Givinostat

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Givinostat
Clinical data
Trade namesDuvyzat
License data
By mouth
ATC code
Legal status
Legal status
Identifiers
  • {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate
JSmol)
  • O=C(OCc2cc1ccc(cc1cc2)CN(CC)CC)Nc3ccc(cc3)C(=O)NO
  • 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
 ☒NcheckY (what is this?)  (verify)

Givinostat, sold under the brand name Duvyzat is a

antineoplastic activities.[3] It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and loss of muscle.[2]

The most common side effects include diarrhea, abdominal pain, a decrease in platelets—which can lead to increased bleeding—nausea/vomiting, an increase in triglycerides (a type of fat in the body) and fever.[2]

Givinostat was approved for medical use in the United States in March 2024.[2][4] Givinostat is the first nonsteroidal medication approved by the FDA to treat people with all genetic variants of Duchenne Muscular Dystrophy.[2]

Medical uses

Givinostat is indicated for the treatment of Duchenne muscular dystrophy in people six years of age and older.[1][2]

Adverse effects

In clinical trials of givinostat as a

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

interleukin 1α and β, and interleukin 6.[6]

It also has activity against cells expressing JAK2(V617F), a mutated form of the

erythrocytes and ameliorate the symptoms of the disease.[9]

History

Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas),

polycythaemia vera.[9] and Duchenne muscular dystrophy
.

A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.[12]

ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.[13][6]

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.[2] The primary endpoint was the change from baseline to month 18 using a four stair climb to measure muscle function.[2] 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.[2] 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.[2] 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.[2] Compared to placebo, participants treated with givinostat saw less worsening in their NSAA score after 18 months.[2] The US Food and Drug Administration (FDA) granted the application for givinostat priority review, fast track, orphan drug, and rare pediatric disease designations.[2] The FDA granted the approval of Duvyzat to Italfarmaco S.p.A.[2]

Society and culture

Names

Givinostat is the international nonproprietary name.[14]

References

  1. ^ a b c "Duvyzat- givinostat suspension". DailyMed. 29 March 2024. Archived from the original on 30 April 2024. Retrieved 25 April 2024.
  2. ^ a b c d e f g h i j k l m n "FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy". U.S. Food and Drug Administration (FDA). 21 March 2024. Archived from the original on 23 March 2024. Retrieved 23 March 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ "NCI Drug Dictionary". National Cancer Institute. Archived from the original on 29 June 2023. Retrieved 23 March 2024.
  4. ^ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
  5. PMID 20132536
    .
  6. ^
    PMID 16557334
    .
  7. S2CID 28311699. Archived
    from the original on 1 July 2015. Retrieved 18 September 2010.
  8. PMID 18079739
    .
  9. ^ a b Committee for Orphan Medicinal Products (3 March 2010). "Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera" (PDF). European Medicines Agency. Archived from the original (PDF) on 26 April 2012. Retrieved 17 September 2010.
  10. ^ "Search results for ITF2357". ClinicalTrials.gov. Archived from the original on 13 June 2011. Retrieved 13 September 2010.
  11. ^ 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" (PDF). European Medicines Agency. Archived from the original (PDF) on 3 March 2016. Retrieved 15 September 2010.
  12. ^ "Potential treatment for diastolic dysfunction in heart failure". ScienceDaily. Archived from the original on 19 August 2018. Retrieved 19 August 2018.
  13. ^ WO 9743251, "Compounds with anti-inflammatory and immunosuppressive activities", published 20 November 1997, assigned to Italfarmaco S.p.A. 
  14. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63" (PDF). WHO Drug Information. 24 (1): 58–9. 2010. Archived (PDF) from the original on 15 August 2020. Retrieved 4 October 2020.

Further reading
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