Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA)

Abstract

Risdiplam is an oral, survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12 months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥ 3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥ 0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12 months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24 months was consistent with that observed after 12 months. Risdiplam over 24 months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment.

Keywords: Motor function; Risdiplam; SMA; SUNFISH; Safety; Spinal muscular atrophy.

Fig. 1

Change from baseline in MFM32 total score in patients treated with risdiplam for up to 24 months and those who previously received placebo until study month 12. ^aThirty-one percent (55/180) of the SUNFISH intent-to-treat population were 2–5 years old at baseline. ^b± 95% CI. ^cBaseline is the last measurement prior to the first dose of risdiplam or placebo. ^dData cut-off: 30 Sep 2020. ^eData cut-off: 6 Sep 2019. ^fPatients in the placebo arm received placebo for 12 months followed by risdiplam treatment for 12 months. ^gNumber of patients with valid results = number of patients with an available total score (result) at respective time points. Intent-to-treat patients. ^hPatients in the placebo arm received placebo for 12 months followed by risdiplam treatment for 12 months. Placebo period not shown in this graph. CI confidence interval, MFM32 32-item motor function measure

Fig. 2

MFM-derived total score in the risdiplam group versus the external comparator group. ^a± 95% CI, weighted analysis of change from baseline, MMRM (risdiplam, SUNFISH Part 2 n = 115.0; external comparator n = 114.1, n = sum of weights at baseline). Patients with baseline and at least one post-baseline time point at month 12 or month 24 with MFM (derived) total score were included in the analysis. MFM (derived) total score means the MFM20 total score is used for all patients aged < 6 years and MFM32 total score is used for all patients aged ≥ 6 years. Both scales were transformed to 0–100%. SUNFISH data cut-off: 30 Sep 2020. ^bWeighted analysis. n = sum of weights. ^cSUNFISH data cut-off: 30 Sep 2020. CI confidence interval, LS least squares, MFM Motor Function Measure, MFM20 20-item MFM, MFM32 32-item MFM, MMRM mixed model for repeated measures, SD standard deviation

Fig. 3

Change in RULM and HFMSE total score from baseline in patients receiving risdiplam for up to 24 months and those who previously received placebo up to study month 12. ^a± 95% CI. ^bData cut-off: 30 Sep 2020. ^cData cut-off: 6 Sep 2019. ^dPatients in the placebo arm received placebo for 12 months followed by risdiplam treatment for 12 months. ^eNumber of patients with valid results = number of patients with an available total score (result) at respective time points. Intent-to-treat patients. CI confidence interval, HFMSE Hammersmith Functional Motor Scale—Expanded, RULM Revised Upper Limb Module

Fig. 4

Change in caregiver- and patient-reported SMAIS upper limb total score from baseline in patients receiving risdiplam for up to 24 months and those who previously received placebo up to study month 12. ^a± 95% CI. Baseline is the last measurement prior to the first dose of risdiplam or placebo. ^bData cut-off: 30 Sep 2020. ^cData cut-off: 6 Sep 2019. ^dPatients in the placebo arm received placebo for 12 months followed by risdiplam treatment for 12 months. Risdiplam period not shown in this graph. ^eNumber of patients with valid results = number of patients with an available total score (result) at respective time points. Intent-to-treat patients. SMAIS scores range from 0 to 44 following rescoring to a 0–2 response scale for each item. Higher scores indicate greater independence in completing daily activities. CI confidence interval, SMA spinal muscular atrophy, SMAIS SMA Independence Scale, SMAIS-ULM SMA Independence Scale-Upper Limb Module