Detailed explanation of the efficacy and role of ivonib/ivitinib

Ivosidenib/Ivosidenib is an antineoplastic agent effective in cancers with susceptibility IDH1 mutations, which indicate elevated levels of the oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells. Ivonib reduces D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivonib inhibits mutant and wild-type IDH1, but not IDH2.

Isocitrate dehydrogenase1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status. IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle. 1 A variety of cancers are associated with missense mutations in IDH1, which lead to a substitution of the arginine 132 amino acid in the active site of the enzyme, gaining gain-of-function activity and increasing enzyme activity.

IDH1 mutations lead to the accumulation of D-2-hydroxyglutarate (D-2HG), a tumor metabolite structurally similar to α-KG. D-2HG inhibits alpha-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation as well as other cellular processes. Inhibition of these enzymes results in histone and DNA methylation and blocks cell differentiation, including hematopoietic differentiation. As histones become hypermethylated, methylation-sensitive insulators are unable to regulate oncogene activation. Excessive D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation of tumorigenesis.

Avosidenib inhibits mutant IDH1 at much lower concentrations than the wild-type enzymeIDH1. It targets gene mutations at position R132, of which R132H and R132C are the most common mutations. In an IDH1-mutated AML mouse xenograft model, ivonib reduced D-2HG levels in a dose-dependent manner and induced myeloid differentiation in vitro and in vivo. Ivonib inhibits histone demethylase, restores normal methylation status, promotes cell differentiation and oncogene regulation.