Long‐Term Evaluation of Givinostat in Duchenne Muscular Dystrophy, and Natural History Comparisons
Year: 2025
Type: article
Abstract: OBJECTIVES: This ongoing, open-label extension study is evaluating the long-term safety, tolerability, and efficacy of givinostat, a Class I and II histone deacetylase inhibitor, in patients with Duchenne muscular dystrophy (DMD). METHODS: The recruited patients completed one of two prior clinical studies (one Phase 2 and one Phase 3 [EPIDYS]), receiving givinostat or placebo, or were successfully screened but not randomized into EPIDYS. All receive givinostat oral suspension open-label at a flexible, weight-based dose in addition to systemic corticosteroids, and attend visits every 4 months. RESULTS: A total of 194 patients are included in the current analyses, with a mean duration of givinostat exposure (excluding use in prior studies) of 559.6 days (SD 373.0); when including use in the prior studies, the maximum exposure to givinostat was > 8 years. Although the majority of patients reported ≥ 1 adverse event (169/194 [87.1%]), most were mild/moderate in severity, and the safety profile of givinostat was consistent with prior studies. Post hoc comparisons with natural history datasets (ImagingDMD and CINRG) suggest, in propensity matched populations, givinostat added to systemic corticosteroids significantly delayed the loss of the ability to rise from the floor, the loss of the ability to complete the 4-stair climb test, and the loss of ambulation (by medians of 2.0-3.3 years; all nominal p < 0.05). INTERPRETATION: Overall, the safety and tolerability of long-term administration of givinostat in patients with DMD was consistent with previous studies. Comparisons with natural history data suggest that givinostat delays the occurrence of major disease progression milestones. TRIAL REGISTRATION: EudraCT number: 2017-000397-10; ClinicalTrials.gov identifier: NCT03373968.
DOI: 10.1002/acn3.70165
Authors: Craig M. McDonald, Michela Guglieri, Dragana Vučinić, Gyula Acsadi, John F. Brandsema, Claudio Bruno, Erika L. Finanger, Amy Harper, Mercedes Lopez Lobato, Riccardo Masson, Nuria Muelas, Francina Munell, Yoram Nevo, Yann Péréon, Han Phan, Valeria A. Sansone, Mariacristina Scoto, Tracey Willis, Richard S. Finkel, Krista Vandenborne, Sara Cazzaniga, Silvia Montrasio, Federica Alessi, Paolo Bettica, Eugenio Mercuri, the Givinostat Study 51 Investigators, the ImagingDMD Investigators
Institutions: University of California Davis Medical Center, UC Davis Health, University of California, Davis, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle University, Connecticut Children's Medical Center, Children's Hospital of Philadelphia, Istituto Giannina Gaslini, University of Genoa, Shriners Hospitals for Children - Portland, Virginia Commonwealth University, Children's Hospital of Richmond at VCU, Virginia Commonwealth University Medical Center, Hospital Universitario Virgen del Rocío, Fondazione IRCCS Istituto Neurologico Carlo Besta, Hospital Universitari i Politècnic La Fe, Centre for Biomedical Network Research on Rare Diseases, Instituto de Investigación Sanitaria La Fe, Vall d'Hebron Hospital Universitari, Tel Aviv University, Schneider Children's Medical Center, Centre Hospitalier Universitaire de Nantes, University of Milan, Centro Clinico Nemo, Great Ormond Street Hospital, University College London, Robert Jones and Agnes Hunt Orthopaedic Hospital, Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, St. Jude Children's Research Hospital, Nemours Children's Clinic, University of Florida Health, University of Florida, Italfarmaco (Italy), Università Cattolica del Sacro Cuore, Agostino Gemelli University Polyclinic
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
OpenAlex ID: W4413343333