{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:24:10Z","timestamp":1786375450120,"version":"build-2736575974"},"reference-count":30,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007013","name":"F. Hoffmann-La Roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and\/or mutations in the <jats:italic>SMN1<\/jats:italic> gene. Risdiplam is an orally administered molecule that modifies <jats:italic>SMN2<\/jats:italic> pre\u2010mRNA splicing to increase functional SMN protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>SUNFISH Part 1 was a dose\u2010finding study conducted in 51 individuals with types 2 and 3 SMA aged 2\u201325\u2009years. A dose\u2010escalation 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\u2010week, double\u2010blind, placebo\u2010controlled period, followed by treatment for 24\u2009months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There was no difference in safety findings for all assessed dose levels. A dose\u2010dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4\u2009weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24\u2009months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5\u00a0mg for patients with a body weight \u226520\u2009kg or 0.25\u2009mg\/kg for patients with a body weight &lt;20\u2009kg.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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\u2010term efficacy and safety of risdiplam are being assessed with ongoing treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.15499","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T07:44:53Z","timestamp":1657871093000},"page":"1945-1956","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo\u2010controlled, dose\u2010finding trial followed by 24\u2009months of treatment"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9851-5365","authenticated-orcid":false,"given":"Eugenio","family":"Mercuri","sequence":"first","affiliation":[{"name":"Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Baranello","sequence":"additional","affiliation":[{"name":"The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre Great Ormond Street Institute of Child Health University College London, &amp; Great Ormond Street Hospital Trust  London UK"},{"name":"Developmental Neurology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odile","family":"Boespflug\u2010Tanguy","sequence":"additional","affiliation":[{"name":"I\u2010Motion \u2010 H\u00f4pital Armand Trousseau  Paris France"},{"name":"NeuroDiderot Universit\u00e9 de Paris, UMR 1141  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth","family":"De Waele","sequence":"additional","affiliation":[{"name":"Department of Development and Regeneration KU Leuven  Leuven Belgium"},{"name":"Neuromuscular Reference Centre, Department of Paediatrics and Child Neurology University Hospitals Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Goemans","sequence":"additional","affiliation":[{"name":"Neuromuscular Reference Centre, Department of Paediatrics and Child Neurology University Hospitals Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1618-7386","authenticated-orcid":false,"given":"Janbernd","family":"Kirschner","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine Medical Center\u2010University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Masson","sequence":"additional","affiliation":[{"name":"Developmental Neurology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena S.","family":"Mazzone","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Pechmann","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine Medical Center\u2010University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carmela","family":"Pera","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Vuillerot","sequence":"additional","affiliation":[{"name":"Service de R\u00e9\u00e9ducation P\u00e9diatrique Infantile \u201cL'Escale\u201d H\u00f4pital Femme M\u00e8re Enfant, CHU\u2010Lyon  Bron France"},{"name":"Neuromyogen Institute, CNRS UMR 5310 \u2010 INSERM U1217, Universit\u00e9 de Lyon  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bader\u2010Weder","sequence":"additional","affiliation":[{"name":"Pharma Development Safety, F. 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