P210 Interim results from the RESPOND study evaluating nusinersen in children with spinal muscular atrophy previously treated with onasemnogene abeparvovec

Nusinersen has shown significant and clinically meaningful efficacy across a broad spectrum of SMA populations. Onasemnogene abeparvovec (OA) is an adeno-associated viral (AAV) vector gene replacement therapy. Animal models and limited human postmortem studies suggest 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 an open label, single-arm study evaluating nusinersen in children with SMA treated with OA ≥2 mo previously. We report interim results from the ongoing RESPOND study. RESPOND participants have ≥1 SMN2 copy, are ≤36 mo old, nusinersen-naive, and have investigator-determined suboptimal clinical status for ≥1 of these domains at baseline: 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 mo. As of 15 November 2022, 38 children were enrolled and received nusinersen. Median (range) time from OA treatment to first nusinersen dose was 6.5 (2.6–31.3) mo. Median duration on nusinersen was 230.5 (range: 28.0–677.0) days. At baseline, 32/38 children demonstrated suboptimal clinical status in ≥2 domains after OA treatment; motor function (n=37) and respiratory function (n=25) were most common. Baseline mean (SD) HINE-2 total score was 6.1 (5.63) (n=37). Thirty-four of 38 participants had 2 SMN2 copies. No emerging safety concerns have been identified: AEs occurred in 31 (81.6%) participants. Thirteen (34.2%) participants had serious AEs; all considered unrelated to nusinersen. No events were considered related to the lumbar puncture procedure. No deaths were reported. Additional results including efficacy at day 183 will be presented. Study recruitment is ongoing. This study is sponsored by Biogen. Nusinersen has shown significant and clinically meaningful efficacy across a broad spectrum of SMA populations. Onasemnogene abeparvovec (OA) is an adeno-associated viral (AAV) vector gene replacement therapy. Animal models and limited human postmortem studies suggest 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 an open label, single-arm study evaluating nusinersen in children with SMA treated with OA ≥2 mo previously. We report interim results from the ongoing RESPOND study. RESPOND participants have ≥1 SMN2 copy, are ≤36 mo old, nusinersen-naive, and have investigator-determined suboptimal clinical status for ≥1 of these domains at baseline: 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 mo. As of 15 November 2022, 38 children were enrolled and received nusinersen. Median (range) time from OA treatment to first nusinersen dose was 6.5 (2.6–31.3) mo. Median duration on nusinersen was 230.5 (range: 28.0–677.0) days. At baseline, 32/38 children demonstrated suboptimal clinical status in ≥2 domains after OA treatment; motor function (n=37) and respiratory function (n=25) were most common. Baseline mean (SD) HINE-2 total score was 6.1 (5.63) (n=37). Thirty-four of 38 participants had 2 SMN2 copies. No emerging safety concerns have been identified: AEs occurred in 31 (81.6%) participants. Thirteen (34.2%) participants had serious AEs; all considered unrelated to nusinersen. No events were considered related to the lumbar puncture procedure. No deaths were reported. Additional results including efficacy at day 183 will be presented. Study recruitment is ongoing. This study is sponsored by Biogen.