Givinostat

Givinostat
Clinical data
Trade namesDuvyzat
Other namesITF-2357; ITF2357
AHFS/Drugs.comMonograph
MedlinePlusa624025
License data
Routes of
administration		Oral (suspension)[1]
Drug classHistone deacetylase inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUnknown[5]
Protein binding96%[6][1]
MetabolismExtensive (not CYP450 or UGT)[6]
Onset of action2–3 hours (TmaxTooltip time to peak levels)[6][1]
Elimination half-life~6 hours[6][1]
ExcretionUrine: <3% unchanged[6][1]
Identifiers
  • {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.258.524
Chemical and physical data
FormulaC24H27N3O4
Molar mass421.497 g·mol−1
3D model (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) X markN
  • Key:YALNUENQHAQXEA-UHFFFAOYSA-N X markN
 X markNcheckY (what is this?)  (verify)

Givinostat, sold under the brand name Duvyzat is a medication used for the treatment of Duchenne muscular dystrophy.[2][7] It is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.[8] It works by targeting pathogenic processes to reduce inflammation and loss of muscle.[7]

The most common side effects include diarrhea, abdominal pain, low platelets (thrombocytopenia), nausea and vomiting, an increase in triglycerides (a type of fat in the body) (hypertriglyceridemia), and fever.[7][9]

Givinostat was approved for medical use in the United States in March 2024.[7][10] 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.[7] The FDA considers it to be a first-in-class medication.[11]

Medical uses

Givinostat is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people six years of age and older.[2][7][1]

Available forms

Givinostat is available in the form of an oral suspension.[6][1]

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.[12]

Pharmacology

Mechanism of action

Givinostat activities
EnzymeIC50Tooltip Half-maximal inhibitory concentration (nM)
HDAC1133–198
HDAC2293–325
HDAC3136–157
HDAC41,059
HDAC5532
HDAC6312–315
HDAC7524
HDAC8837–854
HDAC9512–541
HDAC10331–340
HDAC11287–292
Refs: [13][14]

Givinostat is a potent pan-histone deacetylase (HDAC) inhibitor.[1][14] It non-selectively inhibits all 11 of the HDAC enzymes, with several-fold variation in inhibitory potency across them.[13][14] The drug inhibits several pro-inflammatory cytokines, including reducing expression of tumour necrosis factor (TNF), interleukin-1α (IL-1α) and 1β (IL-1β), and interleukin-6 (IL-6) in preclinical research[15] and in humans.[1]

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.[16][17] In patients with polycythemia, 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.[18]

Pharmacokinetics

The bioavailability of givinostat is unknown.[5] The time to peak levels of givinostat is 2 to 3 hours taken orally.[6][1] Givinostat efficiently crosses into the brain in rodents.[19][20][21][22] It is described as unique in this regard, as many other histone deacetylase inhibitors poorly penetrate into the brain.[19] However, in another study, givinostat was reported to have poor brain penetrance and only subtle brain HDAC inhibition in rodents.[23] The plasma protein binding of givinostat is 96%.[6][1] It is extensively metabolism, but cytochrome P450 (CYP450) and glucuronosyltransferase (UGTs) enzymes are not majorly involved.[6] The elimination half-life of givinostat is approximately 6 hours.[6][1] It is mainly eliminated via metabolism and is excreted in urine less than 3% unchanged.[6][1]

History

Givinostat was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.[24][15]

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.[7] The primary endpoint was the change from baseline to month 18 using a four stair climb to measure muscle function.[7] 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.[7] 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.[7] 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.[7] Compared to placebo, participants treated with givinostat saw less worsening in their NSAA score after 18 months.[7] The US Food and Drug Administration (FDA) granted the application for givinostat priority review, fast track, orphan drug, and rare pediatric disease designations.[7] The FDA granted the approval of Duvyzat to Italfarmaco S.p.A.[7] The FDA approved givinostat based on evidence from a single clinical trial (NCT02851797[25]) 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.[2][9] The trial was conducted at 45 sites in 11 countries in North America and Europe.[9] Twenty-eight of the participants were from the United States.[9]

Society and culture

In April 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Duvyzat, intended for the treatment of Duchenne muscular dystrophy (DMD).[3] The applicant for this medicinal product is Italfarmaco S.p.A.[3] The CHMP's opinion is based on data from a subgroup of 120 participants (79 treated with givinostat and 41 with placebo) in a randomized, placebo-controlled study in ambulant participants with Duchenne muscular dystrophy aged six years of age or older on concomitant steroid treatment.[26] The safety profile of Duvyzat is based on data from 179 participants.[26] The most common events in participants treated with givinostat were diarrhoea, abdominal pain, thrombocytopenia (low levels of blood platelets), vomiting, hypertriglyceridaemia (high blood levels of triglycerides, a type of fat) and fever.[26] Givinostat was authorized for medical use in the European Union in June 2025.[3][4]

