Real-World Outcomes Following Onasemnogene Abeparvovec in Patients with SMA and One SMN2 Gene Copy: Findings from the RESTORE Registry


Clinical Management

Poster Number: S102


Richard Finkel, MD, Center for Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, Katherine Mathews, MD, FAAN, University of Iowa, Saunder Bernes, MD, PHOENIXCHILDRENS, Arpita Lakhotia, MD, Norton Children’s, Eduardo Tizzano, MD, PhD, Hospital Vall d’Hebron, Dheeraj Raju, PhD, Novartis Gene Therapies, Inc., Kamal Benguerba, MD, Novartis Gene Therapies Switzerland GmbH, Sandra Reyna, MD, Novartis, Omar Dabbous, MD, Novartis Gene Therapies, Inc., Laurent Servais, MD, PhD, University of Oxford

Background: Spinal muscular atrophy (SMA) severity generally correlates with SMN2 gene copy number. Patients with only one SMN2 copy are at risk for the most severe SMA phenotype, characterized by profound hypotonia and respiratory insufficiency at birth and a rapidly progressive and fatal course. Clinical trials of onasemnogene abeparvovec (OA), a one-time gene therapy for SMA, did not include patients with one SMN2 copy. Therefore, little is known about treatment outcomes in these patients, who may receive treatment in real-world practice.
Objective: To describe outcomes following OA for patients with SMA and one SMN2 copy enrolled in RESTORE, a multinational, noninterventional SMA registry.
Results: As of May 23, 2023, RESTORE enrolled four OA-treated patients with one SMN2 copy. All were treated in the United States and identified by newborn screening. One patient was bridged to OA with nusinersen from 1–3 months of age, and also received add-on therapy with risdiplam, initiated at 13 months of age. Median age at OA was 1.5 months (range, 1–2). Median follow-up since OA was 22.5 months (range, 19–32). All patients were alive at data cutoff. Three patients received ventilatory support, all before OA. Baseline CHOP INTEND score of 15 was recorded for one patient. Post-OA CHOP INTEND was recorded for all patients; all achieved scores >40 or significant (≥4 points) improvements during the observation period. All patients achieved head control. One patient sat independently, and two patients walked with assistance. Adverse events were recorded for two patients. None were serious and treatment-related, and event types were consistent with the established safety profile of OA. Investigation of potential gene modifier is ongoing.
Conclusions: SMA patients with one SMN2 copy survived and achieved significant motor improvements after OA, indicating positive benefit/risk in these particularly vulnerable children.