Eugenio Mercuri1, Nicolas Deconinck2, Elena S Mazzone3, Andres Nascimento4, Maryam Oskoui5, Kayoko Saito6, Carole Vuillerot7, Giovanni Baranello8, Odile Boespflug-Tanguy9, Nathalie Goemans10, Janbernd Kirschner11, Anna Kostera-Pruszczyk12, Laurent Servais13, Marianne Gerber14, Ksenija Gorni14, Omar Khwaja15, Heidemarie Kletzl14, Renata S Scalco14, Hannah Staunton16, Wai Yin Yeung16, Carmen Martin16, Paulo Fontoura14, John W Day17. 1. Paediatric Neurology and Nemo Center, Catholic University and Policlinico Gemelli, Rome, Italy. Electronic address: eugeniomaria.mercuri@unicatt.it. 2. Neuromuscular Reference Center, UZ Gent, Ghent, Belgium; Neuromuscular Reference Center and Paediatric Neurology, Queen Fabiola Children's University Hospital, Université Libre de Bruxelles, Brussels, Belgium. 3. Paediatric Neurology and Nemo Center, Catholic University and Policlinico Gemelli, Rome, Italy. 4. Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Déu, CIBERER - ISC III, Barcelona, Spain. 5. Department of Pediatrics and Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. 6. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan. 7. Service de Rééducation Pédiatrique Infantile "L'Escale", Hôpital Femme Mère Enfant, CHU-Lyon, Bron, France; Neuromyogen Institute, CNRS UMR 5310 - INSERM U1217 Université de Lyon, Lyon, France. 8. The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, Great Ormond Street NHS Trust, London, UK; Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 9. I-Motion, Institut de Myologie, APHP, Hôpital Armand Trousseau, Paris, France; NeuroDiderot, UMR 1141, Université de Paris, Paris, France. 10. Neuromuscular Reference Centre, Department of Paediatrics and Child Neurology, University Hospitals Leuven, Leuven, Belgium. 11. Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Freiburg, Germany; Division of Neuropediatrics, Faculty of Medicine, University Hospital Bonn, Bonn, Germany. 12. Department of Neurology, Medical University of Warsaw, Warsaw, Poland. 13. I-Motion, Institut de Myologie, APHP, Hôpital Armand Trousseau, Paris, France; MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, UK; Reference Center for Neuromuscular Disease, Centre Hospitalier Régional de La Citadelle, Liège, Belgium. 14. F Hoffmann-La Roche, Basel, Switzerland. 15. F Hoffmann-La Roche, Basel, Switzerland; Voyager Therapeutics, Cambridge, MA, USA. 16. Roche Products, Welwyn Garden City, UK. 17. Department of Neurology, Stanford University, Palo Alto, CA, USA.
Abstract
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.
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.
Authors: Eugenio Mercuri; Charlotte J Sumner; Francesco Muntoni; Basil T Darras; Richard S Finkel Journal: Nat Rev Dis Primers Date: 2022-08-04 Impact factor: 65.038
Authors: Jennifer M Kwon; Kapil Arya; Nancy Kuntz; Han C Phan; Cory Sieburg; Kathryn J Swoboda; Aravindhan Veerapandiyan; Beverly Assman; Silvia Bader-Weder; Travis L Dickendesher; Jennifer Hansen; Helen Lin; Ying Yan; Vamshi K Rao Journal: Ann Clin Transl Neurol Date: 2022-05-14 Impact factor: 5.430