Modeling disease progression in Duchenne muscular dystrophy: reduced decline in forced vital capacity with givinostat compared with standard of care

Topic:

Clinical Trials

Poster Number: P85

Author(s):

Erika L Finanger, MD, MS, Oregon Health and Science University, Chamindra Laverty, MD, University of California, Federica Alessi, Italfarmaco SpA., Sara Cazzaniga, Msc, Italfarmaco SpA., Paolo Bettica, MD, PhD, Italfarmaco SpA., Anna Largajolli, PhD, Certara, Francesco Bellanti, PhD, Certara, Yann Péréon, MD, PhD, CHU Nantes, Reference Centre for Neuromuscular Diseases AOC, Craig McDonald, MD, University of California Davis Health, Eugenio Mercuri, MD, PhD, Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemel

Background: Givinostat is an oral histone deacetylase inhibitor recently approved in the US for the treatment of Duchenne muscular dystrophy (DMD) in patients aged ≥6 years, based on findings from the phase 3 EPIDYS study. Objective: Using the validated DMD Clinical Trial Simulation tool, developed by C-Path’s Duchenne Regulatory Science Consortium, updated with data from EPIDYS and the ongoing long-term safety and tolerability study, simulations were conducted to assess differences in the time course of worsening forced vital capacity (FVC) among patients receiving givinostat or standard of care (SoC). Methods: As few givinostat-treated patients in the long-term safety and tolerability study demonstrated a decaying trend in FVC over time, a modeling approach was unable to be adequately implemented to quantify the full disease progression curve for this cohort. Thus, for this analysis, simulations of the published SoC model of FVC were applied to a virtual patient population with data beyond 15 years of age (N=64) using baseline demographics matching those from the EPIDYS and long-term safety and tolerability studies and compared to the observed givinostat data. Simulations were conducted in NONMEM (version 7.5.1) using 500 replicates and accounting for interindividual variability. Results: The published DMD disease progression model of FVC was validated with data from patients receiving SoC in the EPIDYS study. Results from the visual predictive check diagnostics demonstrated good agreement between the observed and simulated data, suggesting that the available model was suitable for performing comparative simulations with the DMD population from the available studies. Simulated and observed FVC profiles in patients >15 years of age were summarized assessing the percentage of patients with FVC <1L. Compared with simulated SoC, treatment with givinostat showed a lower percentage of patients aged >15 years with FVC <1L (3.1% vs 12.5%; 95% CI, 6.2%-20.3%). This corresponds to 4-fold higher odds (95% CI, 2.0-6.5) of observing FVC <1L in patients receiving SoC compared to those treated with givinostat. Conclusions: These simulations suggest a potential benefit of givinostat in delaying respiratory decline in DMD, as evidenced by lower rates of FVC reduction among treated patients. Further research is needed to validate findings given limited data availability in patients aged >15 years (when a decrease in FVC function is anticipated) in the givinostat studies.