• Source: Givinostat

Givinostat, sold under the brand name Duvyzat is a medication used for the treatment of Duchenne muscular dystrophy. It is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and loss of muscle.
The most common side effects include diarrhea, abdominal pain, low platelets (thrombocytopenia), nausea/vomiting, an increase in triglycerides (a type of fat in the body) (hypertriglyceridemia), and fever.
Givinostat was approved for medical use in the United States in March 2024. Givinostat is the first nonsteroidal medication approved by the US Food and Drug Administration (FDA) to treat people with all genetic variants of Duchenne muscular dystrophy.




Medical uses


Givinostat is indicated for the treatment of Duchenne muscular dystrophy in people six years of age and older.




Adverse effects


In clinical trials of givinostat as a salvage therapy for advanced Hodgkin's lymphoma, the most common adverse reactions were fatigue (seen in 50% of participants), mild diarrhea or abdominal pain (40% of participants), moderate thrombocytopenia (decreased platelet counts, seen in one third of patients), and mild leukopenia (a decrease in white blood cell levels, seen in 30% of patients). One-fifth of patients experienced prolongation of the QT interval, a measure of electrical conduction in the heart, severe enough to warrant temporary suspension of treatment.




Mechanism of action


Givinostat inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6.
It also has activity against cells expressing JAK2(V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera. In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease.




History


ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.
The efficacy of givinostat for the treatment of Duchenne muscular dystrophy was evaluated in a randomized, double-blind, placebo-controlled 18-month phase III study. The primary endpoint was the change from baseline to month 18 using a four stair climb to measure muscle function. All participants continued to receive a standard of care steroid regimen throughout the study and, after 18 months of treatment, participants treated with givinostat showed statistically significant less decline in the time it took to climb four stairs compared to placebo. The mean change from baseline to month 18 in time to climb four stairs was 1.25 seconds for participants receiving givinostat compared to 3.03 seconds for participants receiving placebo. A secondary efficacy endpoint was the change from baseline to month 18 in physical function as assessed by the North Star Ambulatory Assessment (NSAA)—a scale commonly used to rate the motor function in boys with Duchenne muscular dystrophy who are capable of walking. Compared to placebo, participants treated with givinostat saw less worsening in their NSAA score after 18 months. The US Food and Drug Administration (FDA) granted the application for givinostat priority review, fast track, orphan drug, and rare pediatric disease designations. The FDA granted the approval of Duvyzat to Italfarmaco S.p.A. The FDA approved givinostat based on evidence from a single clinical trial (NCT02851797) of 179 males with Duchenne muscular dystrophy who were six years of age and older who could walk and were on stable background therapy with steroids. The trial was conducted at 45 sites in 11 countries in North America and Europe. Twenty-eight of the participants were from the United States.




Society and culture






= Names

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Givinostat is the international nonproprietary name.




Research


Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas), and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis, polycythaemia vera. and Duchenne muscular dystrophy.
A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.




References






Further reading

Kata Kunci Pencarian:

• Givinostat
• Duchenne muscular dystrophy
• Histone deacetylase inhibitor
• Muscular dystrophy
• Becker muscular dystrophy
• ATC code M09
• Ketone bodies
• Nicotinamide
• Capsaicin
• Sulforaphane