, Volume 78, Issue 14, pp 1509–1516 | Cite as

Ivosidenib: First Global Approval

  • Sohita Dhillon
AdisInsight Report


Ivosidenib (Tibsovo®) is a small molecule, orally available inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1) that is being developed by Agios Pharmaceuticals for the treatment of cancer in patients with IDH1 mutations. The mutated form of the IDH1 enzyme produces a metabolite, 2-hydroxyglutarate (2-HG), which is thought to play a role in the formation and progression of acute myeloid leukaemia (AML), gliomas and other cancers. Elevated 2-HG levels interfere with cellular metabolism and epigenetic regulation, thereby contributing to oncogenesis. Ivosidenib targets the IDH1 metabolic pathway to prevent a build-up of the oncometabolite 2-HG. This article summarizes the milestones in the development of ivosidenib leading to this first approval in the USA for the treatment of patients with relapsed or refractory AML with a susceptible IDH1 mutation. Clinical development for AML, cholangiocarcinoma, glioma, myelodysplastic syndromes and solid tumours is ongoing worldwide.


Compliance with Ethical Standards


The preparation of this review was not supported by any external funding.

Conflicts of interest

During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Sohita Dhillon is a salaried/ contracted employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.


  1. 1.
    Buege MJ, DiPippo AJ, DiNardo CD. Evolving treatment strategies for elderly leukemia patients with IDH mutations. Cancers (Basel). 2018;10(6).CrossRefGoogle Scholar
  2. 2.
    Almeida AM, Ramos F. Acute myeloid leukemia in the older adults. Leuk Res Rep. 2016;6:1–7.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016;27(4):599–608.CrossRefGoogle Scholar
  4. 4.
    Mondesir J, Willekens C, Touat M, et al. IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. J Blood Med. 2016;7:171–80.CrossRefGoogle Scholar
  5. 5.
    US Food & Drug Administration. FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation [media release]. 20 July 2018.
  6. 6.
    Celgene Corporation, Agios Pharmaceuticals. Celgene Corporation and Agios Pharmaceuticals announce global strategic collaboration to advance unique science of cancer metabolism [media release]. 15 Apr 2010.
  7. 7.
    Agios Pharmaceuticals. Celgene and Agios extend cancer metabolism collaboration [media release]. 5 Oct 2011.
  8. 8.
    Agios Pharmaceuticals. Agios advances cancer metabolism collaboration with Celgene [media release]. 11 Dec 2013.
  9. 9.
    Agios Pharmaceuticals. Agios Pharmaceuticals exercises option to US development and commercialization rights for IDH1 program under Celgene collaboration [media release]. 3 Feb 2014.
  10. 10.
    Celgene Corporation. Celgene reports second quarter 2015 operating and financial results [media release]. 23 July 2015.
  11. 11.
    Agios Pharmaceuticals. Agios and Celgene establish new collaboration in metabolic immuno-oncology and amend certain rights from 2010 agreement [media release]. 17 May 2016.
  12. 12.
    Agios Pharmaceuticals, CStone Pharmaceuticals. Agios and CStone Pharmaceuticals announce exclusive collaboration and license agreement to develop and commercialize ivosidenib in Greater China [media release]. 26 June 2018.
  13. 13.
    Agios Pharmaceuticals. TIBSOVO® (Ivosidenib): US prescribing Information. 2018. Accessed 11 Aug 2018.
  14. 14.
    Popovici-Muller J, Lemieux RM, Artin E, et al. Discovery of AG-120 (ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med Chem Lett. 2018;9(4):300–5.CrossRefGoogle Scholar
  15. 15.
    Heredia V, Mendiola M, Ortiz E, et al. AG-120, a novel IDH1 targeted molecule, inhibits invasion and migration of chondrosarcoma cells in vitro [abstract no. 1524P]. Ann Oncol. 2017;28(Suppl. 5):v538.Google Scholar
  16. 16.
    Nicolay B, Narayanaswamy R, Aguado E, et al. The IDH1 mutant inhibitor AG-120 shows strong inhibition of 2-HG production in an orthotopic IDH1 mutant glioma model in vivo [abstract no. EXTH-59 plus poster]. Neuro-oncology. 2017;19(Suppl. 6):vi86.CrossRefGoogle Scholar
