Safety and Efficacy of Intravenous Onasemnogene Abeparvovec in Pediatric Patients with Spinal Muscular Atrophy: Findings from the Phase 3b SMART Study


Clinical Trials

Poster Number: S110


Hugh McMillan, MD, Children’s Hospital of Eastern Ontario, Giovanni Baranello, MD, PhD, University College London Great Ormond Street Institute of Child Health, Michelle Farrar, PhD, School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Craig Zaidman, MD, Washington University in St. Louis School of Medicine, Julia Seibert, PhD, Novartis Pharmaceuticals, Roberto Bernardo, MD, Novartis Global Drug Development – Neuroscience, Iulian Alecu, MD, Novartis Pharmaceuticals, Frank Freischläger, Freischläger Consulting, Francesco Muntoni, FRCPCH, FMedSci, University College London, National Institute for Health Research Great Ormond Street Hospital

Background: Clinical trials have demonstrated safety and efficacy of intravenous onasemnogene abeparvovec for patients with spinal muscular atrophy (SMA) weighing <8.5 kg. Objective: SMART was a phase 3b study to evaluate the safety, tolerability, and efficacy of intravenous onasemnogene abeparvovec over 52 weeks for patients weighing ≥8.5 to ≤21 kg. Results: Of 24 enrolled patients, seven, eight, and nine were in the 8.5–13 kg, >13–17 kg, and >17–21 kg weight groups, respectively. Nineteen discontinued prior nusinersen; 2 discontinued prior risdiplam; 3 were treatment-naïve. No study withdrawals or deaths occurred. All patients had ≥1 TEAE; 15/24 (62.5%) had ≥1 SAE; 7/24 (29%) had SAEs related to onasemnogene abeparvovec. 20/24 patients (83.3%) had aminotransferase elevation adverse events; all cases were asymptomatic and managed with prophylactic prednisolone. Transaminase elevations (all Grade 1) were ongoing in 14 patients at the end of study. No bilirubin elevations or Hy’s law cases were observed. Steroids were used over a median of 175.0 days. Transient thrombocytopenia was reported in 17/24 patients (70.8%); all resolved with no reported bleeding events. 3/24 patients (13%) had cardiac AEs (all unrelated to onasemnogene abeparvovec). No events of thrombotic microangiopathy or dorsal root ganglionopathy were observed. Frequency/severity of AEs were similar across weight groups. Motor function (RULM, HFMSE, and motor milestones) was maintained or improved for most patients. Mean (SD) change from baseline at Week 52 was 2.0 (4.0) for RULM and 3.7 (4.73) for HFMSE. By Week 52, three patients achieved standing with assistance, one patient achieved independent standing, and one patient achieved walking with assistance.
Conclusions: The safety of onasemnogene abeparvovec in SMART was consistent with previously reported findings. Most patients experienced transaminase elevations with no difference between weight groups; all cases were asymptomatic and managed with steroids. Most patients maintained or improved motor function, suggesting clinical benefit of intravenous onasemnogene abeparvovec for heavier patients with SMA.