Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Background: Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy.
Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete.
Findings: Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred.
Interpretation: Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy.
Funding: Italfarmaco.
Competing Interests: Declaration of interests EM declares payment or honoraria for lectures and symposia from Sarepta Therapeutics, PTC Therapeutics, and Roche; and participation on advisory boards for Sarepta Therapeutics, NS Pharma, Santhera, PTC Therapeutics, Roche, Pfizer, WAVE Life Sciences, Italfarmaco, and Dyne Therapeutics, all outside the scope of this manuscript. JJV declares grants from PTC Therapeutics; consulting fees from Santhera, Sarepta Therapeutics, and PTC Therapeutics; and payment for lectures, presentations, speakers bureaus, manuscript writing or educational events from PTC Therapeutics, all outside the scope of this manuscript. OB-T declares grants to her institution from Roche, Novartis, Biogen, Genethon, and Metafora Biosystems; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis; support for attending meetings and/or travel from Novartis; participation on a data safety monitoring board or advisory board for Minoryx Therapeutics; and unpaid leadership roles with AFM-Téléthon (scientific board president) and Société Francophone de Neurogenetique, all outside the scope of this manuscript. CMZ declares grants or contracts from Biogen and Novartis; consulting fees from Sarepta Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sarepta Therapeutics and Optum; support for attending meetings and/or travel from Sarepta Therapeutics and Optum; and participation on a data safety monitoring board or advisory board for Sarepta Therapeutics, all outside the scope of this manuscript. JKM declares research grants to her institution from Italfarmaco, Biogen, Novartis, NS Pharma, Pfizer, PTC Therapeutics, ReveraGen Biopharma, Roche, Sarepta Therapeutics, and Alberta Children's Hospital Foundation, all outside the scope of this manuscript. NG declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen; and participation on a data safety monitoring board or advisory board for Pfizer, Biogen, and WAVE Life Sciences, all outside the scope of this manuscript. WM-F declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, Roche, Sarepta Therapeutics, Sanofi-Aventis, and Novartis; payment to his institution for expert testimony from Astellas Pharma; participation on a data safety monitoring board or advisory board with payment to himself from PTC Therapeutics, Roche, and Novartis, and to his institution from Astellas Pharma; and unpaid leadership roles for the Deutsche Gesellschaft für Muskelkranke and Glykogenose Deutschland, all outside the scope of this manuscript. EHN declares grants to his institution from Pfizer and PTC Therapeutics; and consulting fees to his institution from Pfizer, Edgewise Therapeutics, Sarepta Therapeutics, Epirium Bio, Regenxbio, Janssen Pharmaceuticals, all outside the scope of this manuscript. US-S declares consulting fees from Santhera, PTC Therapeutics, Sarepta Therapeutics, and Pfizer, all outside the scope of this manuscript. EB declares participation on advisory boards for Pfizer, Roche, Biogen, and Novartis, all outside the scope of this manuscript. GPC declares payment for a lecture from Biogen; participation on advisory boards for PTC Therapeutics, Roche, and Sanofi Genzyme; and an unpaid leadership role (president) of the Italian Association of Myology, all outside the scope of this manuscript. KDM declares grants to her institution from Italfarmaco, Sarepta Therapeutics, PTC Therapeutics, FibroGen, Capricor Therapeutics, Pfizer, Edgewise Therapeutics, Biomarin Pharmaceutical, Centers for Disease Control and Prevention, and the National Institutes of Health; an honorarium to cover travel costs from the Muscular Dystrophy Association; reimbursement to her institution of support to attend meetings and/or travel from the Parent Project Muscular Dystrophy; participation on a data safety monitoring board or advisory board for Dyne Therapeutics, NS Pharma, TRiNDS, and Sarepta Therapeutics; and payment to her institution for participation in a grant review board for the Muscular Dystrophy Association, all outside the scope of this manuscript. LS declares grants to his institution from Roche, Novartis, Biogen, Sysnav Healthcare, Zentech, and Perkin Elmer; consulting fees from Pfizer, Santhera, Dynacure, Dyne Therapeutics, Audentes Therapeutics, Zentech, Sarepta Therapeutics, Roche, Novartis, Biohaven, Biogen Digital Health, Scholar Rock, Regenexbio, and Evox Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Biogen, and Novartis; payment for expert testimony from Audentes Therapeutics; participation on a data safety monitoring board or advisory board for FibroGen, Lupin Therapeutics, and Illumina; and unpaid leadership roles for the World Muscle Society, SMA Europe, and the Association Belge contre les Maladies neuro-Musculaires , all outside the scope of this manuscript. KV declares a research service agreement for the current clinical trial. Outside of this 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, Gainesville, FL, USA. JJ declares consulting fees from Biogen, AveXis, Sarepta Therapeutics, and Roche; and receipt of travel and speaker fees from PTC Therapeutics, all outside the scope of this manuscript. SM declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Biogen, and Novartis, all outside the scope of this manuscript. SS declares payments for participation in ad-hoc advisory boards for PTC Medical, Sarepta Therapeutics, Pfizer, and Roche; and payment for chairing a symposium sponsored by Sarepta Therapeutics at the British Neuropsychiatry Association 2019 annual meeting, all outside the scope of this manuscript. LM declares study funding and payments to her institution for provision of study materials in the current clinical trial. Outside the current manuscript she declares grants to her institution from Anavex Life Sciences. KS declares grants or contracts from Biogen (principal investigator and clinical trial site for a nusinersen study), ReveraGen-Santhera (principal investigator for a vamorolone study), and PTC Therapeutics (principal investigator for an ataluren study); payment to her institution from Roche for a teaching and educational seminar on spinal muscular atrophy; an honorarium from Novartis for a TREAT NMD talk on spinal muscular atrophy; and attendance at advisory boards for Biogen and Roche (including travel), all outside the scope of this manuscript. CGL declares contracts (as principal investigator) from Sarepta Therapeutics, Dyne Therapeutics, Avidity Biosciences, FibroGen, Scholar Rock, and Biohaven; consulting fees from Sarepta Therapeutics (payments to her institution), NS Pharma (payments to herself), and Avidity (payments to her institution and to herself); payments for participation in a speakers bureau from Biogen; and support for attending meetings and/or travel from the Muscular Dystrophy Association, CureCMD, and CureSMA, all outside the scope of this manuscript. KC declares payments directly to KJC Statistics for statistical support of the current trial. SC, NC, and PB are employees of Italfarmaco, the sponsor of the current trial. CMM reports receiving grants or research support from Astellas Pharma, BioMarin Pharmaceutical, Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Italfarmaco, Pfizer, PTC Therapeutics, and Santhera Pharmaceuticals; and consulting fees from Sarepta Therapeutics, Astellas Pharma, Avidity Biosciences, BioMarin Pharmaceutical, Bristol Myers Squib, Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Eli Lilly, Epirium Bio, Entrada Therapeutics, Gilead Sciences, Halo Therapeutics, Italfarmaco, Novartis, PepGen, Pfizer, PTC Therapeutics, Prosensa, and Santhera Pharmaceuticals, all outside the scope of this manuscript. BB and GZ declare no competing interests.
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