givinostat

givinostat, drug used to help slow the advance of Duchenne muscular dystrophy (DMD), a genetic condition characterized by progressive muscle degeneration and weakness. Givinostat is the first nonsteroidal medication available to treat all genetic variants of DMD. The drug was approved in 2024 by the U.S. Food and Drug Administration (FDA) for the treatment of DMD; it is marketed under the trade name Duvyzat.

Development and mechanism of action

Givinostat belongs to a class of drugs known as histone deacetylase (HDAC) inhibitors. HDAC inhibitors gained attention in the early 2000s for their ability to modify gene expression, which could be beneficial for treating cancer, inflammation, and genetic diseases. Italfarmaco SpA, a pharmaceutical company based in Italy, began developing givinostat as an HDAC inhibitor to target diseases with high levels of inflammation and fibrosis, recognizing the potential of HDAC inhibition in controlling these processes. In the 2010s the company focused its efforts primarily on the promise of givinostat for treating DMD.

HDAC inhibition allows for increased acetylation of histone proteins, which combine with DNA to form nucleoproteins. Increased acetylation in turn leads to a more open chromatin structure that enhances the expression of genes. In DMD, these effects help combat dystrophin deficiency, a central feature of the disease—the absence of dystrophin protein is responsible for the loss of structural integrity of muscle fibers, which results in muscle degeneration. Through HDAC inhibition, givinostat promotes the production of larger muscle fibers, thereby influencing muscle size and structure and leading to overall enhanced muscle regeneration. Givinostat also is able to reduce inflammation and fibrosis in muscle tissue. These effects, combined with improved muscle fiber structure, can potentially help slow disease progression in DMD.

Administration and side effects

Givinostat is taken orally. Dosing depends generally on age and weight but may be modified on the basis of platelet and triglyceride levels, which can change during the course of treatment and therefore require regular monitoring. Potential side effects include gastrointestinal symptoms, such as diarrhea, nausea, and vomiting, as well as general fatigue and muscle weakness. Decreased appetite and hypothyroidism can also occur. Givinostat can also cause QTc interval prolongation, in which the electrical system of the heart takes longer than normal to reset between heartbeats. Thus, the drug is avoided in patients with ventricular arrhythmias, including congenital long QT syndrome (a genetic condition that can result in sudden cardiac death), and those affected by coronary heart disease or electrolyte imbalances.

Ongoing research

Givinostat is under investigation for additional applications, particularly polycythemia vera, a type of myeloproliferative disorder (MPD) characterized by excess production of red blood cells by the bone marrow. Givinostat can potentially improve the regulation of blood cell production in polycythemia vera and other MPDs, helping reduce excess blood cells and lowering the risk of complications such as blood clots.