Ivosidenib

Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma.[1] It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. The U.S. Food and Drug Administration (FDA) awarded orphan drug designation for acute myeloid leukemia and for cholangiocarcinoma.[2][3][4][5]

Ivosidenib
Clinical data
Pronunciationeye"voe sid' e nib
Trade namesTibsovo
Other namesAG-120
AHFS/Drugs.comMonograph
MedlinePlusa618042
License data
Routes of
administration		By mouth
Drug classAntineoplastic Agents
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3- difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine2-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC28H22ClF3N6O3
Molar mass582.97 g·mol−1
3D model (JSmol)
SMILES
  • C1CC(=O)N(C1C(=O)N(C2=CC(=CN=C2)F)C(C3=CC=CC=C3Cl)C(=O)NC4CC(C4)(F)F)C5=NC=CC(=C5)C#N

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.[6]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[7]

Medical uses

In July 2018, ivosidenib was approved in the United States for relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.[6][8][9]

In May 2019, ivosidenib was approved in the United States for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.[10]

In August 2021, the FDA approved ivosidenib for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.[11]

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.[12]

Research

In tumors from patients 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.[13]

Ivosidenib, in in vitro studies, showed non-competitive inhibitory behavior towards the alpha-ketoglutarate (ɑ-KG) substrate and to the NADPH cofactor. This is what is believed to lead to Ivonsidenib being a rapid equilibrium inhibitor of the mIDH1-R132H homodimer, however NADPH is found to be pre-bound in recombinant enzyme preparations, which means this is not conclusive.

The drug is also believed to 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.[14]

References
  1. "Tibsovo- ivosidenib tablet, film coated". DailyMed. 24 April 2019. Retrieved 18 December 2019.
  2. "Tibsovo Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 18 December 2019.
  3. "Ivosidenib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 18 December 2019.
  4. "Ivosidenib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Retrieved 26 August 2021.
  5. "Ivosidenib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Retrieved 26 August 2021.
  6. "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) (Press release). 20 July 2018. Archived from the original on 11 December 2019. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
  7. New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.
  8. "Drug Trials Snapshots: Tibsovo". U.S. Food and Drug Administration (FDA). 2 August 2018. Archived from the original on 19 December 2019. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
  9. "FDA approves ivosidenib for relapsed or refractory acute myeloid leukemia". U.S. Food and Drug Administration (FDA). 23 January 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
  10. "FDA approves ivosidenib as first-line treatment for AML with IDH1 mutation". U.S. Food and Drug Administration (FDA). 3 May 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
  11. "FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma". U.S. Food and Drug Administration (FDA). 26 August 2021. Retrieved 26 August 2021.
  12. Stein EM, DiNardo CD, Mims AS, Savona MR, Pratz K, Stein AS, et al. (2017-12-07). "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. doi:10.1182/blood.V130.Suppl_1.726.726.
  13. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. (June 2018). "Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML". The New England Journal of Medicine. 378 (25): 2386–2398. doi:10.1056/NEJMoa1716984. PMID 29860938. S2CID 205102890.
  14. Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, et al. (April 2018). "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. doi:10.1021/acsmedchemlett.7b00421. PMC 5900343. PMID 29670690.

Further reading
  • "Ivosidenib". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02074839 for "Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation" at ClinicalTrials.gov
  • Clinical trial number NCT02989857 for "Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy) (ClarIDHy)" at ClinicalTrials.gov
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