Names

Givinostat is the generic name of the drug and its International Nonproprietary Name (INN).[27]

Research

In addition to being approved for Duchenne muscular dystrophy (DMD), givinostat is under development for the treatment of polycythemia vera and myeloproliferative disorders.[28][29] As of June 2026, it is in phase 3 clinical trials for polycythemia vera and phase 2 trials for myeloproliferative disorders.[28] The drug was also previously under development for a wide variety of other cancers and inflammatory diseases, including chronic lymphocytic leukemia, Crohn's disease, diffuse large B cell lymphoma (DLBCL), hereditary autoinflammatory diseases, Hodgkin's disease (Hodgkin lymphoma), juvenile rheumatoid arthritis, and multiple myeloma, but development for these uses was discontinued.[28]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 Lamb YN (July 2024). "Givinostat: First Approval". Drugs. 84 (7): 849–856. doi:10.1007/s40265-024-02052-1. PMID 38967716.
  2. 1 2 3 4 "Duvyzat- givinostat suspension". DailyMed. 29 March 2024. Archived from the original on 30 April 2024. Retrieved 25 April 2024.
  3. 1 2 3 4 "Duvyzat EPAR". European Medicines Agency (EMA). 25 April 2025. Retrieved 2 May 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. 1 2 "Duvyzat PI". Union Register of medicinal products. 6 June 2025. Retrieved 14 June 2025.
  5. 1 2 "Givinostat: Uses, Interactions, Mechanism of Action". DrugBank. Retrieved 2 August 2026.
  6. 1 2 3 4 5 6 7 8 9 10 11 "Highlights of prescribing information - DUVYZAT (givinostat) oral suspension" (PDF). Archived from the original (PDF) on 23 March 2024.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "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.
  8. ↑ "NCI Drug Dictionary". National Cancer Institute. Archived from the original on 29 June 2023. Retrieved 23 March 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  9. 1 2 3 4 "Drug Trials Snapshots: Duvyzat". U.S. Food and Drug Administration. 21 March 2024. Archived from the original on 25 June 2024. Retrieved 8 July 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  10. ↑ "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.
  11. ↑ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
  12. ↑ Tan J, Cang S, Ma Y, Petrillo RL, Liu D (February 2010). "Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents". Journal of Hematology & Oncology. 3 5. doi:10.1186/1756-8722-3-5. PMC 2827364. PMID 20132536.
  13. 1 2 Matalon S, Palmer BE, Nold MF, Furlan A, Kassu A, Fossati G, et al. (May 2010). "The histone deacetylase inhibitor ITF2357 decreases surface CXCR4 and CCR5 expression on CD4(+) T-cells and monocytes and is superior to valproic acid for latent HIV-1 expression in vitro". J Acquir Immune Defic Syndr. 54 (1): 1–9. doi:10.1097/QAI.0b013e3181d3dca3. PMC 3534976. PMID 20300007.
  14. 1 2 3 Li S, Fossati G, Marchetti C, Modena D, Pozzi P, Reznikov LL, et al. (January 2015). "Specific inhibition of histone deacetylase 8 reduces gene expression and production of proinflammatory cytokines in vitro and in vivo". J Biol Chem. 290 (4): 2368–2378. doi:10.1074/jbc.M114.618454. PMC 4303687. PMID 25451941.
  15. 1 2 Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, et al. (2005). "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. doi:10.2119/2006-00005.Dinarello. PMC 1449516. PMID 16557334.
  16. ↑ Vannucchi AM, Guglielmelli P, Pieri L, Antonioli E, Bosi A (February 2009). "Treatment options for essential thrombocythemia and polycythemia vera". Expert Review of Hematology. 2 (1): 41–55. doi:10.1586/17474086.2.1.41. PMID 21082994. S2CID 28311699. Archived from the original on 1 July 2015. Retrieved 18 September 2010.
  17. ↑ Guerini V, Barbui V, Spinelli O, Salvi A, Dellacasa C, Carobbio A, et al. (April 2008). "The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F)". Leukemia. 22 (4): 740–7. doi:10.1038/sj.leu.2405049. hdl:11380/1331657. PMID 18079739.
  18. ↑ 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.
