Early Motor Development Observed in Phase II Risdiplam Trial for Presymptomatic SMA

A recent open-label Phase II clinical trial has showcased promising results regarding early motor milestones in infants treated with risdiplam, a small-molecule drug designed to modify RNA splicing in the context of spinal muscular atrophy (SMA). Led by Richard S. Finkel and colleagues, the study examined the effects of initiating risdiplam therapy in presymptomatic infants identified through newborn screening. The trial involved infants with two or more copies of the SMN2 gene, which influences disease severity.

SMA is a hereditary neuromuscular disorder characterized by the degeneration of motor neurons in the spinal cord and brainstem, leading to muscle weakness and paralysis. It affects approximately one in 10,000 births, with severe forms causing significant morbidity and mortality early in life. The genetic basis involves mutations or deletions in the SMN1 gene and reliance on the compensatory but less efficient SMN2 gene.

The study enrolled infants before the onset of symptoms and monitored their motor development over 12 and 24 months. Results indicated that at 12 months, an impressive 96% were able to sit unsupported for five seconds, and 81% could do so for 30 seconds. By 24 months, 81% of the remaining participants could walk independently. Well before the appearance of clinical symptoms, most infants showed normal or near-normal motor development, highlighting the importance of presymptomatic treatment.

Only a small subset of children developed clinical SMA during the trial; notably, all of these children carried two copies of SMN2, with those having the lowest baseline muscle action potentials showing subsequent disease. Risdiplam's ability to cross the blood-brain barrier and its broad tissue distribution contribute to its effectiveness. It is one of three approved treatments for SMA, alongside nusinersen and onasemnogene abeparvovec.

Administering these treatments early, ideally before symptoms manifest, significantly enhances outcomes. This approach has led to the implementation of newborn screening programs across numerous countries, enabling early diagnosis and prompt initiation of therapy. The observed peak in SMN protein levels during fetal development suggests that early intervention may not only prevent neurodegeneration but also promote proper motor neuron and muscle development.

Despite these advances, many infants with SMA and multiple copies of SMN2 still experience residual motor deficits. Continued research aims to understand the long-term outcomes of single and combination therapies. Risdiplam's success as a targeted RNA-processing agent demonstrates the potential for small-molecule drugs to safely and effectively modulate gene expression, opening avenues for treating other genetic diseases.

Source: https://medicalxpress.com/news/2025-08-phase-ii-trial-early-motor.html