Givinostat effects on DMD pathogenesis


Translational Research

Poster Number: S71


SIMONETTA ANDREA LICANDRO, PhD, ITALFARMACO S.P.A., SILVIA CONSALVI, Unicamillus International Medical University in Rome, Rome, Italy, STEFANIA PETRINI, Confocal Microscopy Core Facility, Ospedale Pediatrico Bambino Gesù, Rome, Italy., Krista Vandenborne, PT, PhD, University of Florida, SARA CAZZANIGA, Msc, ITALFARMACO S.P.A., GIANLUCA FOSSATI, ITALFARMACO SPA, Paolo Umberto Bettica, MD. PhD, Italfarmaco SpA, Lorenzo Puri, MD, Children's National Medical Center, Annemieke Aartsma-Rus, PhD, Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: 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 (Consalvi, 2013; Licandro, 2021) and in DMD boys (Bettica, 2016). 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 fibres 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 all 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.