Ivosidenib

Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma.^[5] 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.^[9]

Ivosidenib

Clinical data
Pronunciation	/ˌaɪvoʊˈsɪdənɪb/ EYE-voh-SID-ə-nib
Trade names	Tibsovo
Other names	AG-120
AHFS/Drugs.com	Monograph
MedlinePlus	a618042
License data	US DailyMed: Ivosidenib
Pregnancy category	AU: D[1]
Routes of administration	By mouth
Drug class	Antineoplastic agent
ATC code	L01XX62 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1][2] CA: ℞-only[3] US: WARNING[4]Rx-only[5][6] EU: Rx-only[7][8]
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	1448347-49-6
PubChem CID	71657455
DrugBank	DB14568
ChemSpider	38772333
UNII	Q2PCN8MAM6
KEGG	D11090
ChEBI	CHEBI:145430
ChEMBL	ChEMBL3989958
CompTox Dashboard (EPA)	DTXSID801027928
Chemical and physical data
Formula	C28H22ClF3N6O3
Molar mass	582.97 g·mol−1
3D model (JSmol)	Interactive image
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

Ivosidenib was approved for medical use in the United States in July 2018,^{[9][10][11][12]} and in the European Union in May 2023.^[7][13] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[14]

Medical uses

Ivosidenib is indicated for people with acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma.^[5][15][16]

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.^[17]

History

The US Food and Drug Administration (FDA) awarded orphan drug designations for acute myeloid leukemia and for cholangiocarcinoma.^{[18][19][20][21]}

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.^[22] The applicant for this medicinal product is Les Laboratoires Servier.^[22] Tibsovo was approved for medical use in the European Union in May 2023.^[7]

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.^[23]

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.^[24]

References

1. "Tibsovo". Therapeutic Goods Administration (TGA). 19 April 2023. Archived from the original on 19 April 2023. Retrieved 29 April 2023.
2. "Tibsovo (Servier Laboratories (Aust) Pty Ltd)". Therapeutic Goods Administration (TGA). 26 April 2023. Retrieved 28 April 2023.
3. "Notice: Multiple additions to the Prescription Drug List (PDL) [2024-10-18]". Health Canada. 18 October 2024. Retrieved 25 October 2024.
4. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
5. "Tibsovo- ivosidenib tablet, film coated". DailyMed. 24 April 2019. Archived from the original on 2 July 2019. Retrieved 18 December 2019.
6. "Tibsovo- ivosidenib tablet, film coated". DailyMed. 9 June 2022. Archived from the original on 3 December 2022. Retrieved 3 December 2022.
7. "Tibsovo EPAR". European Medicines Agency (EMA). 12 May 2023. Archived from the original on 10 March 2024. Retrieved 12 May 2023.
8. "Tibsovo". Union Register of medicinal products. 8 May 2023. Archived from the original on 11 May 2023. Retrieved 6 June 2023.
9. "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.
10. "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.
11. "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.
12. "Drug Approval Package: Tibsovo (ivosidenib)". U.S. Food and Drug Administration (FDA). Archived from the original on 25 June 2021. Retrieved 19 December 2019.
13. "Tibsovo". Union Register of medicinal products. 8 May 2023. Archived from the original on 11 May 2023. Retrieved 12 May 2023.
14. New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Archived from the original on 17 September 2020. Retrieved 16 September 2020.
15. "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.
16. "FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma". U.S. Food and Drug Administration (FDA). 26 August 2021. Archived from the original on 26 August 2021. Retrieved 26 August 2021.
17. Stein EM, DiNardo CD, Mims AS, Savona MR, Pratz K, Stein AS, et al. (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. doi:10.1182/blood.V130.Suppl_1.726.726. Archived from the original on 29 September 2019. Retrieved 12 April 2019.
18. "Tibsovo Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Archived from the original on 25 June 2021. Retrieved 18 December 2019.
19. "Ivosidenib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Archived from the original on 25 June 2021. Retrieved 18 December 2019.
20. "Ivosidenib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Archived from the original on 10 July 2021. Retrieved 26 August 2021.
21. "Ivosidenib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). Archived from the original on 9 July 2021. Retrieved 26 August 2021.
22. "Tibsovo: Pending EC decision". European Medicines Agency. 24 February 2023. Archived from the original on 24 February 2023. Retrieved 24 February 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
23. 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.
24. 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.

External links

• 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