Efficacy and safety of nusinersen in children with later-onset spinal muscular atrophy (SMA): results of the phase 3 CHERISH study

Background/Purpose: Nusinersen is an antisense oligonucleotide for the treatment of SMA that alters SMN2 gene splicing to promote the production of full-length SMN protein. The phase 3, multicenter, randomized, double-blind, sham-procedure controlled CHERISH study (NCT02292537) assessed the efficacy and safety of nusinersen in children with later-onset SMA.

Methods: Children with symptomatic SMA aged 2-12 years were randomized 2:1 (stratified based on screening age <6 versus ≥6 years) to receive 4 doses of intrathecal nusinersen (12mg non-scaled) or sham procedure over 15 months. Key inclusion criteria include confirmed 5q SMA and onset of SMA clinical symptoms at age >6 months. The primary endpoint was change in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at month 15. Secondary endpoints included proportion of children with ≥3-point increase in HFMSE score, proportion with achievement of new WHO motor milestones, and change in revised Upper Limb Module (RULM) test at month 15. Safety/tolerability were also assessed.

Results: At the time of this pre-specified interim analysis (August 31, 2016), CHERISH enrolled 126 children. A highly clinically and statistically significant difference in motor function as assessed by mean HFMSE score at 15 months was observed between the nusinersen and sham-control group (least square mean treatment difference [95% CI] = 5.9 [3.7,8.1] points; P = 0.0000002). HFMSE scores increased ≥3 points in 57.3% of nusinersen-treated versus 20.5% of sham-treated children; 17.1% versus 10.5% achieved new WHO motor milestones, respectively. Greater improvement in RULM score was observed in the nusinersen versus sham-control group (least square mean treatment difference = 3.4 points). Nusinersen demonstrated a favorable safety profile consistent with other published results, and no children discontinued the study or treatment. Additional secondary endpoints will be reported.

Conclusions: Significant improvements in motor function were observed in nusinersen- versus sham-treated children. Nusinersen demonstrated a favorable safety profile. Children from CHERISH will be transitioned into the SHINE (NCT02594124) open-label extension study.

Disclosures: Study supported by Ionis Pharmaceuticals, Inc. and Biogen. Writing and editorial support for the preparation of this presentation was provided by Excel Scientific Solutions (Southport, CT, United States): funding was provided by Biogen

Authors Disclosures: JK: advisory boards for Roche, Ionis Pharmaceuticals, Inc., Biogen, and AveXis for SMA studies. EM: advisory boards for SMA studies for Avexis, Biogen, Ionis Pharmaceuticals, Inc., Novartis and Roche; principal investigator for ongoing Ionis/Biogen and Roche clinical trials; receives funding from Famiglie SMA Italy, Italian Telethon and SMA Europe. RSF: grants and personal fees from Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; grants and advisor fees from Biogen, grants from Cytokinetics and advisor to Roche outside the submitted work; advisory capacity to non-profit organizations: the SMA Foundation, Cure SMA, SMA Reach (UK) and SMA Europe; serves on the Data Safety Monitoring Board for the AveXis gene transfer study. CAC: advisory boards for Roche, Ionis Pharmaceuticals, Inc., Biogen, and AveXis for SMA studies; grants from Ionis Pharmaceuticals, Inc., Biogen and the SMA Foundation. NK: advisory boards for Biogen; outside of the submitted work, advisory boards and consulting fees for AveXis, Catalyst, Cytokinetics, Marathon, PTC, and Sarepta; advisory capacity to CureSMA and MGFA. BTD: scientific advisory board consultant for AveXis, Biogen, Marathon Pharmaceuticals, Sarepta, Cytokinetics, PTC Therapeutics and Roche; advisor for Ionis Pharmaceuticals, Inc.; Receives research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA and the SMA Foundation, grants from Ionis Pharmaceuticals during ENDEAR, CHERISH, CS12, CS11 studies, Cytokinetics, Sarepta, PTC, Summit and Fibrogen. PBS: advisory boards for Biogen; outside of current submitted work: Advisory boards for AveXis, Marathon, PTC, and Sarepta; Clinical trial research contracts with Biogen, Ionis, PTC, Sarepta, Marathon, Catalyst, Ultragenyx, Pfizer, and BMS. KS: advisory for Biogen and Roche/Chugai. Research fund for IONIS Pharmaceuticals; Received research funding from Biogen and Roche/Chugai for research consultation and from IONIS Pharmaceuticals Inc. for execution of clinical trial projects. DCD: advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Roche, Sarepta and the SMA Foundation, with no financial interests in these companies; grants from the Department of Defense, Hope for Children Research Foundation, the National Institutes of Health and the SMA Foundation ESM: advisory board for Biogen and Roche; consultant for Ionis Pharmaceuticals, Inc., Cytokinetics, and Roche. JM: advisory board for Biogen and Roche; consultant to Ionis Pharmaceuticals, Inc.; Receives support from Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) 1K01HD084690-01A1. QY, CFB, and ES: employees of and hold stock/stock options in Ionis Pharmaceuticals, Inc. ZJZ, SG and WF: employees of and hold stock/stock options in Biogen.