Enasidenib (IDH2 Inhibitor)

Proposed Mechanism of Action

Enasidenib is an oral, reversible, selective inhibitor of mutated isocitrate dehydrogenase (IDH) 2.1,2 In vitro studies suggest that the oncometabolite 2-hydroxyglutarate (2-HG), which is present at high levels in patients with IDH mutations,3-5 may drive epigenetic changes that block normal cellular differentiation, leading to a cancerous state.2,4 As demonstrated in preclinical studies, enasidenib binds and inhibits the mutant IDH2 enzyme that is responsible for the accumulation of 2-HG.2,6

Enasidenib by Disease State

Enasidenib in Acute Myeloid Leukemia

  • Post Approval Research Acute Myeloid Leukemia Relapsed/refractory IDH2 mutation

Rationale for Clinical Development

IDH2 mutations occur in various cancers but are more predominant in hematologic malignancies and occur in approximately 8% to 19% of patients with AML.5,7,8 There is currently no difference in the treatment of IDH2-mutated vs wild-type AML.9 Preclinical data suggest that enasidenib may have clinical activity in IDH2-mutant AML through the reduction of 2-HG levels and the induction of blast differentiation.2,6 In vitro studies have shown that enasidenib may reduce 2-HG levels by > 90%, reverse histone and DNA hypermethylation, and induce differentiation in leukemia cell models.2,6 In a primary human mutant IDH2 AML xenograft model, enasidenib reduced 2-HG levels and induced dose-dependent proliferation and differentiation.2

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.


  1. Stein EM, et al. Blood. 2014;124 [abstract 115].
  2. Yen K, et al. Blood. 2013;122 [abstract 240].
  3. Ward PS, et al. Cancer Cell. 2010;17:225-234.
  4. Gross S, et al. J Exp Med. 2010;207:339-344.
  5. Losman JA, Kaelin WG Jr. Genes Dev. 2013;27:836-852.
  6. Celgene Corporation/Agios Pharmaceuticals. Data on file.
  7. Green CL, et al. Blood. 2011;118:409-412.
  8. Im AP, et al. Leukemia. 2014;28:1774-1783.
  9. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. V1.2015.