Background: Onasemnogene abeparvovec (OA) is an adeno-associated viral (AAV) vector gene therapy for SMA in children age <2 years. Animal models and limited human postmortem studies have demonstrated incomplete transduction of motor neurons by the AAV9 vector. Nusinersen has potential to increase SMN protein in untransduced motor neurons, which may provide additional clinical benefit to individuals with SMA. RESPOND (NCT04488133) is a single-arm study evaluating nusinersen in children with SMA treated with OA ≥2 months previously. Study participants have ≥1 SMN2 copy, are age ≤36 months, nusinersen-naïve, and have suboptimal clinical status at baseline. Suboptimal clinical status (investigator-determined) includes ≥1 of these domains: motor function, respiratory support, swallowing/feeding ability, and other. Participants receive the approved 12-mg nusinersen regimen: 4 loading doses followed by maintenance doses every 4 months. Recruitment is ongoing.
Objectives: To provide baseline characteristics and interim safety findings in RESPOND.
Results: As of 15 August 2022, 34 children were enrolled and dosed. Median time from OA treatment to first nusinersen dose was 6.9 (range: 3–31) months. At baseline, 28/34 children demonstrated suboptimal clinical status in ≥2 domains after OA treatment; motor function (n=33) and respiratory function (n=22) were most common. Baseline mean±SD HINE-2 total score was 6.7±5.7 (n=33). Median duration on nusinersen was 183 (range: 1–540) days. Thirty of 34 participants had 2 SMN2 copies. AEs were typical of SMA; the most common were upper respiratory tract infection (n=6) and viral upper respiratory tract infection (n=5). Two participants had mild proteinuria considered nusinersen-related, which resolved. Nine participants had serious AEs; all were considered unrelated to nusinersen and resolved. No deaths or post-lumbar puncture syndrome events occurred. Additional data will be presented.
Conclusions: In RESPOND, the majority of enrolled children previously treated with OA had suboptimal clinical status in ≥2 domains. Interim safety findings were overall consistent with nusinersen’s safety profile.
Study Support: Biogen