Introduction: Givinostat is a histone deacetylase inhibitor indicated for the treatment of Duchenne muscular dystrophy (DMD) in ambulant boys aged ≥6 years. The phase 3 EPIDYS trial was a randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of givinostat. Contractile cross-sectional area (cCSA) and fat fraction are quantitative measures of DMD disease progression, reflecting the amount of functional muscle tissue available for force generation and the extent of muscle tissue replacement by fat, respectively.
Objective: To measure cCSA and fat fraction in patients with a baseline vastus lateralis fat fraction >5% to ≤30% measured by magnetic resonance spectroscopy from the EPIDYS trial.
Methods: Of the 179 patients enrolled in EPIDYS, 120 were in the target population and completed the study (givinostat n=81, placebo n=39). cCSA and fat fraction were determined via magnetic resonance imaging (givinostat n=76, placebo n=37). Data were analyzed with a mixed model for repeated measures to determine change over time with covariates including treatment group, visit, baseline value, and interaction.
Results: At the end of the 18-month EPIDYS trial, the differences in least squares (LS) means (95% CI) between the givinostat and placebo groups for cCSA in the biceps femoris long head, hamstrings, quadriceps, semitendinosus, and vastus lateralis were 0.43 (0.14, 0.73; P=0.005), 1.02 (0.47, 1.58, P<0.001), 1.20 (0.16, 2.23; P=0.023), 0.47 (0.13, 0.80, P=0.006), and 0.61 (0.04, 1.17, P=0.035), respectively. Further, differences in LS means for fat fraction in the same muscles were −4.60 (−8.22, −0.99; P=0.013), −4.00 (−6.59, −1.40; P=0.003), −4.07 (−6.42, −1.72; P=0.001), −3.43 (−5.80, −1.06; P=0.005), and −3.86 (−6.36, −1.35; P=0.003), respectively. Similar results were observed as early as 48 weeks into the study. Conclusions: Givinostat treatment appears to be associated with significantly less decline in muscle contractile area and reduced fat infiltration compared with placebo, suggesting attenuation of muscle loss in patients with DMD.