[en] BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein.
METHODS: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured.
RESULTS: There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight <20 kg.
CONCLUSIONS: SUNFISH Part 1 demonstrated a twofold increase in SMN protein after treatment with risdiplam. The observed safety profile supported the initiation of the pivotal Part 2 study. The long-term efficacy and safety of risdiplam are being assessed with ongoing treatment.
Disciplines :
Neurology Pediatrics
Author, co-author :
Mercuri, Eugenio ; Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Baranello, Giovanni; 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 Hospital Trust, London, UK ; Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Boespflug-Tanguy, Odile; I-Motion - Hôpital Armand Trousseau, Paris, France ; NeuroDiderot, Université de Paris, UMR 1141, Paris, France
De Waele, Liesbeth; Department of Development and Regeneration, KU Leuven, Leuven, Belgium ; Neuromuscular Reference Centre, Department of Paediatrics and Child Neurology, University Hospitals Leuven, Leuven, Belgium
Goemans, Nathalie; Neuromuscular Reference Centre, Department of Paediatrics and Child Neurology, University Hospitals Leuven, Leuven, Belgium
Kirschner, Janbernd ; Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany
Masson, Riccardo; Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Mazzone, Elena S; Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Pechmann, Astrid; Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany
Pera, Maria Carmela; Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Vuillerot, Carole; 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
Kletzl, Heidemarie; Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
Martin, Carmen; Roche Products Ltd, Welwyn Garden City, UK
McIver, Tammy; Roche Products Ltd, Welwyn Garden City, UK
Scalco, Renata S; Pharma Development Neurology, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Yeung, Wai Yin; Roche Products Ltd, Welwyn Garden City, UK
Servais, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; I-Motion - Hôpital Armand Trousseau, Paris, France ; MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, UK
We thank all patients, families, site staff, and study groups in the risdiplam, OLEOS, and NatHis‐SMA studies; and Nosheen Hussain of Nucleus Global for providing medical writing support, funded by F. Hoffmann‐La Roche in accordance with Good Publication Practice guidelines ( http://www.ismpp.org/gpp3 ). The study was sponsored by F. Hoffmann‐La Roche.E.M. reports nonfinancial support from F. Hoffmann‐La Roche during the conduct of the study; and personal fees from F. Hoffmann‐La Roche, Biogen, Novartis, and Scholar Rock outside the submitted work. G.B. reports consulting fees and payment/honoraria from F. Hoffmann‐La Roche, Biogen, and Novartis Gene Therapies. He has served on safety monitoring boards (SABs)/advisory boards for and received equipment from F. Hoffmann‐La Roche. O.B.‐T. reports nonfinancial support from Minoryx outside the submitted work. L.D.W. reports nonfinancial support and personal fees from F. Hoffmann‐La Roche during the conduct of the study; and personal fees and grants from Novartis and Biogen outside the submitted work. N.G. has served on SABs/advisory boards for F. Hoffmann‐La Roche and Novartis. She has received grants from Biogen and payment/honoraria from Biogen and F. Hoffmann‐La Roche. J.K. reports grants from F. Hoffmann‐La Roche during the conduct of the study; and grants and personal fees from F. Hoffmann‐La Roche, Biogen, and Novartis, and personal fees from Scholar Rock and Pfizer outside the submitted work. R.M. reports nonfinancial support from F. Hoffmann‐La Roche during the conduct of the study. He also reports personal fees from F. Hoffmann‐La Roche, Novartis Gene Therapies, and Biogen outside the submitted work. E.S.M. reports that she has served on advisory boards for F. Hoffmann‐La Roche. A.P. reports grants/research support from Biogen and Novartis Gene Therapies and has served on an advisory board for Novartis Gene Therapies. M.C.P. has received payment for presentations from F. Hoffmann‐La Roche, and support for attending meetings and/or travel from F. Hoffmann‐La Roche and Biogen. C.V. has received grants, consulting fees, honoraria, and support for attending meetings and/or travel from and has served on advisory boards for F. Hoffmann‐La Roche, Biogen, and Novartis Gene Therapies. S.B.‐W., M.G., K.G., J.H., H.K., C.M., T.M., R.S.S., and W.Y.Y. report that they are current employees and stockholders in F. Hoffmann‐La Roche. L.S. reports investigator‐initiated trial, consultancy, and lecture fees from F. Hoffmann‐La Roche, Biogen, and Novartis, and consultancy fees from Scholar Rock.
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