Thursday, March 28, 2024

Givinostat for Duchenne and Becker muscular dystrophy

Duvyzat (givinostat; Italfarmaco SpA, Milan, Italy), a histone deacetylase (HDAC) inhibitor, was approved by the Food and Drug Administration (FDA) to treat Duchenne muscular dystrophy (DMD) in individuals aged >6 years. This is the first nonsteroidal drug approved to treat DMD.

FDA approval was based upon results from the EPIDYS clinical trial (NCT02851797), a phase 3, randomized, double-blind, placebo-controlled trial, which evaluated the safety and efficacy of Duvyzat in ambulant boys with DMD. The study included 179 boys aged ≥6 years with genetically confirmed DMD, who were stratified based on their baseline vastus lateralis fat fraction (VLFF) into group A (VLFF >5% to ≤30%) and group B (VLFF ≤5% or >30%). Participants were randomized 2:1 to receive oral Duvyzat or placebo twice daily for 72 weeks, with dose adjustments based on weight and tolerability.

The study met the primary endpoint, which compared the mean change between baseline and 72 weeks in the ability to climb 4 stairs in the intention-to-treat, group A population. Additionally, secondary endpoints assessing muscle function and strength showed favorable results.

Duvyzat-treated individuals showed a slower decline in performing the four-stair climb assessment compared to placebo-treated individuals (difference vs placebo of 1.78 seconds, P=.037).
Duvyzat treatment was associated with 40% less decline in the North Star Ambulatory Assessment (NSAA) total score and item loss.
Duvyzat-treated individuals had a 30% reduction in vastus lateralis fat fraction (VLFF), a predictor of loss of ambulation, compared to the placebo-treated cohort.

The most common adverse events associated with givinostat treatment were diarrhea (36% vs 18% with placebo) and vomiting (29% vs 13% with placebo). No treatment-related deaths occurred.

According to prescribing information provided for Duvyzat, health care providers need to evaluate patient’s platelet counts and triglycerides prior to prescribing Dyvyzat and on an ongoing basis following treatment. Duvyzat also may cause QTc prolongation, and patients taking medications associated with QTc prolongation or who have certain heart disease types should avoid taking Duvyzat.

Comi GP, Niks EH, Vandenborne K, Cinnante CM, Kan HE, Willcocks RJ, Velardo D, Magri F, Ripolone M, van Benthem JJ, van de Velde NM, Nava S, Ambrosoli L, Cazzaniga S, Bettica PU. Givinostat for Becker muscular dystrophy: A randomized, placebo-controlled, double-blind study. Front Neurol. 2023 Jan 30;14:1095121. doi: 10.3389/fneur.2023.1095121. PMID: 36793492; PMCID: PMC9923355.


Objective: No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD.

Methods: Males aged 18-65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations.

Results: Of 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12 (least squares mean [LSM] difference 1.04%; p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat-placebo differences at Month 12 of -1.35% (p = 0.0149) and -1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo.

Conclusion: The study failed to achieve the primary endpoint. However, there was a potential signal from the MRI assessments suggesting givinostat could prevent (or slow down) BMD disease progression.

Giovarelli M, Zecchini S, Catarinella G, Moscheni C, Sartori P, Barbieri C, Roux-Biejat P, Napoli A, Vantaggiato C, Cervia D, Perrotta C, Clementi E, Latella L, De Palma C. Givinostat as metabolic enhancer reverting mitochondrial biogenesis deficit in Duchenne Muscular Dystrophy. Pharmacol Res. 2021 Aug;170:105751. doi: 10.1016/j.phrs.2021.105751. Epub 2021 Jun 29. PMID: 34197911.


Duchenne Muscular Dystrophy (DMD) is a rare disorder characterized by progressive muscle wasting, weakness, and premature death. Remarkable progress has been made in genetic approaches, restoring dystrophin, or its function. However, the targeting of secondary pathological mechanisms, such as increasing muscle blood flow or stopping fibrosis, remains important to improve the therapeutic benefits, that depend on tackling both the genetic disease and the downstream consequences. Mitochondrial dysfunctions are one of the earliest deficits in DMD, arise from multiple cellular stressors and result in less than 50% of ATP content in dystrophic muscles. Here we establish that there are two temporally distinct phases of mitochondrial damage with depletion of mitochondrial mass at early stages and an accumulation of dysfunctional mitochondria at later stages, leading to a different oxidative fibers pattern, in young and adult mdx mice. We also observe a progressive mitochondrial biogenesis impairment associated with increased deacetylation of peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) promoter. Such histone deacetylation is inhibited by givinostat that positively modifies the epigenetic profile of PGC-1α promoter, sustaining mitochondrial biogenesis and oxidative fiber type switch. We, therefore, demonstrate that givinostat exerts relevant effects at mitochondrial level, acting as a metabolic remodeling agent capable of efficiently promoting mitochondrial biogenesis in dystrophic muscle.


  1. Mercuri E, Vilchez JJ, Boespflug-Tanguy O, Zaidman CM, Mah JK, Goemans N, Müller-Felber W, Niks EH, Schara-Schmidt U, Bertini E, Comi GP, Mathews KD, Servais L, Vandenborne K, Johannsen J, Messina S, Spinty S, McAdam L, Selby K, Byrne B, Laverty CG, Carroll K, Zardi G, Cazzaniga S, Coceani N, Bettica P, McDonald CM; EPIDYS Study Group. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X. PMID: 38508835.


    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. (continued)

  2. (continued)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, 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