Interim analysis of the phase 3 CHERISH study evaluating nusinersen in patients with later-onset spinal muscular atrophy (SMA): Primary and descriptive secondary endpoints

Abstract

Objective: Nusinersen is an antisense oligonucleotide that modifies SMN2 pre- mRNA splicing to promote the production of functional SMN protein. In the phase 3, multicenter, randomized, double-blind, sham-procedure controlled CHERISH study (NCT02292537), the clinical efficacy and safety of nusinersen in children with later-onset spinal muscular atrophy (SMA) were assessed. Methods: Children between the ages of 2–12 years with symptomatic SMA were randomized 2:1 (stratified based on age <6 versus ≥>=6 years at screening) to receive 4 doses of nusinersen (12-mg non-scaled) or sham procedure over the 15-month study. Key inclusion criteria include documented 5q SMA homozygous gene deletion or mutation and onset of SMA clinical symptoms at age >6 months. The primary endpoint is change from baseline to month 15 in Hammersmith Functional Motor Scale-Expanded (HFMSE) score. Secondary endpoints include proportion of children at 15 months (1) with ≥>=3-point increase in HFMSE score, (2) who achieve any new motor milestone, (3) with ability to stand alone, and (4) with ability to walk with assistance, as well as the number of motor milestones achieved per child and change from baseline in the revised Upper Limb Module (RULM) test at month 15. Safety and tolerability are also assessed. Results: The CHERISH study has enrolled 126 children with symptomatic SMA. In a pre-planned interim analysis, there was a statistically significant difference in motor function for nusinersen versus sham-control (P=0.0000002) assessed by the HFMSE score at 15 months. Nusinersen demonstrated a favorable safety profile, and no children discontinued the study. Analyses are ongoing; results for interim primary and descriptive secondary endpoints including RULM and motor milestone achievement data will be reported. Conclusion: In this interim analysis, nusinersen-treated children demonstrated clinically and statistically significantly greater improvements in HFMSE score from baseline to 15 months versus control. Nusinersen demonstrated a favorable safety profile.