12IN - Genomic-guided metabolism drug development in myeloid diseases

Date 05 March 2018
Event TAT 2018 - Targeted Anticancer Therapies
Session New concepts and new targets in haematology early drug development
Presenter David Schenkein
Citation Annals of Oncology (2018) 29 (suppl_3): iii1-iii6. 10.1093/annonc/mdy046
Authors D. Schenkein
  • Agios Pharmaceuticals, Inc., 02139 - Cambridge/US

Abstract

Mutations in isocitrate dehydrogenase (IDH)1 or IDH2 are seen in ~15–20% of patients with acute myeloid leukemia (AML). Mutant IDH (mIDH) reduces α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), leading to histone hypermethylation and a block in myeloid differentiation. Ivosidenib (AG-120) and enasidenib (AG-221) are potent, selective, oral small molecule inhibitors of mIDH1 and mIDH2, respectively. Both have been shown preclinically to reduce aberrant 2-HG levels and promote myeloid differentiation, and as monotherapy are associated with robust overall response rates in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Enasidenib received full approval in the United States in Aug 2017 for the treatment of adult patients with R/R AML with an IDH2 mutation. A New Drug Application was recently submitted to the FDA for ivosidenib for the treatment of patients with R/R AML and an IDH1 mutation, based on evidence in patients showing clinical activity and observation of clinical benefit, including achievement of transfusion independence, and a decrease in the frequency of comorbidities such as febrile neutropenia and infections in responding patients. Additional data demonstrate that ivosidenib monotherapy results in deep IDH1 mutation clearance in a subset of patients with R/R AML and untreated AML who achieve clinical response. Tolerability and preliminary clinical activity data were also recently presented from two Phase 1 studies evaluating ivosidenib and enasidenib in combination with standard induction (7+3) chemotherapy or azacitadine in newly diagnosed AML patients. Independent clinical trials are currently underway for ivosidenib in mIDH1-positive malignancies in the solid tumor context. This presentation will focus on the discovery of these investigational medicines, as well as the promising clinical and translational results from the hematologic malignancy and solid tumor trials.