Givinostat Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:451563965
Tradename:Duvyzat
Dailymedid:Givinostat
Routes Of Administration:By mouth
Class:Histone deacetylase inhibitor
Atc Prefix:M09
Atc Suffix:AX14
Legal Us:Rx-only
Legal Us Comment:[1]
Cas Number:497833-27-9
Pubchem:9804992
Iuphar Ligand:7490
Drugbank:DB12645
Chemspiderid:7980752
Unii:5P60F84FBH
Kegg:D12742
Chebi:94187
Chembl:1213492
Pdb Ligand:QCM
Iupac Name:methyl [4-(hydroxycarbamoyl)phenyl]carbamate
C:24
H:27
N:3
O:4
Smiles:O=C(OCc2cc1ccc(cc1cc2)CN(CC)CC)Nc3ccc(cc3)C(=O)NO
Stdinchi: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)
Stdinchikey:YALNUENQHAQXEA-UHFFFAOYSA-N

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.[2] 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.[3] [4] 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.[5]

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.[6] [7] 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.[8] [9]

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[10]) 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.[11]

Society and culture

Names

Givinostat is the international nonproprietary name.[12]

Research

Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas),[13] and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis,[14] polycythaemia vera.[15] and Duchenne muscular dystrophy.

A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.[16]

Further reading

Notes and References

  1. Web site: Duvyzat- givinostat suspension . DailyMed . 29 March 2024 . 25 April 2024 . 30 April 2024 . https://web.archive.org/web/20240430043651/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a28a3db-7880-4ac2-a2f2-2b4e362aafb6 . live .
  2. Web site: NCI Drug Dictionary . National Cancer Institute . 23 March 2024 . 29 June 2023 . https://web.archive.org/web/20230629035243/https://www.cancer.gov/publications/dictionaries/cancer-drug/def/givinostat . live .
  3. Web site: FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy . U.S. Food and Drug Administration (FDA) . 21 March 2024 . 23 March 2024 . 23 March 2024 . https://web.archive.org/web/20240323061939/https://www.fda.gov/news-events/press-announcements/fda-approves-nonsteroidal-treatment-duchenne-muscular-dystrophy . live .
  4. Web site: Novel Drug Approvals for 2024 . U.S. Food and Drug Administration (FDA) . 29 April 2024 . 30 April 2024 . 30 April 2024 . https://web.archive.org/web/20240430031024/https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 . live .
  5. Tan J, Cang S, Ma Y, Petrillo RL, Liu D . Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents . Journal of Hematology & Oncology . 3 . 5 . February 2010 . 20132536 . 2827364 . 10.1186/1756-8722-3-5 . free .
  6. Vannucchi AM, Guglielmelli P, Pieri L, Antonioli E, Bosi A . Treatment options for essential thrombocythemia and polycythemia vera . Expert Review of Hematology . 2 . 1 . 41–55 . February 2009 . 21082994 . 10.1586/17474086.2.1.41 . 28311699 . 18 September 2010 . 1 July 2015 . https://web.archive.org/web/20150701173907/http://www.medscape.com/viewarticle/589735 . live .
  7. Guerini V, Barbui V, Spinelli O, Salvi A, Dellacasa C, Carobbio A, Introna M, Barbui T, Golay J, Rambaldi A . The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F) . Leukemia . 22 . 4 . 740–7 . April 2008 . 18079739 . 10.1038/sj.leu.2405049 . free .
  8. WO . 9743251 . Compounds with anti-inflammatory and immunosuppressive activities . 20 November 1997 . Italfarmaco S.p.A. .
  9. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, Modena D, Moras ML, Pozzi P, Reznikov LL, Siegmund B, Fantuzzi G, Dinarello CA, Mascagni P . The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo . Molecular Medicine . 11 . 1–12 . 1–15 . 2005 . 16557334 . 1449516 . 10.2119/2006-00005.Dinarello .
  10. Web site: Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy . ClinicalTrials.gov . 8 July 2024.
  11. Web site: Drug Trials Snapshots: Duvyzat . U.S. Food and Drug Administration . 21 March 2024 . 8 July 2024 . 25 June 2024 . https://web.archive.org/web/20240625070317/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-duvyzat . live .
  12. 2010 . International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63 . WHO Drug Information . 24 . 1 . 58–9 . 4 October 2020 . 15 August 2020 . https://web.archive.org/web/20200815110506/https://www.who.int/medicines/publications/druginformation/innlists/RL63.pdf . live .
  13. Web site: Search results for ITF2357. ClinicalTrials.gov. 13 September 2010. 13 June 2011. https://web.archive.org/web/20110613140155/http://clinicaltrials.gov/ct2/results?term=ITF2357. live.
  14. Web site: Committee for Orphan Medicinal Products. 23 February 2010. Public summary of opinion on orphan designation: Givinostat for the treatment of systemic-onset juvenile idiopathic arthritis. European Medicines Agency. 15 September 2010. 3 March 2016. https://web.archive.org/web/20160303181524/http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/02/WC500074739.pdf. dead.
  15. Web site: Committee for Orphan Medicinal Products. 3 March 2010. Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera. European Medicines Agency. 17 September 2010. 26 April 2012. https://web.archive.org/web/20120426182252/http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/03/WC500075167.pdf. dead.
  16. News: Potential treatment for diastolic dysfunction in heart failure. ScienceDaily. 19 August 2018. 19 August 2018. https://web.archive.org/web/20180819214302/https://www.sciencedaily.com/releases/2018/02/180207164033.htm. live.