Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study

Abstract

Introduction: The EMBRACE study (Clinical Trials No. NCT02462759) evaluated nusinersen in infants/children with infantile- or later-onset spinal muscular atrophy (SMA) who were ineligible for the ENDEAR and CHERISH studies.

Methods: Participants were randomized to intrathecal nusinersen (12-mg scaled equivalent dose; n = 14) or sham procedure (n = 7) in part 1 (~14 months) and subsequently received open-label nusinersen for ~24 months in part 2 of the study.

Results: Part 1 was stopped early after the demonstration of motor function benefit with nusinersen in ENDEAR. There were no nusinersen-related adverse events (AEs) and no study discontinuations due to nusinersen-related AEs. The most common AEs included pyrexia, cough, pneumonia, and upper respiratory tract infections. Motor milestone responder rates were higher in those receiving nusinersen at last available assessment (93%) than in those receiving sham procedure in part 1 (29%) or transitioned from sham to nusinersen in part 2 (83%). This functional improvement was observed despite the small sample size and shortened part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level.

Discussion: Nusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.

Keywords: clinical tria; nusinersen; safety; spinal muscular atrophy; therapeutic use.

Conflict of interest statement

G.A. has participated in advisory boards for AveXis/Novartis, Biogen, Genentech, and Sarepta; and has participated in consultation and speaker engagements for Biogen. T.O.C. has been an advisor/consultant for AveXis/Novartis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Novartis, Roche, Sarepta, and the SMA Foundation. W.M.‐F. has participated in advisory boards for AveXis/Novartis, Biogen, PTC, Roche, and Sarepta; has received honoraria from AveXis/Novartis, Biogen, and PTC; has received research funding from BMBF; and has clinical trial research contracts with Biogen, Santhera, and Sarepta. P.B.S. has participated in advisory boards for Biogen and, outside of the submitted work, has participated in advisory boards for AveXis/Novartis, PTC, and Sarepta. R.R. has participated in advisory boards for AveXis/Novartis and Biogen, and has clinical trial research contracts with Biogen. N.N. has received research funding from Biogen for execution of clinical trial projects and National Institutes of Health funding for site principal investigator work on the HEAL‐EEG study. D.C. has participated in advisory board for AveXis/Novartis, Biogen, PTC, and Sarepta; has received research funding from AveXis/Novartis, Biogen, FibroGen, PTC, ReveraGen, and Sarepta; and has participated in medical advisory boards for GBS‐CIDP Foundation, Myasthenia Gravis Foundation, and the Cure SMA Care Center Network. D.R.‐S., G.G., P.S., and W.F. are employees of and hold stock/stock options in Biogen.

© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.

Figures

FIGURE 1

Participant disposition. Part 2 was terminated early to allow participants to transition to the SHINE study [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Mean (standard error) data for: (A) predose CSF nusinersen concentrations (ng/mL; CSF‐evaluable population), (B) change from baseline in HINE‐2 total milestones, and (C) HINE‐2 total milestones. In A, values considered as outliers were excluded from the analyses and included observed concentrations in day 1 predose samples. Only visits with five or more participants are included. In B and C, only visits with four or more participants are included. For the purposes of comparison, the group that initiated nusinersen in part 2 is graphed from day 0 (first nusinersen dose), and in B the initial baseline HINE‐2 score reset to 0. In all graphs, data at each timepoint are offset to allow visualization of all participant groups. CSF, cerebrospinal fluid; HINE‐2, Hammersmith Infant Neurological Examination Section 2; SE, standard error [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Plasma pNF‐H levels over time in part 1 of the study: (A) geometric mean (95% CI) and (B) geometric mean ratio (95% CI). One participant in the sham procedure group had a pNF‐H level below the limit of quantification at day 64 that was not included in the graph. CI, confidence interval; pNF‐H, phosphorylated neurofilament heavy chain [Color figure can be viewed at wileyonlinelibrary.com]