Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

Abstract

Introduction Risdiplam is a survival of motor neuron 2 ( SMN2 ) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1–3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. Methods Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. Results A total of 174 patients enrolled: MOONFISH study ( n = 13), olesoxime ( n = 71 patients), nusinersen ( n = 76), onasemnogene abeparvovec ( n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1–60 years) and 39.1 kg (9.2–108.9 kg), respectively. About 63% of patients aged 2–60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale–Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. Conclusions The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40120-023-00444-1.

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

“…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).…”

“…| 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

“…48 An increase in the total distance walked in the 6MWT was observed in ambulant patients over 24 months of treatment with risdiplam. 48 Real-world experience with risdiplam has also been published and further supported its beneficial effects on motor function in patients with SMA. 49 RAINBOWFISH is an ongoing, multicenter, open-label, single-arm study to assess the efficacy and safety of risdiplam in pre-symptomatic SMA.…”

“…48 An increase in the total distance walked in the 6MWT was observed in ambulant patients over 24 months of treatment with risdiplam. 48 Real-world experience with risdiplam has also been published and further supported its beneficial effects on motor function in patients with SMA. 49…”

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

“…79 The JEWELFISH is an ongoing, multicenter, open-label study designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of risdiplam in the broadest population ever studied in an SMA trial, including patients with types 1 to 3 SMA (n ¼ 174) with a wide range of ages (1 to 60 years), disease severities, and who have previously received other disease-modifying therapies (RG7800,7 nusinersen, olesoxime or onasemnogene abeparvovec). 80 The JEWELFISH study population had a similar safety profile and increase in SMN protein levels after 12 months of treatment with risdiplam compared with treatment-naïve patients who were treated with risdiplam in the FIREFISH and SUNFISH clinical trials. 80 An increase in the total distance walked in the 6MWT was observed (median 30.88 meters) in ambulant patients over 24 months of treatment with risdiplam.…”