How does risdiplam compare in infantile-onset spinal muscular atrophy (SMA)? Preliminary indirect treatment comparisons based on FIREFISH Part 1 data Daigl M,1 Kotzeva A,1 Gorni K,1 Evans R,2 Hawkins N,2 Scott DA,2 Mahajan A,3 Baranello G,4,5 Servais L6,7 1F. Hoffmann-La Roche Ltd, Basel, Switzerland; 2Visible Analytics, Oxford, UK; 3Bridge Medical Consulting Ltd., London, UK; 4The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK (current affiliation);5 Carlo Besta Neurological Research Institute Foundation, Developmental Neurology Unit, Milan, Italy; 6Division of Child Neurology, Neuromuscular Reference Center, Department of Pediatrics, University Hospital Liège, Belgium; 7MDUK Oxford Neuromuscular Centre, Oxford, UK. Background Motor milestones analysis • In the last few years, innovative drugs have emerged for SMA and are being evaluated by • MAIC analysis of HINE-2 motor milestone response with risdiplam versus nusinersen gave an regulators, payers, and HTA bodies across the globe. OR of 5.79 (95% CI 0.98–46.19), while risdiplam versus BSC gave an OR of 379.71 (95% CI 75.19–1070.54) (Figure 2). — None of these drugs have been compared in head-to-head trials. • In this analysis, indirect treatment comparison (ITC) evaluated the relative efficacy of risdiplam Figure 2. HINE-2 motor milestone response* against nusinersen (SPINRAZA®) or onasemnogene abeparvovec-xioi (ZOLGENSMA®) in patients with infantile-onset (Type 1) SMA. 100 • FIREFISH (NCT02913482) is an open-label, multicenter clinical study assessing the safety, 80 tolerability, pharmacokinetics, pharmacodynamics and efficacy of risdiplam in infants with infantile-onset SMA.1 60 — Part 1: Dose-finding period followed by open-label extension. 40 — Part 2: Efficacy and safety at the dose selected in Part 1. Responders, % • Individual patient data (IPD) from the 21 patients in the dose-finding Part 1 of the FIREFISH 20 study of risdiplam1 were included in this analysis. 0 Risdiplam Risdiplam Nusinersen BSC (FIREFISH (FIREFISH (ENDEAR) (ENDEAR) unadjusted) matching-adjusted Methods to ENDEAR) • Comparator studies were identified through a systematic literature review of published articles Comparator Unadjusted comparison MAIC and congress abstracts up to February 2018. (STUDY) Weighted number Responders/ OR for risdiplam OR for risdiplam — Eight studies were identified across four compounds in infantile-onset SMA of responders/sum sample size against comparator† against comparator† (see additional material). of weights (% [95% CI]) (95% CI) (95% CI) 1 (% [95% CI]) — Analyses were performed on the FIREFISH Part 1 study of risdiplam (NCT02913482), 2 the ENDEAR study of nusinersen (NCT02193074) and the CL-101 study of onasemnogene Risdiplam 14/21 13.59/15.87 - - abeparvovec (NCT02122952).3 (FIREFISH Part 1) (67 [43–86]) (86 [70–100]) • Matching-adjusted indirect comparison (MAIC) is a population-adjusted method where IPD Nusinersen 37/73 1.95 37/73 5.79 from studies of one treatment are ‘weighted’ so that summary baseline characteristics match (ENDEAR) (51 [39–63]) (0.73–5.84) (51 [39–63]) (0.98–46.19) other studies.4 BSC 0/37 145.00 0/37 379.71 — MAIC aims to adjust for imbalances between trials that may influence outcome. (ENDEAR sham control arm) (0 [0–9]) (57.00–396.43)‡ (0 [0–9]) (75.19–1070.54)‡ 5,6 • Data was extracted from published comparator manuscripts and digitized, before being *Infants were considered to have a motor milestone response if they met the following two criteria: (1) improvement in at least one category (i.e. an increase in the score for head control, rolling, sitting, crawling, standing, or walking of ≥1 point, an increase in the score for kicking of compared to FIREFISH Part 1 IPD. ≥2 points, or achievement of the maximal score for kicking) and (2) more categories with improvement than worsening (i.e. a decrease in the score for head control, rolling, sitting, crawling, standing, or walking of ≥1 point or a decrease in the score for kicking of ≥2 points). HINE-2 motor milestone achievement in infants is assessed at the latest of Days 183, 302 or 394 for patients in ENDEAR (stopped at interim)5 and at 12 months for FIREFISH Part 1. Infants who died or were withdrawn from the trial were considered to have no response regardless of length of follow-up. †OR >1 favors risdiplam over comparator. ‡OR calculated using the half-cell correction. Bootstrap CIs are calculated from N=1000 bootstrap Results samples for FIREFISH. Clopper Pearson CIs are used for ENDEAR. Baseline characteristics • MAIC analysis of sitting without support with risdiplam versus nusinersen gave an OR of 9.22 (95% CI 2.62–29.06), while risdiplam versus BSC gave an OR of 62.66 • SMN2 copy number, duration of symptoms, age at time of first dose, functional score at (95% CI 21.39–154.41) (Figure 3). baseline and ventilatory/nutritional support have been reported to influence outcomes.7–12 • Duration of symptoms, age at first dose and functional score at baseline were selected for the Figure 3. HINE-2 sitting without support (stable sits and pivots) matching based on expert clinicians’ opinion. 