Onasemnogene Abeparvovec in Patients With <scp>SMA</scp> : Interim Results of the <scp>RESTORE</scp> Registry in Japan

OBJECTIVE: There are limited real-world data regarding the safety and effectiveness of onasemnogene abeparvovec (OA; Zolgensma) infusion, a one-time gene replacement therapy, for Japanese patients with spinal muscular atrophy (SMA). We aimed to improve understanding of the real-world outcomes for OA in Japan. METHODS: We report interim, 5-year results of Japanese post-marketing surveillance of OA (part of the RESTORE registry: NCT04174157). RESULTS: Eighty patients were registered and treated with OA (monotherapy: 30%; bridge or switch to OA: 54%). The median (min, max) age (months) was 3.0 (0, 18) at symptom onset and 10.0 (0, 24) at OA infusion. Forty patients each (50.0%) had two or three survival motor neuron 2 (SMN2) gene copies. Ten patients were identified by newborn screening. Adverse events related to OA were reported in 98.8% (serious: 26.3%; no deaths). Adverse events of special interest occurred in 92.5%, including hepatotoxicity (90.0%), transient thrombocytopenia (62.5%), cardiac adverse events (33.8%), and thrombotic microangiopathy (5.0%). Event-free survival at 3 years since OA administration was 93.0%. There was one death from disease progression. Of 39 patients with two or more developmental milestones, 64.1% achieved new developmental milestones and 15.4% maintained their milestones. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores increased by ≥ 4 points in 81.8% (54/66). INTERPRETATION: The safety profile of OA in Japanese patients with SMA mirrored that of earlier studies. In our real-world observations, patients showed gains in or maintenance of motor milestones or motor function scores that were sustained over the observation period. TRIAL REGISTRATION: NCT04174157 (ClinicalTrials.gov).