Histological effects of givinostat in boys with Duchenne muscular dystrophy

Abstract

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene leading to dystrophin deficiency, muscle fiber degeneration and progressive fibrotic replacement of muscles. Givinostat, a histone deacetylase (HDAC) inhibitor, significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. This study was conducted to evaluate whether the beneficial histological effects of Givinostat could be extended to DMD boys. Twenty ambulant DMD boys aged 7 to <11 years on stable corticosteroid treatment were enrolled in the study and treated for ≥12 months with Givinostat. A muscle biopsy was collected at the beginning and at the end of treatment to evaluate the amount of muscle and fibrotic tissue. Histological effects were the primary objectives of the study. Treatment with Givinostat significantly increased the fraction of muscle tissue in the biopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall the drug was safe and tolerated. Improvement in functional tests was not observed in this study, but the sample size of the study was not sufficient to draw definitive conclusions. This study showed that treatment with Givinostat for more than 1 year significantly counteracted histological disease progression in ambulant DMD boys aged 7 to 10 years.

BRD4 inhibition for the treatment of pathological organ fibrosis

“…Nonetheless, more than 20 clinical trials with BET inhibitors for cancer applications are active or have been completed, and data from these trials should guide future evaluation of this compound class for the treatment of internal organ fibrosis. Furthermore, the feasibility of targeting global epigenetic regulators such as BET proteins for the treatment of human disease is bolstered by the fact that four histone deacetylase (HDAC) inhibitors are FDA-approved for the treatment of cancer 41, 42 , that HDAC inhibitors have also shown promise in treating non-oncologic diseases such as Duchenne muscular dystrophy 43 , and that HDAC inhibitors are fairly well tolerated in humans 1 .…”

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

“…Here, we demonstrate that the HDAC inhibitor ITF2357 (givinostat), currently in a phase 3 trial in patients with Duchenne muscular dystrophy (22), improves relaxation of the heart in rodent models of diastolic dysfunction with preserved EF. ITF2357 did not elicit discernable toxicity, and efficacy was independent of alterations in blood pressure, cardiac hypertrophy, cardiac fibrosis, or cardiac titin and MyHC isoform expression.…”

Advances in the Treatment of Duchenne Muscular Dystrophy: New and Emerging Pharmacotherapies

“…Inhibition of myostatin has been a promising therapeutic option for patients with DMD because it may increase muscle regeneration. Histone deacetylase inhibitors may be beneficial in DMD because they decrease myostatin levels . Givinostat, a histone deacetylase inhibitor, increased muscle regeneration and prevented muscle fibrosis in mdx mice .…”

“…Givinostat, a histone deacetylase inhibitor, increased muscle regeneration and prevented muscle fibrosis in mdx mice . A 12‐month course of givinostat significantly increased the muscle fiber area fraction and decreased the percentage of total fibrosis, necrosis, and adipose tissue replacement in patients with DMD . A phase III study will soon be recruiting patients to evaluate the efficacy of this medication in ambulatory patients with DMD (ClinicalTrials.gov identifier NCT02851797).…”

“…Histone deacetylase inhibitors may be beneficial in DMD because they decrease myostatin levels. 47 Givinostat, a histone deacetylase inhibitor, increased muscle regeneration and prevented muscle fibrosis in mdx mice. 48 A 12-month course of givinostat significantly increased the muscle fiber area fraction and decreased the percentage of total fibrosis, necrosis, and adipose tissue replacement in patients with DMD.…”