How does givinostat work?
DMD and BMD are caused by genetic mutations in the DMD gene, which contains the instructions necessary for cells to make dystrophin. Dystrophin is an important protein that strengthens muscles and helps protect them from injury. When there are mutations in the DMD gene, dystrophin isn’t formed correctly. Without dystrophin, muscles get damaged over time and replaced with scar tissue and fat through a process called fibrosis.
Givinostat is a molecule that inhibits enzymes called histone deacetylases (HDACs) that turn off gene expression and can reduce a muscle’s ability to regenerate. By inhibiting HDACs, givinostat may reduce fibrosis and the death of muscle cells while also enabling muscles to regenerate.
Givinostat in clinical trials
An open-label, two-part Phase 2 trial (NCT01761292) investigated the safety, tolerability, pharmacokinetics (movement in the body), and effects on tissues of givinostat. The trial recruited 20 boys, ages 7 to 10 with DMD in Italy who were still able to walk. During the first part of the study, four boys initially received 25 mg of oral givinostat twice a day. Those four boys plus eight more boys (12 in total) then started receiving 50 mg of givinostat twice a day. One boy dropped out of the study. The other 11 boys joined another seven boys to receive givinostat at a dosage of 37.5 mg twice a day. During the second part of the trial, those 18 boys, plus one more, received 37.5 mg of givinostat twice a day for 12 months.
Researchers published the results of the study in the journal Neuromuscular Disorders. They showed that treatment with givinostat increased the number of muscle fibers and reduced the amount of fibrosis. Givinostat was safe and patients tolerated it well. The study was not able to show improvements in functional tests, however. The authors attributed this to the small sample size.
Ongoing clinical trials
Researchers are currently evaluating givinostat in a randomized, double-blind, placebo-controlled Phase 3 trial (NCT02851797), called EPIDYS. The study has recruited 179 boys with DMD, ages 6–17, at multiple locations in the U.S., Canada, Israel, and Europe. Patients receive either givinostat or a placebo at a 2:1 ratio. Those in the treatment group receive an oral solution of 10 mg/mL of givinostat twice a day with food. The others receive a matching placebo twice a day with food.
The study will look for changes in the four-stair climb test at baseline and after 18 months of treatment. It also will evaluate patients for changes in several functional tasks after 18 months of treatment, as well as changes in fat infiltration by magnetic resonance spectroscopy. The study has finished recruitment and will end in the first quarter of 2022 with top-line data expected in June 2022.
Researchers may invite patients who took part in either of the above trials to continue receiving treatment in an open-label extension study (NCT03373968). The starting dosage for patients will be the same dose they were receiving at the end of their previous trial. The extension trial will monitor the long-term safety, tolerability, and effectiveness of givinostat.
Researchers also are investigating givinostat in a Phase 2 trial (NCT03238235) in adult men with BMD. A total of 51 patients, ages 18–65, enrolled in the trial at locations in Italy and the Netherlands. Patients randomly receive 10 mg/mL of oral givinostat twice a day, or a placebo, for 12 months. The study will investigate changes in muscle cross-sectional areas (CSAs) from biopsies taken at the start of the trial and 12 months later. It also will look at changes in other histological samples, as well as functional tasks. Enrollment is complete and researchers estimate to conclude the trial in March 2021.
The U.S. Food and Drug Administration has granted givinostat orphan drug, fast track, and rare pediatric disease designations for the treatment of DMD and BMD. The European Commission also granted givinostat orphan medicinal product designation for treating DMD and BMD.
Last updated: Nov. 5, 2020
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