March 19, 2024

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

Background. Nusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA).

Methods

We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274.

The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills.

Results

In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4. 0 points) and a least-squares mean decrease in the control group (by –1. 9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5. 9 points; 95% confidence interval, 3. 7 to 8. 1; P<0. 001).

This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0. 001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).

Conclusions

Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials. gov number, NCT02292537. )

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