  19. 1 2 Nakagawa-Saito Y, Mitobe Y, Togashi K, Suzuki S, Sugai A, Kitanaka C, et al. (March 2023). "Givinostat Inhibition of Sp1-dependent MGMT Expression Sensitizes Glioma Stem Cells to Temozolomide". Anticancer Res. 43 (3): 1131–1138. doi:10.21873/anticanres.16258. PMID 36854532. [...] a large number of HDAC inhibitors have been developed and tested in preclinical and clinical studies in GBM. However, HDAC inhibitors are in general characterized by a narrow therapeutic index and poor penetrability of the blood-brain barrier (BBB) [...] givinostat is unique as an HDAC inhibitor in that it effectively crosses the BBB to increase the acetylation of histone H3 in the brain parenchyma (12).
  20. ↑ Gao QC, Liu GL, Wang Q, Zhang SX, Ji ZL, Wang ZJ, et al. (December 2024). "A promising drug repurposing approach for Alzheimer's treatment: Givinostat improves cognitive behavior and pathological features in APP/PS1 mice". Redox Biol. 78 103420. doi:10.1016/j.redox.2024.103420. PMC 11621940. PMID 39577323. [...] Givinostat can effectively cross the blood-brain barrier (BBB) [23].
  21. ↑ Marampon F, Leoni F, Mancini A, Pietrantoni I, Codenotti S, Ferella L, et al. (February 2019). "Histone deacetylase inhibitor ITF2357 (givinostat) reverts transformed phenotype and counteracts stemness in in vitro and in vivo models of human glioblastoma". J Cancer Res Clin Oncol. 145 (2): 393–409. doi:10.1007/s00432-018-2800-8. PMC 11810183. PMID 30474756. [...] in in vivo experiments, ITF2357 efficiently passed the blood-brain barrier, so rapidly reaching high concentration in the brain tissues, [...]
  22. ↑ Taiarol L, Bigogno C, Sesana S, Kravicz M, Viale F, Pozzi E, et al. (June 2022). "Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics". Cancers (Basel). 14 (12): 2978. doi:10.3390/cancers14122978. PMC 9220922. PMID 35740641. [...] the ability of Givinostat to cross the blood-brain barrier (BBB) and reach the brain parenchyma at therapeutic doses have never been directly demonstrated but only deduced from the downstream effects of its administration [12]. [...] The amount of Givinostat measured in the brain is shown in Figure 2B (all concentrations are available in Table S3), suggesting that the encapsulation of Givinostat in liposomes improved drug delivery to the brain. [...] As Givinostat is a hydrophobic small molecule (~400 Da), it is able to cross the BBB by simple diffusion, unlike liposome formulations, which cross the BBB through endo/transcytosis [38].
  23. ↑ Schroeder FA, Wang C, Van de Bittner GC, Neelamegam R, Takakura WR, Karunakaran A, et al. (October 2014). "PET imaging demonstrates histone deacetylase target engagement and clarifies brain penetrance of known and novel small molecule inhibitors in rat". ACS Chem Neurosci. 5 (10): 1055–1062. doi:10.1021/cn500162j. PMC 4198064. PMID 25188794. Quantification of dynamic imaging data revealed that the hydroxamates SAHA and givinostat both resulted in only subtle blockade of radiotracer binding in whole brain (Figure 3A), consistent with recent reports demonstrating poor brain penetrance of the prototypical hydroxamic acid HDAC inhibitor, SAHA.14,15 Poor brain penetrance was overcome in the development of martinostat by the addition of an adamantyl group, a chemical moiety frequently used developing in CNS-penetrant compounds.10
  24. ↑ WO 9743251, "Compounds with anti-inflammatory and immunosuppressive activities", published 20 November 1997, assigned to Italfarmaco S.p.A.
  25. ↑ "Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy". ClinicalTrials.gov. 9 January 2023. Retrieved 8 July 2024.
  26. 1 2 3 "New treatment against Duchenne muscular dystrophy". European Medicines Agency (EMA). 25 April 2025. Retrieved 2 May 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  27. ↑ "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.
  28. 1 2 3 "Italfarmaco". AdisInsight. 16 June 2026. Retrieved 2 August 2026.
  29. ↑ "Search results for ITF2357". ClinicalTrials.gov. Archived from the original on 13 June 2011. Retrieved 13 September 2010.

Further reading

This page is issued from Wikipedia. The text is available under Creative Commons Attribution-Share Alike 4.0 unless otherwise noted. Additional terms may apply for the media files.