Ivosidenib

Ivosidenib, sold under the brand name Tibsovo, is a medication for the treatment of acute myeloid leukemia (AML). It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. The drug is being developed by Agios Pharmaceuticals and is in phase III clinical trials. The U.S. Food and Drug Administration (FDA) awarded orphan drug designation for acute myeloid leukemia and cholangiocarcinoma.[1][2]

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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC28H22ClF3N6O3
Molar mass582.97 g·mol−1
3D model (JSmol)

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[3]

In 2018, ivosidenib was approved in the United States for relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation[4][5][6] and is presently in a phase III clinical trial for cholangiocarcinoma with an IDH1 mutation.[7]

In 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.[8]

Inhibitory behavior

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.[9]

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.[10]

Patient Selection

Patients with AML should be tested for IDH1 mutations in the blood or bone marrow to see if they are suitable candidates for ivosidenib. Patients without the mutation should still be regularly tested to see if the mutation develops.[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]

References
  1. "Tibsovo Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
  2. "Ivosidenib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
  3. New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.
  4. "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.
  5. "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.
  6. "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.
  7. Clinical trial number NCT03173248 for "Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation (AGILE)" at ClinicalTrials.gov
  8. "FDA approves ivosidenib as first-line treatment for AML with IDH1 mutation". U.S. Food and Drug Administration (FDA) (Press release). 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.
  9. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, 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.
  10. 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.
  11. "Tibsovo- ivosidenib tablet, film coated". DailyMed. 24 April 2019. Retrieved 18 December 2019.
  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.

Further reading
  • "Ivosidenib". Drug Information Portal. U.S. National Library of Medicine.
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