Slide 1: Interim Results From the Ongoing RESPOND Study of Nusinersen in Children With SMA
Interim Results From the Ongoing RESPOND Study of Nusinersen in Children With Spinal Muscular Atrophy Previously Treated With Onasemnogene Abeparvovec Brandsema JF,1 Masson R,2 Proud C,3* Parsons JA,4 Kuntz NL,5 Finkel RS,6 Foster R,7 Li W,8 Chary S,8 Rane S,8** Sohn J,8 Youn B,8 Fradette S,8 Paradi
Slide 2: Disclosures
Disclosures • JFB: consultant for Audentes, AveXis, Biogen, Cytokinetics, Genentech, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, and WaVe; speaker for AveXis and Biogen; medical advisory council member for Cure SMA; site investigator for clinical trials with Alexion, AveXi
Slide 3: RESPOND study rationale
RESPOND study rationale • There have been reports of individuals with SMA receiving the AAV vector-based gene therapy OA followed by nusinersen in both clinical trials and postmarketing settings1-3 • However, there has been no systematic evaluation of clinical outcomes or safety of treatment with nu
Slide 4: RESPOND study design
RESPOND study design • RESPOND (NCT04488133) is a Phase 4, multicenter, single-arm, open-label study evaluating nusinersen in participants with SMA who have previously received OA and have suboptimal clinical status as determined by the Investigator • Analysis objective: Provide baseline characteris
Slide 5: Interim analyses
Interim analyses Interim Set (n = 29) Safety Set (N = 38) • Children who received ≥ 1 dose of nusinersen who had the • All children who received ≥ 1 dose of nusinersen as of the opportunity to complete the Day 183 assessment as of the data cut data cuta Outcomes Outcomes • Safety and tolerability •
Slide 6: Baseline demographics and SMA history (Interim Set)
Baseline demographics and SMA history (Interim Set) • All participants were symptomatic at the time of OA dosing Age at First Nusinersen Dose Group ≤ 9 mo > 9 mo 2 SMN2 Copies 2 SMN2 Copies 3 SMN2 Copies Demographics and SMA History n = 14 n = 12 n=3 Male/female, n (%) 9 (64.3) / 5 (35.7) 7 (58.3) /
Slide 7: Baseline disease characteristics (Interim Set)
Baseline disease characteristics (Interim Set) Age at First Nusinersen Dose Group ≤ 9 mo > 9 mo 2 SMN2 Copies 2 SMN2 Copies 3 SMN2 Copies Disease Characteristics n = 14 n = 12 n=3 Suboptimal clinical status at Baseline per Investigator, n (%) Motor function 13 (93) 11 (92) 3 (100) Swallowing or feed
Slide 8: Total HINE-2 Score
Mean total HINE-2 scores increased from Baseline to Day 183 Total HINE-2 Scores by Age at Visit Maximum 26 score 24 22 20 18 Total HINE-2 Score Mean (SD) 16 Change 14 Age at First Actual Mean (SD) from Nusinersen HINE-2 Scores Baseline 12 Dose Group n Baseline n Day 183 n to Day 183 10 8 ≤ 9 mo, 2 1
Slide 9: Neurofilaments
Neurofilaments • Neurofilaments are structural proteins that are released into interstitial fluid (CSF and blood) following axonal damage or neuronal degeneration1,2 • In infants and younger children with SMA, neurofilament levels, including NfL, have been shown to be: – Elevated, reflecting neuroax
Slide 10: Plasma NfL Concentration, pg/mL
Baseline NfL levels were elevated compared with healthy children of similar ages1 Baseline Plasma NfL Concentrations by Age 550 Age at First Nusinersen Dose Group 500 ≤ 9 mo > 9 mo 450 Baseline Plasma 2 SMN2 Copies 2 SMN2 Copies 3 SMN2 Copies Plasma NfL Concentration, pg/mL 400 NfL, pg/mL n = 11 n =
Slide 11: Plasma NfL Concentration, pg/mL
Baseline NfL levels were elevated compared with healthy children of similar ages1 Baseline Plasma NfL Concentrations by Age 550 Age at First Nusinersen Dose Group 500 ≤ 9 mo > 9 mo 450 Baseline Plasma 2 SMN2 Copies 2 SMN2 Copies 3 SMN2 Copies Plasma NfL Concentration, pg/mL 400 NfL, pg/mL n = 11 n =
Slide 12: Plasma NfL Concentration, pg/mL
Mean NfL levels were reduced from Baseline to Day 183 Plasma NfL Concentrations by Study Visit 550 500 450 Plasma NfL Concentration, pg/mL 400 350 Mean (SD) Actual Mean (SD) Change 300 Age at First Plasma NfL Concentrations, pg/mL from Nusinersen Baseline 250 Dose Group n Baseline n Day 183 n to Day
Slide 13: Mean (SE) % Decrease in Plasma NfL Concentration
Continued reductions in NfL levels were observed among participants with 2 SMN2 copies Mean % Decrease in Plasma NfL by Study Visit Mean (SE) % Decrease in Plasma NfL Concentration 20 Study Visit, days 15 29 64 183 0 Mean (SD) –20 % Change from Age at First Nusinersen Baseline to –40 Dose Group n Da
Slide 14: Plasma NfL Concentration, pg/mL
Consistent pattern of decline in NfL levels was observed by age Plasma NfL Concentrations by Age at Visit 550 500 Plasma NfL Concentration, pg/mL 450 400 350 Age at First Nusinersen Dose Group 300 250 ≤ 9 mo > 9 mo 200 2 SMN2 Copies 2 SMN2 Copies 3 SMN2 Copies 150 n = 14 n = 12 n=3 100 Age at first
Slide 15: Plasma NfL Concentration, pg/mL
Consistent pattern of decline in NfL levels was observed by time from OA dose Plasma NfL Concentrations by Time from OA Dose 550 500 Plasma NfL Concentration, pg/mL 450 400 350 Age at First Nusinersen Dose Group 300 250 ≤ 9 mo > 9 mo 200 2 SMN2 Copies 2 SMN2 Copies 3 SMN2 Copies 150 n = 14 n = 12 n=
Slide 16: AEs reported after a median of ~230 days on study (Safety Set)
AEs reported after a median of ~230 days on study (Safety Set) Overall Population Proportion of Participants With Any AEs Overall Population Safety Parameters, n (%) N = 38 and Severity, n (%) N = 38 Participants dosed 38 (100) No AEs 7 (18.4) Time on study, days, median (range) 230.5 (28.0–677.0) M
Slide 17: Summary and Conclusions
Summary and Conclusions Available data support the potential benefit and safety of nusinersen treatment in infants and children with suboptimal clinical response to OA • At Day 183, mean total HINE-2 scores increased across age groups • At Baseline, plasma NfL levels were elevated compared with heal
Slide 18: Acknowledgements
Acknowledgements The authors thank the children who are participating in this study and their parents/guardians and family members, without whom this effort cannot succeed The authors also thank the people who are contributing to this study, including the study site principal investigators, clinical