Initial RCT Data Support Safety, Efficacy of Nusinersen in SMA

Across the studies of a new analysis, there was a significant risk difference in motor milestone response and improvement in Hammersmith Infant Neurological Examination score.

Although more well-designed randomized controlled trials (RCTs) are needed to confirm the safety and efficacy of Spinraza (nusinersen) in infants with spinal muscular atrophy (SMA), initial findings from available RCTs are favorable, say researchers about findings published in Medicina (Kaunas).

The group compiled data from 3 trials—ENDEAR, CHERISH, and EMBRACE—for their meta-analysis comprising close to 300 patients, 178 of whom received nusinersen. Compared with controls, patients receiving the antisense oligonucleotide inhibitor showed clinically meaningful motor responses and improvements in neuromuscular function.

“Despite nusinersen’s promising efficacy results, none of the babies administered nusinersen achieved normal motor development, some required continuous feeding and mechanical ventilation, and some babies even died,” described the researchers. “These results show that nusinersen is not curative in symptomatic patients. However, our results showed improvement in total milestones.”

Across the studies, there was a significant risk difference (RD) in both motor milestone response (RD, 0.51; 95% CI, 0.39-0.62; P < .00001) and improvement in Hammersmith Infant Neurological Examination (HINE-2) score (RD, 0.26; 95% CI, 0.12-0.40; P < .00003) for patients receiving nusinersen vs controls.

The meta-analysis also explored adverse events (AEs) throughout the trials, and findings show that although there were not significant differences in any AEs and serious AEs, patients receiving nusinersen were significantly less likely to experience severe AEs (risk ratio [RR], 0.72; 95% CI, 0.57-0.92; P = .007) and to discontinue treatment due to an AE (RR, 0.40; 95% CI, 0.22-0.74; P = .004).

No patients in the EMBRACE and ENDEAR trials discontinued treatment due to a nusinersen-related AE, although the EMBRACE trial reported that 13 of 80 patients receiving nusinersen discontinued treatment vs 16 of 41 controls due to an AE.

The most common AEs included pyrexia, vomiting, constipation, and cough. Respiratory distress was more commonly reported in patients receiving nusinersen, even though the mean percentage time on ventilator support was significantly lower among these patients: 11.3% vs 29.8%.

“Future investigations will be enhanced by the use of identical inclusion criteria and outcome measures. More stringent criteria for the selection of articles, including ages and rating scales, will enhance future reviews when there are many more articles to include,” wrote the researchers of future studies. “A further limitation of the present meta-analysis is the small number of available RCTs with outcomes that were suitable for pooling through meta-analysis; thus, more RCTs are needed before making clinical recommendations based on these studies.”

The researchers also flagged discrepancies in the 3 RCTs included in their meta-analysis. For example, the ENDEAR trial included only patients with infantile-onset SMA and used both the HINE-2 score and the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders score to evaluate motor milestone response among patients. Meanwhile, the EMBRACE trial, including infantile-onset and later-onset SMA, and the CHERISH trial, including only later-onset SMA, used only the HINE-2 score to evaluate response.


Abbas KS, Eltras MM, El-Shahat NA, Abdelazeem B, Shaqfeh M, Brašic ́JR. The safety and efficacy of nusinersen in the treatment of spinal muscular atrophy: a systemic review and meta-analysis of randomized controlled trials. Medicina (Kaunas). Published online February 1, 2022. doi:10.3390/medicina58020213

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