Open-label phase 4 trial evaluating nusinersen after onasemnogene abeparvovec in children with spinal muscular atrophy.

BACKGROUND Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disease caused by deletions or mutations of the survival motor neuron 1 gene. Despite the availability of genetically-based treatments for SMA, functional impairments and weakness persist in treated symptomatic individuals. This study addresses whether additional treatment after gene transfer therapy could provide further clinical benefits. METHODS Interim Day 302 findings are described from the phase 4 open-label RESPOND trial evaluating nusinersen in participants aged ≤ 36 months who had suboptimal clinical status following onasemnogene abeparvovec (OA) treatment, as determined by the investigator. RESULTS Thirty-seven participants included in the interim analysis were symptomatic at the time of OA administration. Most (92%) had two survival motor neuron 2 gene copies. Age at first nusinersen dose (median [range]) was 9.1 (3-33) months for participants with two SMN2 copies and 34.2 (31-36) months for those with three SMN2 copies, while time from OA dose to first nusinersen dose (median [range]) was 6.3 (3-31) and 13.3 (10-22) months, respectively. Participants had elevated neurofilament light chain (NfL) levels and low compound muscle action potential (CMAP) amplitudes at baseline, suggesting active neurodegeneration and severe denervation at study entry. Improvements from baseline were observed across a range of outcomes at Day 302, including motor function outcomes (HINE-2 and CHOP-INTEND total score), achievement of independent sitting, NfL levels, CMAP, and investigator- and caregiver-reported outcomes. Mean NfL levels decreased rapidly from baseline to Day 183 and remained low at Day 302. Mean ulnar and peroneal CMAP amplitudes increased. No safety concerns were identified. CONCLUSION Improvements in clinical and biomarker outcomes support the benefit of nusinersen treatment in infants and children with suboptimal clinical status following OA. TRIAL REGISTRATION CLINICALTRIALS gov ID, NCT04488133; EudraCT number, 2020-003492-18. FUNDING This study was sponsored by Biogen (Cambridge, MA, USA).