AG-881 is an orally available, brain penetrant, potent, small-molecule inhibitor of isocitrate dehydrogenase (IDH) 1 and IDH2 mutant proteins. Small-molecule inhibition of the mutant IDH (mIDH) protein represents a targeted approach to cancer treatment for patients who harbor an IDH1 and/or an IDH2 mutation. Direct inhibition of the gain-of-function activity of the mIDH protein is intended to inhibit the production of the oncogenic metabolite D-2-hydroxyglutarate (2-HG) and induce tumor cell differentiation.

Biochemical studies of AG-881 demonstrate that it has low nanomolar potency inhibition (IC50) against multiple mIDH homodimer and heterodimer enzymes. It is a rapid-equilibrium inhibitor of mIDH1-R132H and mIDH2-R172K homodimer enzymes and is a slow-binding inhibitor of mIDH2-R140Q homodimer and wild type (wt) IDH1/mIDH1-R132H, wtIDH2/mIDH2-R140Q, and wtIDH2/mIDH2-R172K heterodimers.

The potency against mIDH1 and mIDH2 enzymes has also been shown in cell lines and primary human patient samples. The IC50 range for 2-HG inhibition by AG-881 was 0.04-22 nM in cells expressing mIDH1-R132C, mIDH1-R132G, mIDH1-R132H, or mIDH1-R132S mutations and was 7-14 nM and 130 nM in cells expressing mIDH2-R140Q and mIDH2-R172K mutations, respectively. The treatment of these mIDH cell lines or primary human acute myeloid leukemia samples with AG-881 led to the onset of cellular differentiation.

The pharmacokinetics of AG-881 are characterized by rapid oral absorption and low total body plasma clearance in mice (0.406 L/hr/kg) and rats (0.289 L/hr/kg). Because of these favorable properties, a series of in vivo pharmacology studies were conducted with AG-881 in mouse xenograft models. In these studies, dose-response relationships for the reduction in 2-HG in tumor by AG-881 were established. Twice-daily dosing of AG-881 in the HT1080 (mIDH1-R132C) and U87 (mIDH2-R140Q) mouse models reduced tumor 2-HG levels by >96% at doses ≥30 mg/kg. In the orthotopic glioma model (mIDH1-R132H), brain tumor 2-HG levels were reduced by >97% at doses ≥0.1 mg/kg. Based on in vivo exposure-response analyses, plasma AG-881 AUC0-24hr values of 402 hr•ng/mL and 45,200 hr•ng/mL are projected to result in sustained 97% reduction in tumor 2-HG levels in the glioma indication and the non-glioma solid and liquid tumor indications, respectively. AG-881 also exhibits excellent brain penetration, with brain-to-plasma ratios ranging from 0.62 to 1.96 in mice and 1.11 to 1.48 in rats (based on AUC0-24hr), and has an acceptable preclinical safety profile that supports clinical testing.

Taken together, these data show that AG-881 is a potent inhibitor of the mIDH1 and mIDH2 proteins and suppresses 2-HG production in enzymatic, cell-based, and in vivo systems. Pharmacology studies support that suppression of 2-HG levels by AG-881 results in alterations of cellular downstream markers, leading to a release from blockage of tumor cell differentiation. AG-881 is currently in phase 1 clinical development in patients with an IDH1 and/or IDH2-mutation who have advanced solid tumors including gliomas ( NCT02481154), and advanced hematologic malignancies ( NCT02492737).

Citation Format: Katharine Yen, Zenon Konteatis, Zhihua Sui, Erin Artin, Lenny Dang, Kimberly Straley, Erica Tobin, Carl Campos, Hua Yang, Raj Nagaraja, Yue Chen, Hyeryun Kim, Camelia Gliser, Brandon Nicolay, Andrew Olaharski, Lee Silverman, Scott Biller, Shinsan M. Su, Ingo Mellinghoff, Janeta Popovici-Muller. AG-881, a brain penetrant, potent, pan-mutant IDH (mIDH) inhibitor for use in mIDH solid and hematologic malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B126.