Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND

Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy.

METHODS

In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing.

FINDINGS

Between Oct 9, 2017, and Sept 4, 2018, 180 patients were randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and -0·19 (-1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs ten [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs five [8%]), rash (20 [17%] vs one [2%]), mouth and aphthous ulcers (eight [7%] vs 0), urinary tract infection (eight [7%] vs 0), and arthralgias (six [5%] vs 0). The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group).

INTERPRETATION

Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2-25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam.

FUNDING

F Hoffmann-La Roche.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests EM has received fees for serving on scientific advisory boards; speaker fees from F Hoffmann-La Roche, Biogen, AveXis/Novartis, Scholar Rock, and Cytokinetics; and grants from Biogen during the conduct of the study. ND served on scientific advisory boards for F Hoffmann-La Roche and Novartis pharmaceuticals; he has received personal fees from Biogen for congress and travel support. ESM reports that she has served on advisory boards for Biogen and Scholar Rock. She has received consulting fees, travel support, and speaker honoraria as an independent contractor from F Hoffmann-La Roche, Biogen, AveXis, and Scholar Rock. AN has received fees for serving on scientific advisory boards and speaker fees from F Hoffmann-La Roche. MO reports grants from F Hoffmann-La Roche during the conduct of the study and has received grants as a clinical trial investigator from Biogen. KS reports grants from F Hoffman-La Roche/Chugai Pharmaceutical during the conduct of the study and grants from Biogen Japan and lecture fees from Novartis Pharmaceuticals, outside the submitted work. CV reports personal fees and financial support to her institution from F Hoffmann-La Roche for activities outside the submitted work. GB received consultancy fees and speaker honoraria from F Hoffmann-La Roche and AveXis and speaker fees from PTC Therapeutics. NG reports fees for serving on advisory boards and presentations at symposia from F Hoffmann-La Roche, Biogen, and AveXis. JK received grants or contracts from Novartis Gene Therapies and Biogen. He has received consulting and speaker fees from F Hoffmann La Roche, Biogen, and Novartis Gene Therapies and consulting fees from Scholar Rock. AK-P reports that she received an institutional support grant from Biogen; serving on scientific advisory boards for and receiving speaker honoraria from Biogen, F Hoffmann-La Roche, Novartis, and PTC Therapeutics; and receiving personal fees from Biogen and F Hoffmann-La Roche for travel support. LS received grants and personal fees from F Hoffman-La Roche, Biogen, and AveXis/Novartis Gene Therapy and personal fees from Cytokinetics, outside the submitted work. OK reports that he was previously an employee and stockholder in F Hoffmann-La Roche during the submitted work and that he now holds the position of honorary chief medical officer at The Spinal Muscular Atrophy Foundation. JWD has received fees for serving on scientific advisory boards from Biogen, Novartis, Sarepta, and Avidity; has received consulting fees from Affinia Therapeutics and Shift Therapeutics for a therapeutic platform; and has received grant support for clinical trials from F Hoffman-La Roche, Biogen, Novartis Gene Therapies, Cytokinetics, Scholar Rock, and Sarepta. CM, PF, MG, KG, HK, HS, RSS, and WYY report that they are current employees and stockholders in F Hoffmann-La Roche. OB-T declared no competing interests.