High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial.

High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial. Nature medicine Finkel, R. S., Crawford, T. O., Mercuri, E., Sumner, C. J., Garcia Romero, M. D., Day, J. W., Montes, J., Sun, P., Tichler, B., Paradis, A. D., Boesch, E., Inra, J., Littauer, R., Sohn, J., Monine, M., Gambino, G., Foster, R., Farewell, R., Fradette, S. 2026

Abstract

Despite the remarkable benefits of nusinersen and other disease-modifying therapies in spinal muscular atrophy (SMA), patients may still experience clinical manifestations of the disease. Here we assessed the potential for high-dose nusinersen to rapidly slow neurodegeneration and lead to improved outcomes for patients. The global, three-part, phase 2/3 DEVOTE trial evaluated the efficacy and safety of high-dose nusinersen (50-mg loading dose; 28-mg maintenance dose) in individuals with SMA. In Part B, treatment-naive individuals (n?=?75) were randomized 2:1 to 50/28?mg or 12/12?mg nusinersen. In a supportive open-label cohort (Part C), nusinersen-experienced individuals (12/12?mg for more than 1 year) were enrolled. The primary endpoint (Part B infantile-onset participants) was a 6-month change in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score comparing 50/28?mg with matched ENDEAR participants (n?=?20) who received sham. DEVOTE met its primary endpoint: at day 183, the CHOP-INTEND total score significantly improved (+15.1 points) in those who received 50/28?mg nusinersen and worsened (-11.1 points) in matched ENDEAR participants who received sham (difference, 26.19 (95% confidence interval?=?20.7 to 31.74); statistical testing was performed using the joint-rank test where the difference in ranks was 26.06 (95% confidence interval?=?17.9 to 34.2; P?

View details for DOI 10.1038/s41591-025-04193-6

View details for PubMedID 41634391

View details for PubMedCentralID 6541434