IDH Inhibitors

The enzymes isocitrate dehydrogenase 1 and 2 (IDH-1 and IDH-2) are part of the cell metabolism – the citric acid cycle or tricarboxylic acid (TCA) cycle. IDH-1 (sometimes called IDH1) is in the cytoplasm and IDH-2 or IDH2 is in the mitochondria. There is a third member of this class – IDH3 – also in the mitochondria, but it is not a target of anti-cancer drugs.

These enzymes catalyze the conversion of isocitrate to alpha keto glutarate (αKG). When there is a mutation, this reaction doesn’t occur and there is a gain in a reverse reaction and an increase in an oncometabolite called D-2-hydroxyglutarate (D-2HG).  This leads to leukemia through DNA methylation and through a block in cellular differentiation.

About 20 percent of AML cases involve mutations in IDH1 or IDH2.  Two medicines – called “sidenibs” – are available that target cancers with those mutations.  Both are administered orally.

Enasidenib was approved for patients with acute myeloid leukemia (AML) when those patients have a mutation in the IDH-2 gene. This mutation occurs in fewer than 2 percent of AML cases. Technology Review magazine said the new medicine “has been hailed as the first real advance for the disease in 30 years.”

Ivosidenib was approved for patients with acute myeloid leukemia with an IDH-1 mutation. Ivosidenib must be administered in conjunction with a companion diagnostic test Abbott RealTime.

The half-life of these agents is several days, which is long for oral medication.

Tests show patients on these drugs see rapid reductions in D-2HG. Within a couple weeks, levels can be down to normal.

IDH inhibitors have been approved for use in leukemia, but other cancer with mutations in these genes include enchondromas, chondrosarcomas, brain cancer, myelodysplastic syndromes, and one type of lymphoma.

Mutations have been reported in cases of “thyroid cancer, melanoma, prostate carcinoma, lung cancer, breast adenocarcinoma, colorectal cancer, esophageal cancer, and bladder cancer.”

Cells with these mutations secrete the oncometabolite D-2-hydroxyglutarate (D-2HG) that can be detected in blood tests.  This means doctors can look for that biomarker in patients that might benefit from treatment with these drugs and to see if the treatment is working.

Trials have also shown that use of these drugs in conjunction with induction therapy with older chemo agents produces good results.