Givinostat Effects on DMD Pathogenesis

Neuropediatrics, vol. 55, pp. S1–S25

Abstract

Background/Purpose: Givinostat is an HDAC inhibitor developed for the treatment of DMD. The Givinostat phase 3 study in DMD (Epidys) met its primary endpoint with consistent results in the key secondary endpoints. Givinostat’s mechanism of action (MoA) was elucidated in preclinical and clinical studies. Methods: Givinostat effects on muscle fibers integrity and necrosis, inflammation, muscle regeneration and fibroadipogenic replacement were studied in muscle biopsies in DMD mouse models and in DMD boys. Fatty replacement of the thigh was studied using magnetic resonance (MR) analysis in DMD boys in the phase 3 (Epidys) study, as well as circulating biomarkers of fibrosis (TGFbeta) and inflammation (IP10). Results: Givinostat improved myofiber cell membrane integrity (mouse) and reduced muscle cell necrosis (mouse, DMD boys). Givinostat anti-inflammatory effects were shown both in mouse and DMD boys. Givinostat increased muscle satellite cells and muscle regeneration fibers in muscle biopsies of DMD boys. Givinostat reduction of fibrosis was shown in muscle biopsies (mouse, DMD boys) and confirmed by the reduction of circulating TGFbeta in DMD boys. Givinostat reduction of fatty replacement was shown both in muscle biopsies (mouse, DMD boys) and in MR thigh scans (DMD boys). Conclusion: Givinostat was shown to counteract the pathogenetic events downstream of the lack of dystrophin both in the DMD mouse model and in DMD boys. Combined, these effects result in reduced muscle deterioration. Publication History Article published online: 08 October 2024 Georg Thieme Verlag KG Stuttgart · New York

Authors 8

1. Simonetta Andrea Licandro

   Italfarmaco (Italy)

   Affiliation as printed

   Italfarmaco Spa, Milano, Italy

2. Silvia Consalvi

   Saint Camillus International University of Health and Medical Sciences

   Affiliation as printed

   Unicamillus International Medical University in Rome, Rome, Italy

3. Stefania Petrini

   Bambino Gesù Children's Hospital

   Affiliation as printed

   Confocal Microscopy Core Facility, Ospedale Pediatrico Bambino Gesù, Rome, Italy

4. Krista Vandenborne

   University of Florida

   Affiliation as printed

   Department of Physical Therapy, University of Florida, Gainesville, Florida, United States

5. Gianluca Fossati

   Italfarmaco (Italy)

   Affiliation as printed

   Italfarmaco Spa, Milano, Italy

6. Paolo U. Bettica

   Italfarmaco (Italy)

   Affiliation as printed

   Italfarmaco Spa, Milano, Italy

7. Prem Puri

   Sanford Burnham Prebys Medical Discovery Institute

   Affiliation as printed

   Department of Human Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States

8. Abigaela Rus Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands