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

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 < 0.0001). The safety profile of 50/28 mg nusinersen was similar to the 12/12 mg regimen. The data support that high-dose nusinersen provides benefit in patients with SMA, with a generally well-tolerated safety profile. ClinicalTrials.gov registration: https://clinicaltrials.gov/study/NCT04089566 . EudraCT no: 2019-002663-10.