Givinostat

Givinostat

Clinical data
Trade names	Duvyzat
AHFS/Drugs.com	Monograph
MedlinePlus	a624025
License data	US DailyMed: Givinostat
Routes of administration	By mouth
Drug class	Histone deacetylase inhibitor
ATC code	M09AX14 (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
IUPAC name {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate
CAS Number	497833-27-9 Y
PubChem CID	9804992
IUPHAR/BPS	7490
DrugBank	DB12645
ChemSpider	7980752 N
UNII	5P60F84FBH
KEGG	D12742
ChEBI	CHEBI:94187
ChEMBL	ChEMBL1213492
PDB ligand	QCM (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID70198049
ECHA InfoCard	100.258.524
Chemical and physical data
Formula	C24H27N3O4
Molar mass	421.497 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(OCc2cc1ccc(cc1cc2)CN(CC)CC)Nc3ccc(cc3)C(=O)NO
InChI InChI=1S/C24H27N3O4/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28) N Key:YALNUENQHAQXEA-UHFFFAOYSA-N N
NY (what is this?)  (verify)

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

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.

Further reading

• Job-Deslandre C (January 2007). "Idiopathic juvenile-onset systemic arthritis". Orphanet. Orphan number: ORPHA85414. Archived from the original on 6 September 2010. Retrieved 17 September 2010.
• Amaru Calzada A, Todoerti K, Donadoni L, Pellicioli A, Tuana G, Gatta R, et al. (August 2012). "The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2(V617F) myeloproliferative neoplasm cells". Experimental Hematology. 40 (8): 634–45.e10. doi:10.1016/j.exphem.2012.04.007. PMID 22579713.