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Randomized Controlled Trial
. 2025 Nov;12(11):2335-2348.
doi: 10.1002/acn3.70165. Epub 2025 Aug 19.

Long-Term Evaluation of Givinostat in Duchenne Muscular Dystrophy, and Natural History Comparisons

Craig M McDonald  1 , Michela Guglieri  2 , Dragana Vučinić  3 , Gyula Acsadi  4 , John F Brandsema  5 , Claudio Bruno  6   7 , Erika L Finanger  8 , Amy Harper  9 , Mercedes Lopez Lobato  10 , Riccardo Masson  11 , Nuria Muelas  12   13   14 , Francina Munell  15 , Yoram Nevo  16 , Yann Péréon  17 , Han Phan  18 , Valeria A Sansone  19 , Mariacristina Scoto  20 , Tracey Willis  21 , Richard S Finkel  22   23 , Krista Vandenborne  24 , Sara Cazzaniga  25 , Silvia Montrasio  25 , Federica Alessi  25 , Paolo Bettica  25 , Eugenio Mercuri  26   27 ; Givinostat Study 51 Investigators; Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS) Investigators; ImagingDMD Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Long-Term Evaluation of Givinostat in Duchenne Muscular Dystrophy, and Natural History Comparisons

Craig M McDonald et al. Ann Clin Transl Neurol. 2025 Nov.

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.

Keywords: Duchenne muscular dystrophy; efficacy; long term; safety.

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Conflict of interest statement

