The FDA approved Agios’ and Celgene’s enasidenib for acute myeloid leukaemia (AML), validating metabolism-modulating drugs as a means of killing cancer cells. Enasidenib (formerly AG-221) is a first-in-class inhibitor of mutated isocitrate dehydrogenase 2 (IDH2). The IDH enzymes normally metabolize isocitrate into α-ketoglutarate. When they are mutated in cancers, they also convert α-ketoglutarate into 2-hydroxyglutarate, an oncometabolite that causes cell differentiation defects by impairing histone demethylation. In clinical trials of enasidenib, 23% of treated patients had complete responses or complete responses with partial haematologic recovery lasting a median of 8.2 months. The most common side effects were nausea, vomiting, diarrhoea, elevated bilirubin and decreased appetite. The agency approved the drug with a black box warning noting the risk of differentiation syndrome, a potentially fatal complication that is associated with certain forms of AML. The FDA also approved a companion diagnostic alongside the drug to detect IDH2 mutations. Agios discovered and developed the drug in just 8 years. The company started working on IDH2 inhibitors in 2009 and advanced its lead candidate into clinical trials in 2013. Although the approval highlights the promise of metabolism-modulating anticancer drugs, researchers have struggled to find other therapeutically tractable targets in metabolic pathways (Nat. Rev. Drug Discov. 15, 735–737; 2016). Only a handful of other cancer metabolism candidates have made it into clinical trials. Agios’ IDH1 inhibitor is in phase III trials in AML and bile duct cancer. Calithera Biosciences’ glutaminase 1 inhibitor CB-839 is in phase II trials for
renal cell cancer. Several of the companies that started in the cancer metabolism space have turned their
focus to immunometabolism-modulating drugs that can improve immune cell survival or modify the interactions between cancer cells and immune cells in the microenvironment. Incyte’s phase III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor epacadostat, for example, controls tryptophan metabolism to foster immune cell activity.
Fonte: Nature Reviews Drug Discovery | Published online 1 Sep 2017