Introduction: Givinostat is a histone deacetylase inhibitor indicated for the treatment of Duchenne muscular dystrophy (DMD). In the phase 3 double-blind, placebo-controlled EPIDYS study, patients with DMD received weight-based givinostat dosing plus standard of care (ie, corticosteroids), starting at dose A or B, depending on study protocol. Doses were adjusted (A to B or B to C) based on predefined rules related to tolerability to achieve the highest tolerated dose for each patient.
Objective: To evaluate givinostat efficacy based on the final administered dose at week 72 in patients from EPIDYS.
Methods: The primary endpoint of EPIDYS was mean change from baseline (CFB) at week 72 in 4-stair climb (4SC) time (seconds). A key secondary endpoint was change from baseline in total North Star Ambulatory Assessment (NSAA) score.
Results: Thirty-nine patients started at dose A, 42 patients started at dose B, and 39 patients received placebo. Dose was reduced in 36 patients. Overall, 21 patients received final dose A, 44 dose B, and 16 dose C. All patients had similar givinostat blood concentrations within the range considered efficacious throughout the study (5 samples/patient). At week 72, the placebo-corrected difference in least squares (LS) mean CFB (95% CI) in 4SC time was A: –2.61 (–4.97, –0.26), B: –1.35 (–3.25, 0.54) and C: –1.90 (–4.48, 0.67). For NSAA, the LS mean CFB (placebo-corrected) was A: 3.35 (1.07, 5.64), B: 1.24 (–0.57, 3.05), and C: 1.94 (–0.58, 4.46).
Conclusions: Results numerically favored givinostat over placebo across all 3 doses. Flexible dosing enables the highest tolerated givinostat exposure for maximal efficacy while maintaining tolerability. Despite protocol-driven dose reductions, clinical benefit was achieved across all dosing regiments.