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High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial.
Richard S Finkel1, Thomas O Crawford2, Eugenio Mercuri3,4
1St. Jude Children's Research Hospital, Memphis, TN, USA. richard.finkel@stjude.org.
Nature Medicine
|February 3, 2026
Summary
High-dose nusinersen significantly improved outcomes in spinal muscular atrophy (SMA) patients, as shown by the DEVOTE trial. This higher dosage demonstrated a favorable safety profile, similar to standard doses, supporting its clinical benefit.
Area of Science:
- Neurology
- Genetics
- Clinical Trials
Background:
- Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder.
- Current disease-modifying therapies, including nusinersen, offer benefits but may not fully address all clinical manifestations.
- There is a need to explore higher-dosage regimens for potentially enhanced efficacy.
Purpose of the Study:
- To evaluate the efficacy and safety of a high-dose nusinersen regimen in individuals with SMA.
- To assess if high-dose nusinersen can rapidly slow neurodegeneration and improve patient outcomes.
- To compare the effects of high-dose nusinersen against standard doses and placebo in a randomized controlled trial.
Main Methods:
- The global, phase 2/3 DEVOTE trial (NCT04089566) included treatment-naive SMA patients randomized to high-dose (50/28 mg) or standard-dose (12/12 mg) nusinersen.
- Part B focused on treatment-naive infants, with the primary endpoint being the 6-month change in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score.
- A comparison was made with matched participants from the ENDEAR trial who received sham treatment.
Main Results:
- The DEVOTE trial met its primary endpoint, showing a significant improvement in CHOP-INTEND scores at 183 days for patients receiving high-dose nusinersen (+15.1 points) compared to sham-treated controls (-11.1 points).
- The difference in CHOP-INTEND score change between the high-dose group and sham group was 26.19 (95% CI: 20.7 to 31.74; P < 0.0001).
- The safety profile of the high-dose (50/28 mg) nusinersen regimen was comparable to the standard 12/12 mg dose, indicating good tolerability.
Conclusions:
- High-dose nusinersen demonstrates significant efficacy in improving motor function in infants with SMA.
- The safety profile of high-dose nusinersen is similar to the standard dose, suggesting it is well-tolerated.
- These findings support the use of high-dose nusinersen as a beneficial treatment option for patients with SMA.
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