1. Intrathecal injections of nusinersen in pediatric later-onset spinal muscular atrophy (SMA) patients were associated with increased clinical motor function scores compared to sham treated patients.
2. The overall safety profile of nusinersen in this trial was comparable to sham treated patients.
Evidence Rating Level: 1 (Excellent)
Study Rundown: SMA is a rare and debilitating autosomal recessive condition that leads to impaired skeletal, bulbar, and respiratory muscle development. Nusinersen, a modified antisense oligonucleotide drug, works to increase protein expression necessary for motor neuron development. In the CHERISH trial, efficacy and safety of nusinersen compared to placebo were evaluated in a pediatric population with later-onset SMA. The primary endpoint of this study was the a clinical motor function score, defined by the change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) score at 15 months post-treatment. Secondary endpoints included the percentage of children with clinically meaningful increases in HFMSE score from baseline and other motor function assessments. Interim analyses revealed significantly greater efficacy of nusinersen in improving patient HFMSE scores compared to sham-treatment, leading to early trial termination. Overall incidence of adverse events were similar between both treatment and sham groups.
Strengths of this trial include genetic disease verification, multicenter design, and a 15 month follow-up period, while a notable limitation is exclusion of patients with severe disease manifestations limiting generalizability. Collectively, these results suggest that nusinersen may be a useful therapy option for patients with SMA.
In-Depth [randomized controlled trial]: This multicenter, phase 3, double-blind, sham-controlled study conducted from 2014 to 2017 randomized 126 patients into two treatment arms based on a 2:1 ratio: nusinersen (n = 84) or placebo (n = 42). Eligible patients had genetic SMA documentation, symptom onset after 6 months of age, and were 2 to 12 years old. Excluded patients had severe contractures or scoliosis, or respiratory insufficiency. Both groups received scheduled 12mg intrathecal administrations of nusinersen or a placebo on days 1, 29, 85, and 274 of the trial. The primary endpoint of change in HFMSE from baseline was measured at 15 months.
At interim analysis, the mean change in HFMSE scores increased in the nusinersen group (+4.0 points, indicating improved motor function) and decreased in the placebo group (-1.9 points), leading to a net difference of 5.9 points between the two treatment arms (95% confidence interval [CI], 3.7 to 8.1, p < 0.001). This net difference during the study’s final analysis confirmed the interim results (+3.9 points nusinersen; -1.0 control; mean difference 4.9 points, 95% CI, 3.1 to 6.7). A higher percentage of children assigned to the nusinersen treatment arm were noted to have clinically meaningful improvements in HFMSE scores compared to placebo (57% nusinersen vs 26% placebo, p < 0.001). There were no noted significant differences between groups in the percentage of children who achieved at least one new World Health Organization (WHO) motor milestone (20% vs 6%, p = 0.08). From a safety standpoint, overall incidence of adverse events was comparable in both treatment groups (93% nusinersen, 100% control), as was incidence of severe events (17% nusinersen, 29% control). The most common adverse events included pyrexia, upper respiratory tract infection, headache, and vomiting.
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