Safety and Efficacy of Nusinersen in Infants/Children with Spinal Muscular Atrophy (SMA): Part 1 of the Phase 2 EMBRACE Study (P2.324)

Objective: EMBRACE (NCT02462759) Part 1 is a phase 2, double-blind, sham-procedure controlled study assessing the safety/tolerability of intrathecal nusinersen in symptomatic infants/children with spinal muscular atrophy (SMA) who were not eligible to participate in the ENDEAR or CHERISH studies. Background: Nusinersen is an antisense oligonucleotide that modulates splicing of SMN2 precursor mRNA that has demonstrated clinically meaningful efficacy and a favorable benefit-risk profile across SMA populations. Design/Methods: Eligible participants had genetic documented 5qSMA (homozygous SMN1 gene deletion, mutation, or compound heterozygote) and either onset of signs/symptoms consistent with SMA at ≤6 months with 3 SMN2 gene copies; or onset at ≤6 months, >7 months at screening, and 2 SMN2 gene copies; or onset at >6 months, ≤18 months at screening, and 2/3 SMN2 gene copies. Participants were randomized (2:1) to 12-mg equivalent dose nusinersen or sham-procedure and stratified by age at onset >6 vs ≤6 months. Safety/tolerability was the primary endpoint. Exploratory efficacy endpoints included Hammersmith Infant Neurological Examination (HINE) Section 2 motor milestone attainment, change in ventilator use, and growth parameters. Results: EMBRACE Part 1 was terminated early based on positive results from the phase 3 ENDEAR (NCT02193074) study. The safety/tolerability profile of nusinersen in EMBRACE was similar to that observed in previous trials. A larger proportion of nusinersen-treated (11/14; 79%) vs. sham procedure–treated individuals (2/7; 29%) were HINE motor milestone responders. Between the Day 183 and 302 visits, hours of ventilator use changed by a mean (SD) of +1.236 (3.712) hours in nusinersen-treated individuals (n=12) and by +2.123 (3.023) hours in sham procedure–treated individuals (n=7). Similar increases in weight and body length over time were observed in nusinersen-treated and sham procedure–treated individuals by Day 183. Conclusions: In EMBRACE Part 1 nusinersen demonstrated a favorable benefit-risk profile. These results add to the aggregated efficacy, safety/tolerability data of nusinersen in SMA. Study Supported by: Ionis Pharmaceuticals, Inc. (Carlsbad, CA, USA) and Biogen (Cambridge, MA, USA). Disclosure: Dr. Shieh has nothing to disclose. Dr. Acsadi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Avexis, Biogen, Genentech and Serepta. Dr. Mueller-Felber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for AveXis and Biogen. Dr. Mueller-Felber has received research support from clinical trial research contracts with Biogen, Santhera and Sarepta. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor/consultant for AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Novartis, Roche, Sarepta and the Spinal Muscular Atrophy Foundation. Dr. Richardson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Biogen. Dr. Richardson has received research support from clinical trial research contracts with Biogen. Dr. Natarajan has received research support from Clinical trial research contract with Biogen. Dr. Castro has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Sarepta and Marathon. Dr. Gheuens has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Bhan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Bhan holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Gambino has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Gambino holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Sun has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Sun holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Farwell has nothing to disclose. Dr. Reyna has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Reyna holds stock and/or stock options in Holds stock/stock options in Biogen.