The European Medicines Agency (EMA) has begun reviewing Italfarmaco's application for givinostat, a potential treatment for Duchenne muscular dystrophy (DMD). This follows the U.S. Food and Drug Administration (FDA) granting priority review to the same application, potentially accelerating its approval in the United States. The submissions are based on data from the Phase 3 EPIDYS trial (NCT02851797), a study of 179 boys with DMD.
Mechanism of Action
Givinostat is designed to inhibit histone deacetylases (HDACs), enzymes that regulate gene expression. In individuals with DMD, HDACs become overly active, contributing to muscle weakness and wasting. By blocking HDACs, givinostat aims to restore normal gene expression, including the FST gene, which encodes follistatin. Follistatin is expected to promote muscle mass development and prevent the accumulation of fat and scar tissue, thereby facilitating muscle repair.
EPIDYS Trial Results
The Phase 3 EPIDYS trial evaluated givinostat against a placebo in 179 boys aged 6-17 years with DMD who were still able to walk. Participants were on a stable regimen of Emflaza (deflazacort) or other oral corticosteroids for at least six months. They were randomized in a 2:1 ratio to receive either givinostat (10 mg/mL) or a placebo twice daily for 18 months.
The primary endpoint was the change in the time needed to climb four stairs from the start of the trial to the end of the treatment period. Secondary endpoints included assessments of other motor function measures, muscle strength, fat infiltration in muscles, and the incidence of side effects.
Results from the EPIDYS trial indicated that givinostat significantly slowed the decline in motor function. Boys receiving the placebo took an average of 1.78 seconds longer to climb four stairs compared to those on givinostat. Improvements were also observed in other measures of motor function. Furthermore, givinostat delayed fat build-up in the vastus lateralis muscle in the thigh by approximately 30% compared to the placebo.
The most common side effects reported were diarrhea, abdominal pain, low platelet counts, and elevated triglyceride levels. The majority (95%) of these side effects were mild to moderate in severity, with only three boys discontinuing givinostat treatment due to adverse events.
Implications for DMD Treatment
"The Phase 3 evaluation of Givinostat demonstrated that it can slow DMD progression in boys six years and older. If approved, givinostat could greatly benefit younger and older DMD patients by preserving their motor skills and muscle strength," said Paolo Bettica, MD, PhD, chief medical officer at Italfarmaco.
Givinostat has been granted orphan drug designation for DMD by the EMA, as well as rare pediatric disease, orphan drug, and fast track designations by the FDA.
