Cardiac Safety Data for Givinostat in Ambulant Patients with Duchenne Muscular Dystrophy: Results from the EPIDYS Study

Topic:

Clinical Trials

Poster Number: 42 S

Author(s):

Eugenio M. Mercuri, MD, Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Rome, Italy, Barry Byrne, MD, PhD, University of Florida, Erik Niks, MD, PhD, Leiden University Medical Center, Leiden, Netherlands, Ulrike Schara-Schmidt, MD, Department of Pediatric Neurology, University of Duisburg-Essen, Essen, Germany, Tracey Willis, MD, The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, UK, Thierry Le Tourneau, Institute Of Thorax, University Nantes, Nantes, France, Odile Boespflug-Tanguy, APHP and Université Paris Cité, Paris, France, Michela Guglieri, MD, Newcastle University, Newcastle upon Tyne, England, UK , Nuria Muelas, MD, PhD, Neurology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain, David Gómez Andrés, Hospital Universitario Vall De Hebron, Barcelona, Spain, Han Phan, MD, Rare Disease Research, Atlanta, Georgia, USA, Sergio César Díaz, Universitat de Barcelona, Barcelona, Spain; European Reference Network, Amsterdam, Netherlands, John Bourke, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK, Sara Cazzaniga, MSc, Italfarmaco SpA

Background: Givinostat, a histone deacetylase (HDAC) inhibitor, is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients aged ≥6 years based on results from the multicenter, randomized, double-blind, placebo-controlled, phase 3 EPIDYS trial. DMD is associated with dilated cardiomyopathy, and electrocardiogram (ECG) changes have been observed in clinical trials of other HDAC inhibitors.

Objectives: To evaluate the safety of givinostat on cardiac function assessed by ECG and echocardiogram (ECHO) parameters from patients in the EPIDYS trial.

Methods: For the study, a weight-based flexible dosing approach was used. All patients who were on stable corticosteroids and received ≥1 dose of givinostat (n=118) or placebo (n=61) were assessed throughout the 72-week trial for ECG and pulmonary function.

Results: The mean (standard deviation [SD]) Fridericia-corrected QT interval (QTcF) change from baseline (CFB) at end of study (EOS) was −6.4 (16.87) ms and −1.3 ms (12.83) for the givinostat and placebo groups, respectively; no QTcF prolongation of >450 ms was recorded. A QTcF CFB of >30 ms and <60 ms was observed in 10 (5.6%) patients in the givinostat group; no patients had a CFB of >60 ms at any visit. Other ECG parameters remained stable throughout the study. The mean (SD) left ventricular ejection fraction (ECHO-LVEF) CFB at EOS had a numerically smaller trend with givinostat treatment (−1.2 [6.81]) versus placebo (−3.4 [7.57]).

Conclusions: No QTc prolongation was recorded with givinostat or placebo, and other ECG parameters remained stable. A beneficial trend change in LVEF from baseline to EOS was observed, suggesting that givinostat helped preserve LV-function versus placebo.