Ivosidenib Explained

Pronounce:
Tradename:Tibsovo
Dailymedid:Ivosidenib
Pregnancy Au:D
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth
Class:Antineoplastic agent
Atc Prefix:L01
Atc Suffix:XX62
Legal Au:S4
Legal Au Comment:[2]
Legal Us:Rx-only
Legal Us Comment:[3] [4]
Legal Eu:Rx-only
Legal Eu Comment:[5] [6]
Cas Number:1448347-49-6
Pubchem:71657455
Drugbank:DB14568
Chemspiderid:38772333
Unii:Q2PCN8MAM6
Kegg:D11090
Chebi:145430
Chembl:3989958
Synonyms:AG-120
Iupac Name:(2S)-N--1-(4-cyanopyridin2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine2-carboxamide
C:28
H:22
Cl:1
F:3
N:6
O:3
Smiles:c1ccc(c(c1)[C@@H](C(=O)NC2CC(C2)(F)F)N(c3cc(cnc3)F)C(=O)[C@@H]4CCC(=O)N4c5cc(ccn5)C#N)Cl
Stdinchi Comment:1S/C28H22ClF3N6O3/c29-21-4-2-1-3-20(21)25(26(40)36-18-11-28(31,32)12-18)37(19-10-17(30)14-34-15-19)27(41)22-5-6-24(39)38(22)23-9-16(13-33)7-8-35-23/h1-4,7-10,14-15,18,22,25H,5-6,11-12H2,(H,36,40)/t22-,25-/m0/s1
Stdinchikey:WIJZXSAJMHAVGX-DHLKQENFSA-N

Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. Ivosidenib is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells.

Ivosidenib was approved for medical use in the United States in July 2018,[7] [8] [9] [10] and in the European Union in May 2023.[11] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[12]

Medical uses

Ivosidenib is indicated for people with acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma.[13] [14]

Adverse effects

In ivosidenib-treated patients, reported adverse effects have been febrile neutropenia, alanine aminotransferase increased, aspartate aminotransferase increased, colitis, hypertension, maculopapular rash. However, Ivosidenib was taken in conjunction with standard AML induction treatment, and side effects can not be directly related to the drug.[15]

History

The US Food and Drug Administration (FDA) awarded orphan drug designations for acute myeloid leukemia and for cholangiocarcinoma.[16] [17] [18] [19]

Society and culture

Legal status

On 23 February 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tibsovo, intended for the treatment of adults with newly diagnosed acute myeloid leukemia and for the treatment of adults with locally advanced or metastatic cholangiocarcinoma. The applicant for this medicinal product is Les Laboratoires Servier.[20] Tibsovo was approved for medical use in the European Union in May 2023.

Research

In tumors from people diagnosed with glioma, acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma, somatic mutations in the conserved active site of isocitrate dehydrogenase (IDH) 1 and 2 are observed. With these new mutations, these enzymes exhibit new, neomorphic behavior, which results in the reduction of α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate. The new molecule competitively inhibits α-ketoglutarate–dependent enzymes, ultimately leading to epigenetic alterations and impaired hematopoietic differentiation. Mutations in the IDH1 enzyme mutations occur in approximately 6 to 10% of the patients with AML, and IDH2 mutations occur in approximately 9 to 13% of those with AML, with unknown statistics on other conditions listed.[21]

The drug is also believed to be a slow-binding inhibitor of the IDH1-WT homodimer. Ivosidenib showed uncompetitive inhibition to the NADP cofactor, showing a hyperbolic curve for the rate constant of inhibition relative to concentration. Ivosidenib also showed no time-dependence in IC50 between 1 and 16 hours of incubation for either homodimer.[22]