In addition to the medical writing support disclosed in the acknowledgments section, the authors have the following conflicts of interest to disclose. Craig M. McDonald has served as a consultant for clinical trials with Astellas Pharma, Avidity Biosciences, Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Entrada Therapeutics, Epirium Bio (formerly Cardero Therapeutics), FibroGen, Italfarmaco, Pfizer, PTC Therapeutics, Hoffman La Roche, Santhera Pharmaceuticals, Sarepta Therapeutics, and Solid Biosciences. He has received research support for clinical trials from Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Epirium Bio, Italfarmaco, Pfizer, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta Therapeutics, and Solid Biosciences. He serves on external advisory boards related to DMD for Capricor Therapeutics, Edgewise Therapeutics, Eli Lilly, Entrada Therapeutics, Italfarmaco, NS Pharma, Percheron, PTC Therapeutics, Sarepta Therapeutics, Santhera Pharmaceuticals, and Solid Biosciences. All are outside the scope of the current manuscript. Michela Guglieri has served on external advisory boards or safety monitoring boards related to DMD for NS Pharma, Roche, Italfarmaco, Santhera Pharmaceuticals, Dyne, and Antisense Therapeutics. She is the principal investigator for clinical trials in DMD sponsored by Italfarmaco, Pfizer, ReveraGen, Roche, and PTC Therapeutics. She has received personal speaker honoraria from Italfarmaco, Dyne, Roche, Novartis, and support for attending meetings and travel (conference registration fee, travel and accommodation) from Novartis and Italfarmaco. She declares grants or contracts with Edgewise and Sarepta, and unpaid leadership roles with the TREAT‐NMD Global Data Systems Oversight Committee (Chair), the Cooperative International Neuromuscular Research Group (CINRG; member of the executive committee), and the DMD Hub UK (principal investigator). All are outside the scope of the current manuscript. Dragana Vučinić has no other conflicts of interest to disclose. Gyula Acsadi serves as the Chair of the Sarepta Safety Monitoring Board. John F. Brandsema declares grants or contracts from Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Janssen, Pfizer, PTC Therapeutics, Sarepta, and Scholar Rock; consulting fees from Alexion, Argenx, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, and Takeda; support for attending meetings and/or travel from CureSMA and the Muscular Dystrophy Association; participation on a data safety monitoring board or advisory board for Cure Rare Disease; and that he is a member of the Cure SMA Medical Advisory Council. All are outside the scope of the current manuscript. Claudio Bruno has received honoraria for advisory boards from Roche, Biogen, Novartis, and for conferences from Roche. All are outside the scope of this manuscript. Erika L. Finanger declares grants or contracts from Novartis, Biogen, Scholar Rock, Fibrogen, PTC Therapeutics, Sarepta, Dyne, and NSPharma; consulting fees from Reata, Pfizer, IFT Therapeutics, Novartis, and Sarepta; support for attending meetings and/or travel from the Muscular Dystrophy Association; and participation on a data safety monitoring board or advisory board for Italfarmaco and Edgewise Therapeutics. All are outside the scope of the current manuscript. Amy Harper declares receipt by Virginia Commonwealth University of contracted funding as principal investigator in clinical research studies related to DMD, SMA, FSHD, and LGMD from Novartis, MLBio, Regenxbio, Santhera, Dyne, and Fulcrum, and as coinvestigator for MDStarNet, and compensation for attendance at an advisory board for Sarepta Gene Therapy. In addition, she declares unpaid roles as an executive committee member for CINRG, director of the Children's Hospital of Richmond MDA Clinic, director of the Children's Hospital of Richmond PPMD DMD Certified Center, and a member of the Nominating Committee of the Child Neurology Society. All are outside the scope of the current manuscript. Mercedes Lopez Lobato has no other conflicts of interest to disclose. Riccardo Masson declares receipt of consulting fees from Roche, Biogen, Novartis, and PTC Therapeutics, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Biogen, and Novartis, support for attending meetings and/or travel from Roche and Novartis, and medical writing support from Novartis. All are outside the scope of the current manuscript. Nuria Muelas declares receipt of grant PI21/01532, supported by the Instituto de Salud Carlos III (ISCIII) and co‐funded by the European Union, and grants PROMETEO/2019/075 and PROMETEO/2023/053 from the Valencian Council for Innovation, Universities Science and Digital Society, consulting fees from PTC Therapeutics, Pfizer, Sanofi, Amicus, and Astellas, honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from PTC Therapeutics, Pfizer, Sanofi, and Amicus, support for attending meetings and/or travel from Sanofi, and participation on a data safety monitoring board or advisory board for PTC Therapeutics, Pfizer, Sanofi, Amicus, and Astellas. All are outside the scope of the current manuscript. Francina Munell declares that she was the principal investigator of the Vall d'Hebron University Hospital, Barcelona, site of the current study. She has no other relevant conflicts of interest to disclose. Yoram Nevo declares that he was the principal investigator of Schneider Children's Medical Center, Israel, site of the current study. Outside the scope of the current manuscript, he received a research grant from Pfizer; was principal investigator for clinical trials conducted by Pfizer, PTC, Sarepta, Biomarin, Santera, and multiple CINRG clinical trials; received honoraria for presentations from PTC, Pfizer, Roche, Sarepta, and Neopharm Israel; attended advisory boards for PTC, Sarepta, and Roche; and was an ad hoc advisor for TEVA. In addition, he declares previous unpaid roles as an executive committee member for CINRG and the head of the Israeli pediatric neurology association. Yann Péréon declares honoraria from Italfarmaco SpA for presentation in symposium and for participation in an advisory board. All are outside the scope of the current manuscript. Han Phan declares that travel and lodging were covered by Italfarmaco SpA to present at World Muscle Society, outside the scope of the current manuscript. Valeria A. Sansone declares consulting fees for scientific activities from Roche, Biogen, Novartis, Dyne, Sanofi, and Solid Biosciences; payment for teaching services from Roche, Biogen, Novartis, Dyne, Sanofi, and Solid Biosciences; and participation in advisory boards for Roche, Biogen, Novartis, Dyne, Sanofi, and Solid Biosciences. All are outside the scope of the current manuscript. Mariacristina Scoto has no other conflicts of interest to disclose. Tracey Willis declares consulting fees from PTC Therapeutics, Pfizer, Santhera, and Sarepta, Novartis, Biogen, and Roche; honoraria for symposia from PTC Therapeutics, Biogen, and Novartis; and support for attending meetings and/or travel from Novartis. All are outside the scope of the current manuscript. Richard S. Finkel declares personal compensation for advisory board/data safety monitoring board participation from Astellas, Biogen, Dyne, Genentech, Ionis, Italfarmaco, ReveraGen, Roche, Sarepta, and Scholar Rock; research funding from Biogen, Dyne, Genentech, Genethon, Italfarmaco, Roche, and Sarepta, Scholar Rock; editorial fees from Elsevier for coediting a neurology textbook; license fees from the Children's Hospital of Philadelphia. All are outside the scope of the current manuscript. Krista Vandenborne declares a research service agreement for the current clinical trial. Outside the current manuscript, she declares grants from the National Institutes of Health and research service support from Sarepta Therapeutics, Catabasis Pharmaceuticals, PTC Therapeutics, Summit Therapeutics, Astellas Pharma, ML Bio/VCU, and Edgewise Therapeutics, all directed to the University of Florida. Sara Cazzaniga, Silvia Montrasio, Federica Alessi, and Paolo Bettica are employees of Italfarmaco SpA, the sponsor of the study. Eugenio Mercuri reports payments for lectures and symposia from Sarepta, PTC, and Roche, and for advisory boards from Sarepta, NS, Santhera, PTC, Roche, Pfizer, wave, Italfarmaco, Dyne, Solid, and Edgewise. All are outside the scope of the current manuscript.

Figures

FIGURE 1
FIGURE 1
Study design and patient flow through the study.
FIGURE 2
FIGURE 2
Mean observed values for (A) platelet counts and (B) triglyceride concentrations. *All patients were also receiving systemic corticosteroids for the full duration of the follow‐up period. †No patients have reached this timepoint. N indicates the number available for assessment. CTCAE, Common Terminology Criteria for Adverse Events.
FIGURE 3
FIGURE 3
Outcome analyses, matching patients from the givinostat study population and the natural history datasets. *All patients were also receiving systemic corticosteroids for the full duration of the follow‐up period.
See this image and copyright information in PMC

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