Milestones Reported in Phase II Trial of Risdiplam for Presymptomatic SMA

Dr. Charlotte J. Sumner from Johns Hopkins University School of Medicine presents an editorial commentary on a study led by Richard S. Finkel and colleagues, which reports the results of an open-label Phase II trial investigating risdiplam—a pre-messenger RNA splicing modifier—in infants with presymptomatic spinal muscular atrophy (SMA).

First documented in 1891, SMA is a genetic neuromuscular condition leading to the degeneration of motor neurons in the spinal cord and brainstem. It primarily affects proximal muscles, respiratory muscles, and pharyngeal skeletal muscles.

Striking approximately one in 10,000 births globally, SMA is one of the most common inherited causes of infant mortality, especially outside developed nations. Without effective intervention, about 60% of SMA cases are classified as type 1, where infants develop severe weakness within days or weeks after birth, miss motor milestones, and succumb by age two.

Type 2 SMA patients strengthen enough to sit but not walk, while type 3 allows for some walking. The disease results from recessive loss-of-function genetic variants in SMN1 and decreased expression of the universally essential SMN protein.

A related gene, SMN2, is retained in variable copies but partly compensates due to a nucleotide variation that causes alternative splicing exclusion of exon 7, leading to a truncated and unstable protein. A small percentage of SMN2 mRNAs retain exon 7, producing functional full-length SMN proteins. Typically, type 1 SMA individuals carry two copies of SMN2, whereas types 2 and 3 have three or four.

The underlying mechanism by which SMN deficiency leads to motor neuron degeneration remains unclear.

In her editorial titled "Presymptomatic Treatment of a Genetic Disease with a Small-Molecule Drug," published in New England Journal of Medicine, Sumner discusses insights from the Phase II trial and future directions for SMA treatment using risdiplam.

In this design, eight infants with two SMN2 copies and 18 others with three or more were enrolled via newborn screening to evaluate early daily risdiplam administration. The study measured motor functions and survival, reporting motor milestones at 12 and 24 months, while muscle action potentials were assessed at baseline.

At 12 months, 96% of infants could sit unsupported for five seconds and 81% for 30 seconds. At 24 months, 81% of the remaining 23 children could walk alone.

During the trial, only six out of 26 children developed clinically obvious SMA symptoms (one unable to sit was withdrawn by caregivers, three were unable to walk, and others who were also taken off the study). All of these children had two SMN2 copies. Infants with low baseline muscle action potential (<1.5 mV) later showed clinical disease.

Risdiplam effectively spreads through various tissues and crosses the blood-brain barrier. It is one of three approved therapies for SMA, along with nusinersen (a splice-switching antisense oligonucleotide) and onasemnogene abeparvovec (an adeno-associated virus 9 gene-transfer therapy).

All treatments are more successful when started before symptoms appear, which has propelled many countries to adopt neonatal screening programs for SMA.

In human fetal spinal cords, SMN protein levels peak during development, suggesting that its presence is critical in early motor neuron formation. Timely treatment of SMA likely prevents irreversible neurodegeneration and aids normal motor neuron and muscle development.

More research is necessary to determine long-term outcomes with individual treatments or combinations. Some infants with SMA and two SMN2 copies still exhibit clinical deficiencies despite neonatal interventions.

As the pioneering example of a successful gene-specific RNA-processing drug, risdiplam demonstrates that small-molecule drugs can safely target mRNA. Ongoing research seeks to develop comparable RNA-targeting molecules for other diseases.

Written by our author Justin Jackson, edited by Sadie Harley, and reviewed by Robert Egan—this article represents careful human journalism. We depend on readers like you to support independent science reporting. If this story resonates with you, please consider donating (preferably monthly). As a thank-you for your support, you'll receive an ad-free account.