EPIDYS Extension Studies Provide Context to Givinostat’s Longterm Efficacy and Safety

Paolo Bettica, MD, PhD

Investigators have published long-term extension data for the phase 3 EPIDYS trial (NCT02851797), the pivotal study that led to givinostat’s (Duvyzat; Italfarmaco) approval in Duchenne muscular dystrophy (DMD) in 2024. All told, the safety and efficacy data continued to be consistent with prior studies, as treated patients experienced a delay in disease progression when compared with natural history cohorts.¹

This international, multicenter, open-label extension study of givinostat began in October 2017 and included males aged at least 6 years with DMD. Eligible participants (n = 194) either continued givinostat from prior studies, switched from placebo in EPIDYS, or started treatment at the “treatment naïve” dose if previously unrandomized. When excluding use in prior studies, the mean duration of givinostat exposure was 559.6 days (SD, 373.0).

In terms of safety, adverse events (AEs) were reported in 87.1% of patients, most of which were mild or moderate in severity. The most common AEs observed included increases in blood triglyceride levels, falls, and diarrhea; although, diarrhea was reportedly less common with more prolonged use. Three patients (2 placebo; 1 givinostat) withdrew from the study because of AEs such as nausea (n = 1; givinostat), increases in blood triglyceride levels (n = 1; placebo), and atrial fibrillation, considered the only treatment-related severe AE, observed in a patient on placebo.

"These data represent an important step in building a robust body of evidence for the long-term use of givinostat in DMD,” Paolo Bettica, MD, PhD, chief medical officer at Italfarmaco, said in a statement.¹ "The sustained benefit observed across functional outcomes reinforces the potential of givinostat to meaningfully alter the course of the disease. With its well-established safety profile and ease of administration, givinostat continues to emerge as a valuable treatment option for patients affected by DMD and their families."

Over the long-term period, AEs that led to dose reductions were found in 14.5% (16 of 110), 27.8% (15 of 54), and 13.3% (4 of 30) of patients in the givinostat throughout, prior placebo, and not included groups, respectively. Five of the 110 patients (4.5%) who received givinostat throughout reduced givinostat dose due to low platelet counts, compared to 4/54 (7.4%) and 1/30 (3.3%) in the prior placebo and not included groups, respectively; none of whom had any overt clinical manifestations.

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Coming into the open-label extension, most patients (94.3%; 183 of 194) were still ambulant. In exploratory efficacy comparisons of the givinostat-throughout and prior-placebo groups, no between-group differences were observed across endpoints at 24 months, suggesting similar disease progression. Specifically, the least squares mean differences at 24 months were 0.02 tasks/s (95% CI, –0.177 to 0.222) for 4SC velocity and –1.65 (95% CI, –5.181 to 1.882) for NSAA, reinforcing the lack of treatment effect between the two groups.

The non-ambulant group, was quite small, with only 11 patients in the open-label extension, all of which completed EPIDYS. Of these, 8 received givinostat throughout and 3 previously received placebo. Study authors noted that because of the limited numbers, there was a high variability, with limited changes observed from baseline.

A propensity-matched analysis within the extension pinned 142 patients on givinostat with 142 patients from a natural history cohort. All told, patients treated with givinostat showed delayed disease progression compared with a natural history cohort across all endpoints. Adding givinostat to corticosteroids prolonged the ability to rise from the floor by a median of 2.0 years (HR, 0.66; 95% CI, 0.45–0.96; P = 0.028), complete 4SC by 3.3 years (HR, 0.39; 95% CI, 0.24–0.65; P <0.001), and maintain ambulation by 2.9 years (HR, 0.42; 95% CI, 0.23–0.76; P = 0.004). Similar results were observed when the full givinostat cohort was compared against all patients in the natural history datasets.

Craig M. McDonald, MD, PhD

"These new findings show that treatment with givinostat continues to have a positive impact by addressing symptoms that patients are most concerned about, and that these long-term benefits are achieved over several years while treatment remains safe and tolerable," lead investigator Craig M. McDonald, MD, PhD, chair of the department of Physical Medicine & Rehabilitation, at the University of California Davis Health, said in a statement.

REFERENCES
1. ITF Therapeutics Announces Publication of Positive Long-Term Data Reinforcing Givinostat Efficacy and Safety as a Treatment for Duchenne Muscular Dystrophy. News release. ITF Therapeutics. August 25, 2025. Accessed August 28, 2025. https://www.prnewswire.com/news-releases/itf-therapeutics-announces-publication-of-positive-long-term-data-reinforcing-givinostat-efficacy-and-safety-as-a-treatment-for-duchenne-muscular-dystrophy-302537372.html
2. 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