Association Identified Between Vastus Lateralis Fat Fraction and Givinostat Treatment Response in Duchenne Muscular Dystrophy

A post-hoc analysis of the phase 3 EPIDYS trial (NCT02851797) revealed that vastus lateralis fat fraction (VLFF) was associated with a number of efficacy-related outcomes among patients with Duchenne muscular dystrophy (DMD) treated with givinostat (Duvyzat; Italfarmaco), an FDA-approved oral histone deacetylase inhibitor (HDAC).¹

After 18 months of treatment with givinostat, results showed that VLFF had a relatively high reciprocal correlation with 4-stair climb (4SC; 0.539; P = .026), 6-minute walking test (6MWT; –0.528; P = .029), and North Star Ambulatory Assessment (NSAA; –0.527; P = .030). Presented at the 2025 Child Neurology Society (CNS) Annual Meeting, held October 8-11 in Charlotte, North Carolina, investigators found no significant correlation between VLFF and time to rise (TTR; 0.409; P = .100).

Led by Paolo Bettica, MD, PhD, chief medical officer at Italfarmaco, the findings point to the value of reducing VLFF in the context of DMD. By definition, VLFF represents the percentage of fat within the vastus lateralis muscle relative to the total tissue. As DMD advances, skeletal muscles–including the quadriceps–undergo progressive degeneration and fat infiltration. VLFF increases steadily over time, even before changes in functional tests become obvious.

EPIDYS, a pivotal, double-blind, placebo-controlled, phase 3 study, was the trial that led to givinostat’s approval in March 2024. With the approval, givinostat, designed to inhibit HDACs, became the first and only nonsteroidal drug marketed to treat patients with all genetic variants of DMD. The therapy is administered orally, twice daily, with food, and has dosage determined by the patient’s body weight.²

The latest post-hoc analysis of EPIDYS comprised 77 patients treated with givinostat or placebo in addition to standard of care (ie, corticosteroids; n = 37) with baseline VLFF between 5% and 30%. In the original trial, 179 ambulant males were randomly assigned 2:1 to either givionstat or placebo, for an 18-month period, followed by an open-label extension. Of these, 120 boys formed the target population.

Published in The Lancet Neurology, results from EPIDYS showed a slower decline in givinostat-treated patients on the primary end point of 4SC in comparison with placebo (difference, 1.78 seconds; P = .0345). Fat infiltration in the vastus lateralis muscle—a hallmark of DMD progression—was evaluated using magnetic resonance spectroscopy, revealing that givinostat treatment delayed fat accumulation by about 30% compared with placebo (–2.9%; nominal P = .035).³

Heading into the open-label extension, most patients (94.3%; 183 of 194) were still ambulant. In exploratory efficacy analyses comparing the givinostat-throughout and prior-placebo groups, no significant differences were observed across endpoints at 24 months, indicating comparable disease trajectories. The least squares mean differences were 0.02 tasks/s (95% CI, –0.177 to 0.222) for 4-stair climb (4SC) velocity and –1.65 points (95% CI, –5.181 to 1.882) for the North Star Ambulatory Assessment (NSAA), supporting the absence of a measurable treatment effect between groups.⁴

In a propensity-matched analysis conducted within the extension study, 142 patients receiving givinostat were compared with 142 matched individuals from a natural history cohort. Results showed that givinostat treatment slowed disease progression across all functional measures. When combined with corticosteroids, givinostat extended the median time to loss of key motor abilities—by 2.0 years for rising from the floor (HR, 0.66; 95% CI, 0.45–0.96; P = 0.028), 3.3 years for completing the 4SC (HR, 0.39; 95% CI, 0.24–0.65; P < 0.001), and 2.9 years for maintaining ambulation (HR, 0.42; 95% CI, 0.23–0.76; P = 0.004). Comparable outcomes were noted when the full givinostat cohort was analyzed against all patients from the natural history datasets.

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REFERENCES
1. Bettica P, McDonald C, Bellanti F, et al. Vastus lateralis fat fraction is associated with functional efficacy endpoints in patients with Duchenne muscular dystrophy treated with givinostat. Presented at: 2025 Child Neurology Society Annual Meeting; October 8-11; Abstract 312
2. FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy. FDA. News release. March 21, 2024. Accessed October 8, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-nonsteroidal-treatment-duchenne-muscular-dystrophy
3. Mercuri E, Vilchez JJ, Boespflug-Tanguy O, et al. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024;23(4):393-403. doi:10.1016/S1474-4422(24)00036-X
4. McDonald CM, Guglieri M, Vucinic D, et al. Long-Term Evaluation of Givinostat in Duchenne Muscular Dystrophy, and Natural History Comparisons. Annals of Clinical and Translational Neurology. Published online August 19, 2025. doi:10.1002/acn3.70165