EXTH-59. THE IDH1 MUTANT INHIBITOR AG-120 SHOWS STRONG INHIBITION OF 2-HG PRODUCTION IN AN ORTHOTOPIC IDH1 MUTANT GLIOMA MODEL IN VIVO

Abstract

Mutations in isocitrate dehydrogenase (IDH) 1 and 2 result in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which drives multiple oncogenic processes, including increased histone and DNA methylation, leading to a block in cellular differentiation. IDH1/2 mutations occur in >70% of diffuse low-grade gliomas (LGG). Standard of care treatment for patients with diffuse LGG involves combined modality approaches including surgery, radiation, and chemotherapy. Here we present preclinical data from studies using AG-120, a potent, orally available inhibitor of the mIDH1 protein currently in clinical trials. In an orthotopic mouse xenograft model of a human mIDH1-R132H glioma, strong inhibition of 2-HG production in brain tumor samples (>77% inhibition) was observed when AG-120 was dosed orally at 150 mg/kg twice daily. Pharmacokinetic analysis revealed that AG-120 was detectable in the brain and brain-tumor tissues of the mice, although at much lower exposures than in the plasma, indicating that AG-120 is highly potent against the mIDH1-R132H protein in vivo. Results from ongoing preclinical studies testing the potential activity of AG-120 combined with radiation therapy in an orthotopic human mIDH1-R132H glioma model will also be shared.