Safety and Effectiveness of Onasemnogene Abeparvovec (OA) Alone or with Other Disease-Modifying Therapies (DMTs): Findings from RESTORE

We aimed to describe real-world safety and effectiveness of OA alone or in combination with other DMTs for patients with SMA. RESTORE is an ongoing, prospective, multicenter, multinational, observational SMA patient registry. We evaluated patients with 2 or 3 SMN2 gene copies receiving OA alone or with any other DMTs. As of Nov. 23, 2021, data were available for 247 patients who received OA: 121 (49.0%) received OA alone (group 1); 48 (19.4%) received OA before (group 2); and 78 (31.6%) received OA after (group 3) another DMT. All patients in group 3 received nusinersen, and none received risdiplam. Of patients with ≥2 milestone assessments (≥1 post-OA administration; n=112), 71 (63.4%) achieved new milestones: 35 (49.3%) in group 1, 15 (21.1%) in group 2, and 21 (29.6%) in group 3. There was no significant difference in time to first milestone achievement after OA administration among groups (p=0.2). Median changes in CHOP INTEND scores for Groups 1, 2, and 3 were 11 (n=43; 38 [88.4%] achieved increase of ≥4 points), 11 (n=19; 16 [84.2%] achieved increase of ≥4 points), and 4 (n=33; 20 [60.6%] achieved increase of ≥4 points), respectively. Median changes in HFMSE scores for groups 1, 2, and 3 were 13.5 (n=12; 10 [83.3%] achieved increase of ≥3 points), 5 (n=9; 6 [66.7%] achieved increase of ≥3 points), and 4 (n=10; 7 [70%] achieved increase of ≥3 points), respectively. Median changes in HINE scores for groups 1, 2, and 3 were 6.5 (n=14), 6.5 (n=6), and 3.5 (n=8), respectively. Any-grade treatment-emergent AEs were recorded in groups 1, 2, and 3 for 51 (42.2%; 23 [19.0%] with grade ≥3), 28 (58.3%; 15 [31.3%] with grade ≥3), and 49 (62.8%; 26 [33.3%] with grade ≥3) patients, respectively. No new safety signals were identified. Real-world effectiveness was observed for patients receiving OA monotherapy and in patients who switched from nusinersen or who received subsequent DMTs. Patients who received nusinersen experienced more frequent and severe AEs.