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.

Efficacy of risdiplam in spinal muscular atrophy: A systematic review and meta‐analysis

“…This improvement and subsequent stabilization is directly related to increased SMN expression, which doubles its expression as suggested by the authors 33 . This expression leads to the survival and better function of the remaining motor neurons, 44 but the benefit would be limited precisely by this number of motor neurons 36 …”

“…Of the 582 records identified, 11 studies were included in the systematic review (Table 1, Figure 1), 25–36 and seven were included in the meta‐analyses, while 10 studies were excluded with justified reasons (Table S2).…”

“…33 This expression leads to the survival and better function of the remaining motor neurons, 44 but the benefit would be limited precisely by this number of motor neurons. 36 Although our main objective was not to investigate the safety profile and adverse events related to risdiplam, and the number of trials did not allow for a comprehensive analysis in this regard, some data from our review and the included trials are worth mentioning. Thus, 15%-20% of participants experienced a risdiplam-related adverse event related, but dose changes were rarely required and serious adverse events were anecdotal.…”

“…| RE SULTSOf the 582 records identified, 11 studies were included in the systematic review (Table1, Figure1),[25][26][27][28][29][30][31][32][33][34][35][36] and seven were included in the meta-analyses, while 10 studies were excluded with justified reasons (TableS2).The studies were conducted in the Americas, Asia, and Europe (TableS3). A total of 641 participants were included and, in general, the studies investigated SMA1 or SMA2/3.…”

Gene-based therapies for neuromuscular disorders

“…46 At month 24, 32% of patients demonstrated improvement from baseline in MFM32 total score, and 58% showed stabilization. 47 The JEWELFISH is an ongoing, open-label study designed to assess the effects of risdiplam in the broadest population, including patients with SMA types 1-3 (n ¼ 174) with a wide range of ages (1-60 years), disease severities, and who have previously received other therapies (RG7800, 7 nusinersen, olesoxime or onasemnogene abeparvovec). 48 The study showed a favorable safety profile and an increase in SMN protein levels after 12 months of treatment.…”