Notes and References

  1. Web site: Tibsovo . Therapeutic Goods Administration (TGA) . 19 April 2023 . 29 April 2023 . 19 April 2023 . https://web.archive.org/web/20230419093254/https://www.tga.gov.au/resources/auspmd/tibsovo . live .
  2. Web site: Tibsovo (Servier Laboratories (Aust) Pty Ltd) . Therapeutic Goods Administration (TGA) . 26 April 2023 . 28 April 2023.
  3. Web site: Tibsovo- ivosidenib tablet, film coated . DailyMed . 24 April 2019 . 18 December 2019 . 2 July 2019 . https://web.archive.org/web/20190702162259/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5b6d8ae8-bac8-4e1b-b1b4-7f9665e62de5 . live .
  4. Web site: Tibsovo- ivosidenib tablet, film coated . DailyMed . 9 June 2022 . 3 December 2022 . 3 December 2022 . https://web.archive.org/web/20221203180724/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=65d254c0-67ad-42c4-b972-ad463b755b2d . live .
  5. Web site: Tibsovo EPAR . European Medicines Agency (EMA) . 12 May 2023 . 12 May 2023 . 10 March 2024 . https://web.archive.org/web/20240310060238/https://www.ema.europa.eu/en/medicines/human/EPAR/tibsovo-0 . live .
  6. Web site: Tibsovo . Union Register of medicinal products . 8 May 2023 . 6 June 2023 . 11 May 2023 . https://web.archive.org/web/20230511033825/https://ec.europa.eu/health/documents/community-register/html/h1728.htm . live .
  7. FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation . U.S. Food and Drug Administration (FDA) . 20 July 2018 . https://web.archive.org/web/20191211204726/https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-treatment-patients-relapsed-or-refractory-acute-myeloid-leukemia-who . 11 December 2019 . live . 18 December 2019.
  8. Web site: Drug Trials Snapshots: Tibsovo . U.S. Food and Drug Administration (FDA) . 2 August 2018 . https://web.archive.org/web/20191219004016/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-tibsovo . 19 December 2019 . live . 18 December 2019.
  9. Web site: FDA approves ivosidenib for relapsed or refractory acute myeloid leukemia . U.S. Food and Drug Administration (FDA) . 23 January 2019 . https://web.archive.org/web/20191219005029/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-relapsed-or-refractory-acute-myeloid-leukemia . 19 December 2019 . live . 18 December 2019.
  10. Web site: Drug Approval Package: Tibsovo (ivosidenib) . U.S. Food and Drug Administration (FDA) . 19 December 2019 . 25 June 2021 . https://web.archive.org/web/20210625094257/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211192Orig1s000TOC.cfm . live .
  11. Web site: Tibsovo . Union Register of medicinal products . 8 May 2023 . 12 May 2023 . 11 May 2023 . https://web.archive.org/web/20230511033825/https://ec.europa.eu/health/documents/community-register/html/h1728.htm . live .
  12. New Drug Therapy Approvals 2018 . U.S. Food and Drug Administration (FDA) . January 2019 . PDF . 16 September 2020 . 17 September 2020 . https://web.archive.org/web/20200917055627/https://www.fda.gov/media/120357/download . live .
  13. Web site: FDA approves ivosidenib as first-line treatment for AML with IDH1 mutation . U.S. Food and Drug Administration (FDA) . 3 May 2019 . https://web.archive.org/web/20191219004831/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-first-line-treatment-aml-idh1-mutation . 19 December 2019 . live . 18 December 2019.
  14. Web site: FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma . U.S. Food and Drug Administration (FDA) . 26 August 2021 . 26 August 2021 . 26 August 2021 . https://web.archive.org/web/20210826135915/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-advanced-or-metastatic-cholangiocarcinoma . live .
  15. Stein EM, DiNardo CD, Mims AS, Savona MR, Pratz K, Stein AS, Fathi AT, Stone RM, Pollyea DA, Odenike O . 6 . 7 December 2017 . Ivosidenib or Enasidenib Combined with Standard Induction Chemotherapy Is Well Tolerated and Active in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation: Initial Results from a Phase 1 Trial . Blood . 130 . Suppl 1 . 726 . 10.1182/blood.V130.Suppl_1.726.726 . 12 April 2019 . 29 September 2019 . https://web.archive.org/web/20190929205025/http://www.bloodjournal.org/content/130/Suppl_1/726 . live .
  16. Web site: Tibsovo Orphan Drug Designation and Approval . U.S. Food and Drug Administration (FDA) . 18 December 2019 . 25 June 2021 . https://web.archive.org/web/20210625094256/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=481515 . live .
  17. Web site: Ivosidenib Orphan Drug Designation and Approval . U.S. Food and Drug Administration (FDA) . 18 December 2019 . 25 June 2021 . https://web.archive.org/web/20210625094259/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=562216 . live .
  18. Web site: Ivosidenib Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 26 August 2021 . 10 July 2021 . https://web.archive.org/web/20210710013318/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=739720 . live .
  19. Web site: Ivosidenib Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 26 August 2021 . 9 July 2021 . https://web.archive.org/web/20210709185137/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=637718 . live .
  20. Web site: Tibsovo: Pending EC decision . European Medicines Agency . 24 February 2023 . 24 February 2023 . 24 February 2023 . https://web.archive.org/web/20230224165542/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/tibsovo . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  21. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, Kantarjian HM . 6 . Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML . The New England Journal of Medicine . 378 . 25 . 2386–2398 . June 2018 . 29860938 . 10.1056/NEJMoa1716984 . 205102890 . free . doi .
  22. Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, Cianchetta G, Cai Z, Zhou D, Cui D, Chen P, Straley K, Tobin E, Wang F, David MD, Penard-Lacronique V, Quivoron C, Saada V, de Botton S, Gross S, Dang L, Yang H, Utley L, Chen Y, Kim H, Jin S, Gu Z, Yao G, Luo Z, Lv X, Fang C, Yan L, Olaharski A, Silverman L, Biller S, Su SM, Yen K . 6 . Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers . ACS Medicinal Chemistry Letters . 9 . 4 . 300–305 . April 2018 . 29670690 . 5900343 . 10.1021/acsmedchemlett.7b00421 .

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