  17. 17.
    Yen K, Chopra V, Tobin E, et al. Functional characterization of the ivosidenib (AG-120) and azacitidine combination in a mutant IDH1 AML cell model [abstract no. 4956]. Cancer Res. 2018;78(13 Suppl.).CrossRefGoogle Scholar
  18. 18.
    Dai D, Dinardo CD, Stein E, et al. Clinical pharmacokinetics/pharmacodynamics (PK/PD) of ivosidenib in patients with IDH1-mutant advanced hematologic malignancies from a phase 1 study [abstract no. 2581 plus poster]. J Clin Oncol. 2018;36(Suppl).CrossRefGoogle Scholar
  19. 19.
    Fan B, Goyal L, Lowery MA, et al. Pharmacokinetic/pharmacodynamic (PK/PD) profile of AG-120 in patients with IDH1-mutant cholangiocarcinoma from a phase 1 study of advanced solid tumors [abstract no. 4082 plus poster]. J Clin Oncol. 2017;35(15 Suppl.).CrossRefGoogle Scholar
  20. 20.
    Ishii Y, Sigel C, Lowery MA, et al. AG-120 (ivosidenib), a first-in-class mutant IDH1 inhibitor, promotes morphologic changes and upregulates liver-specific genes in IDH1 mutant cholangiocarcinoma [abstract no. A071 plus poster]. Mol Cancer Ther. 2017;17(1 Suppl.).Google Scholar
  21. 21.
    Birendra KC, DiNardo CD. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk. 2016;16(8):460–5.CrossRefGoogle Scholar
  22. 22.
    DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–98.CrossRefGoogle Scholar
  23. 23.
    Fan B, Dai D, Connor G, et al. Evaluation of food effect on pharmacokinetics of ivosidenib (AG-120), an oral, potent, targeted, small molecule inhibitor of mutant IDH1, in healthy subjects [abstract no. PF256 plus poster]. In: 23rd congress of the European Hematology Association. 2018.Google Scholar
  24. 24.
    Dinardo CD, Stein AS, Stein EM, et al. Mutant IDH (mIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML) [abstract no. 7042 plus poster]. J Clin Oncol. 2018;36(15 Suppl.).CrossRefGoogle Scholar
  25. 25.
    Stein EM, DiNardo CD, Mims AS, et al. 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 [abstract no. 726 plus oral presentation]. Blood. 2017;130(Suppl. 1).Google Scholar
  26. 26.
    Wehler E, Storm M, Kowal S. A health state utility model estimating the impact of ivosidenib on quality of life in patients with relapsed/refractory acute myeloid leukemia [abstract no. PS1442 plus poster]. In: 23rd congress of the European Haematology Association. 2018.Google Scholar
  27. 27.
    Lowery MA, Abou-Alfa GK, Burris HA, et al. Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: results from the cholangiocarcinoma dose escalation and expansion cohorts [abstract no. 4015 plus poster]. J Clin Oncol. 2017;35(15 Suppl.).CrossRefGoogle Scholar
  28. 28.
    Tap W, Villalobos V, Cote G, et al. A phase 1 study of AG-120, an IDH1 mutant enzyme inhibitor: results from the chondrosarcoma dose escalation and expansion cohorts [abstract no. P1-138 plus poster]. In: Connective Tissue Oncology Society (CTOS) annual meeting. 2016.Google Scholar
  29. 29.
    Mellinghoff IK, Touat M, Maher E, et al. AG-120, a first-in-class mutant IDH1 inhibitor in patients with recurrent or progressive IDH1 mutant glioma: updated results from the phase 1 non-enhancing glioma population [abstract no. ACTR-46 plus oral presentation]. Neuro-oncol. 2017;19(Suppl. 6):vi10–1.CrossRefGoogle Scholar
  30. 30.
    US FDA. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). 2018. Accessed 10 Aug 2018.
  31. 31.
    Stein E, Dinardo CD, Jang JH, et al. AGILE: a phase 3, multicenter, randomized, placebo-controlled study of ivosidenib in combination with azacitidine in adult patients with previously untreated acute myeloid leukemia with an IDH1 mutation [abstract no. TPS7074 plus poster]. J Clin Oncol. 2018;36(15 Suppl.).CrossRefGoogle Scholar
  32. 32.
    Lowery MA, Abou-Alfa GK, Valle JW, et al. ClarIDHy: A phase 3, multicenter, randomized, double-blind study of AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation [abstract no. TPS4142 plus poster]. J Clin Oncol. 2017;35(15 Suppl.).CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

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