100 • All patients had two SMN2 gene copies (Table 1). 80 • Duration of symptoms was not reported in the CL-101 study.3,6 Age at symptom onset was used in the matching adjustment. 60 Table 1. Baseline characteristics before matching 40 Nusinersen and Onasemnogene Risdiplam Responders, % BSC abeparvovec Baseline characteristic (FIREFISH Part 1)1 20 (ENDEAR)2, 5 (CL-101)3,6 N=21 N=121 N=12 0 Risdiplam Risdiplam Nusinersen BSC Mean age at first dose, days 178 169 ~103* (FIREFISH (FIREFISH (ENDEAR) (ENDEAR) (SD [range]) (42 [102–213]) (NR [30–262]) (NR [27–240]) unadjusted) matching-adjusted to ENDEAR) Female gender, % 71 55 58 Comparator Unadjusted comparison MAIC White race, % 81 NR 92 (STUDY) Weighted number Responders/ OR for risdiplam † of responders/sum OR for risdiplam Mean age at symptom onset, weeks 8.1 8.5 ~6.1 sample size against comparator† † of weights against comparator (SD [range]) (3.2 [4–13.1]) (NR [1–20]) (NR [0–13]) (%; 95% CI) (95% CI) (95% CI) (%; 95% CI) Mean disease duration at screening, 104 ~94‡ NR Risdiplam 6/21 7.18/15.87 days (SD [range]) (38 [37–163]) (NR [0–181]) - - (FIREFISH) (29 [10–48]) (45; [18–72]) 14.1 14.3 ~8.6§ Mean age at diagnosis, weeks (SD [range]) Nusinersen 6/73 4.47 6/73 9.22 (5.8 [4–23.3]) (NR [0–30]) (NR [0–19]) (ENDEAR) (8 [3–17]) (1.18-10.15) (8; [3–17]) (2.62–29.06) CHOP-INTEND, mean score 24 27 28 BSC 0/37 31.45 0/37 62.66 (SD [range]) (6 [10–34]) (7.94 [NR]) (NR [12–50]) (ENDEAR sham control arm) (0 [0–9]) (9.62–68.48)‡ (0 [0–9]) (21.39–154.41)‡ Patients with nutritional support: Unable to 5 10 NR HINE-2 motor milestone achievement in infants is assessed at the latest of Days 183, 302 or 394 for patients in ENDEAR (stopped at interim)5 swallow/gastrointestinal tube feeding, % and at Day 365 for FIREFISH Part 1. Infants who died, or were withdrawn from the trial were considered to have no response regardless of length of follow-up. †OR>1 favors risdiplam over comparator; ‡OR calculated using the half-cell correction. Bootstrap CIs are calculated from N=1000 Patients with ventilatory support, % 24 22 17 bootstrap samples for FIREFISH. Clopper Pearson CIs are used for ENDEAR. 1.0 1.4 • ITC of adverse events (AEs) was not performed, however; HINE-2 score, mean (SD [range]) NR (0.7 [0–3]) (1.2 [NR]) — as of February 2019, there have been no drug-related safety findings in FIREFISH Part 1 13 Proportion of patients with two copies leading to withdrawal of any patients 100 100 100 13 of SMN2, % — AEs were reflective of the underlying disease. In ENDEAR, the incidence and severity 5 *3.4 months, †1.4 months, ‡13.2 weeks, §60 days. of AEs were similar in treatment and control groups. Matching factors are in bold. Treatment with risdiplam, nusinersen and onasemnogene abeparvovec are always undertaken in conjunction with BSC. The BSC population in this analysis is taken from the sham control arm of the ENDEAR study.5 MAIC analysis to compare with CL-101 (onasemnogene abeparvovec) • Matching the average characteristics of ENDEAR with FIREFISH Part 1 was successful. • MAIC of FIREFISH Part 1 versus CL-101 aggregate data was not feasible due to lack of overlap The ESS of FIREFISH Part 1 was reduced to 12.8 after matching (see supplementary material). of mean values and ranges. — Matching FIREFISH Part 1 to CL-101 gave an ESS of 1.8 (see supplementary material). MAIC analyses to compare with ENDEAR (nusinersen) • An unadjusted (naïve) comparison would be expected to be biased in favor of onasemnogene Event-free survival* abeparvovec due to: — younger age of patients at time of treatment initiation • MAIC of event-free survival comparing risdiplam (FIREFISH Part 1) with nusinersen (ENDEAR) or BSC (ENDEAR sham control arm) gave HRs of 0.23 (95% CI 0.00–0.66) and 0.11 — differences in disease duration prior to treatment (95% CI 0.00–0.30), respectively (Figure 1; Table 2). — greater CHOP-INTEND total scores at baseline. Figure 1. Kaplan–Meier curves for event-free survival* Risdiplam Risdiplam (FIREFISH (FIREFISH Nusinersen BSC Conclusions unadjusted) matching-adjusted (ENDEAR) (ENDEAR) 1.00 to ENDEAR) • Preliminary results suggest that treatment of infantile-onset SMA with risdiplam may lead to longer event-free survival versus nusinersen, or BSC. • Risdiplam may also yield a better achievement of HINE-2 motor milestones versus nusinersen 0.75 or BSC alone.