Disease progression modeling in Duchenne muscular dystrophy: delayed decay in four-stair climb with givinostat compared with standard of care

Topic:

Clinical Trials

Poster Number: P76

Author(s):

Chamindra Laverty, MD, University of California, Eugenio Mercuri, MD, PhD, Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemel, 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, Erika L Finanger, MD, MS, Oregon Health and Science University

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: To explore its potential impact on disease progression, the DMD Clinical Trial Simulation tool, developed by C-Path’s Duchenne Regulatory Science Consortium (D-RSC), was updated with data from EPIDYS and the ongoing long-term safety and tolerability study (LTSE) to simulate the 4-stair climb (4SC) endpoint and assess differences in the time course of DMD progression between patients receiving givinostat or standard of care (SoC). Methods: The analysis used nonlinear mixed-effects modeling. To align with the D-RSC model, 4SC was transformed into climb velocity (1/s). The published DMD disease progression model of 4SC was validated with baseline demographic data from patients in the EPIDYS study receiving SoC. The model was then re-estimated using only data from givinostat-treated patients. The model performance was assessed using visual predictive check (VPC) diagnostics. Simulations were then conducted in 1000 virtual patients using baseline demographic data from the available studies, comparing the updated (givinostat) and published (SoC) models; 100 replicates were simulated accounting for interindividual variability. Virtual patients were followed for 5 years, and the effects of givinostat and SoC were compared using the median curve with 95% CI. Results: Baseline data from a total of 357 patients were included in the model, with 296 receiving givinostat and 61 receiving SoC. Patients with missing baseline age, baseline 4SC scores, observations, or those who became nonambulant and unable to perform the 4SC were excluded. VPC diagnostics showed good agreement between model predictions and observed data for both SoC-treated patients from EPIDYS and givinostat-treated patients from EPIDYS and the LTSE. Results of the 5-year simulations showed that givinostat was associated with a delay of approximately 2 years in the DMD progression curve for 4SC starting at 9 years of age. At 14 years of age, the model showed that patients treated with givinostat were able to climb 4 stairs faster (approximately 0.1 1/s) than those receiving SoC. Conclusion: Using the D-RSC disease progression model, this analysis demonstrated a delay in DMD progression, as measured by decline in 4SC, in patients treated with givinostat compared with SoC.