Givinostat

Givinostat (ITF2357) is an experimental oral therapy being developed by Italfarmaco to treat Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

How givinostat works

DMD and BMD are caused by mutations in the DMD gene, which contains the instructions for cells to make dystrophin. Dystrophin is an important protein for muscle health, preventing wear and tear (mechanical stress) during movement (muscle contraction). Mutations in the DMD gene lead to shortage of working dystrophin. Without this protein, muscles become damaged over time and replaced with scar tissue (fibrosis) and fat, leading to muscle wasting and weakness.

Givinostat is a molecule that works to inhibit enzymes called histone deacetylases (HDACs), which turn off gene activity and can affect the ability of muscle cells to regenerate. By blocking HDACs, givinostat aims to lessen muscle fibrosis and wasting, while enabling muscle cells to regenerate.

Givinostat in clinical trials

An open-label, two-part Phase 2 trial (NCT01761292) investigated the safety, tolerability, pharmacokinetics (movement into, through and out of the body), and effects on tissues of givinostat. The trial recruited 20 boys with DMD, ages 7 to 11, who were still able to walk. All enrolled also remained on a stable dose of corticosteroids.

During the study’s first dose-establishing part, four boys initially received 25 mg of oral givinostat twice a day. Once safety was determined, these four plus eight other boys (12 in total) were given 50 mg of givinostat twice daily (one left the study). Seven other boys joined, with all now given givinostat at 37.5 mg twice a day. This part ran for two months and those who completed it moved into the trial’s second part.

Here, 19 boys were treated with 37.5 mg of givinostat, determined as the best dose in part one, twice a day for 12 months. Seven boys stayed at that dose for the year, while 12 others were moved to a 25 mg twice daily dose.

Results showed that treatment with givinostat increased the proportion of muscle fibers and reduced fibrosis and tissue death. Givinostat was seen to be safe and well-tolerated overall, with lower levels of platelets being a dose-limiting side effect. The study was not able to show improvements in functional exams, like the six-minute walk test (6MWT), which the investigators attributed to its small number of patients.

Givinostat is being assessed in the double-blind Phase 3 trial (NCT02851797) called EPIDYS. The study recruited 169 boys with DMD, ages 6 to 17, at multiple sites in the U.S., Canada, Israel, and Europe. Patients were randomized 2:1 to either givinostat as a 10 mg/mL oral solution or a placebo solution, given twice a day with food.

Its primary goal is changes in the four-stair climb test after 18 months of treatment. Other functional tasks — like the 6MWT and time to rise from the floor — will be assessed, as will fat infiltration of muscle via magnetic resonance spectroscopy. Top-line results are expected by June 2022.

Patients who took part in a givinostat clinical trial may also continue or start on treatment in an open-label extension study (NCT03373968). The starting dosage will be the same given at the end of their previous trial. The extension study is monitoring the long-term safety, tolerability, and effectiveness of givinostat when used with corticosteroids.

Givinostat was also investigated in a double-blind Phase 2 trial (NCT03238235) in adult men with BMD. A total of 51 patients, ages 18 to 65, were enrolled in at locations in Italy and the Netherlands. Patients randomly received 10 mg/mL of givinostat as an oral solution, or a placebo solution, twice a day for 12 months. The study investigated changes in muscle fibrosis from biopsies taken at the trial’s start and after a year of treatment. It also looked at other changes in tissue samples, as well as functional tasks, and evaluated safety through reported adverse events.

One-year results showed the trial at it’s main goal, that of significantly reducing fibrosis relative to placebo. Givinostat’s use, however, stopped muscle decline and fat infiltration compared with patients given a placebo. No serious side effects were reported. The common treated-related side effects were diarrhea, decreased platelet count, and increased triglycerides, all in keeping with results of earlier trials.

Other information

The U.S. Food and Drug Administration (FDA) designated givinostat a rare pediatric disease in 2020, a status  given to potential therapies aiming to treat rare, serious or life-threatening diseases that primarily affect children. If givinostat is approved, Italfarmaco is eligible for a priority review voucher that can be used on a subsequent application for a different product.

The FDA also has granted givinostat orphan drug and fast track designations for the treatment of DMD and BMD, and it was designated an orphan medicinal product for Duchenne by the European Medicines Agency (EMA). These designations are aimed at accelerating givinostat’s clinical development and provide certain benefits to the company, such as a period of marketing exclusivity if the therapy is approved.

 

Last updated: March 24, 2022, by Teresa Carvalho MS

 


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