Evaluation of the Pharmacokinetics of AG-221, a Potent Mutant IDH2 Inhibitor, in Patients with IDH2-Mutation Positive Advanced Hematologic Malignancies in a Phase 1/2 Trial

Background: Isocitrate dehydrogenase 1 and 2 (IDH1/2) are critical enzymes in the citric acid cycle that catalyze the production of α-ketoglutarate (α-KG) from isocitrate. Mutant IDH1/2 enzymes promote enzymatic production of D-2-hydroxyglutarate (2-HG) from α-KG. 2-HG is elevated in a broad range of solid and hematologic malignancies and drives multiple oncogenic processes including increased histone and DNA methylation and impaired cellular differentiation. AG-221 is a first-in-class, oral, selective, potent inhibitor of mutant IDH2. In in vitro studies, AG-221 reduced 2-HG levels by >90%, reversed histone and DNA hypermethylation, and induced cellular differentiation in leukemia cell models. Preliminary data indicated that sustained reductions of 2-HG in plasma associated with AG-221 treatment are dose- and exposure-dependent (Fan, Haematologica, 2015, Abstract 4104). Further pharmacokinetic assessment of AG-221 in humans is underway in this ongoing, first-in-human, phase 1/2 dose-escalation and expansion trial in patients with IDH2 mutation-positive advanced hematologic malignancies [NCT01915498].

Objectives: Assess dose proportionality of AG-221 exposure after single doses ranging from 50 to 450 mg, plasma AG-221 exposure after multiple daily doses over time, and the influence of patient-intrinsic factors on drug clearance in patients with advanced hematologic malignancies.

Methods: Patients with advanced mutant IDH2-positive acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were enrolled in sequential cohorts with increasing AG-221 dose levels. AG-221 was administered orally once or twice daily (QD or BID) in continuous 28-day cycles at 30, 50, 75, 100 or 150 mg BID, or 50, 75, 100, 150, 200, 300, or 450 mg QD. Patients fasted for ≥2 hours before AG-221 administration. Blood samples were collected at multiple time points, beginning after a single dose on Day -3 and collected for up to 72 hours. Additional PK samples were collected on Days 1, 8, 15, and 22 of Cycle 1 and on Days 1 and 15 of Cycle 2 and beyond. AG-221 concentrations in plasma were determined using a validated liquid chromatography-tandem mass spectrometry-based method. PK analyses were performed using WinNonLin^® (Pharsight Corporation, Mountain View, CA).

Results: Following oral administration of an initial AG-221 dose of 50 to 450 mg on Day -3 (n=90), mean AG-221 plasma exposure (AUC_0-24) increased from below the limit of detection predose to ~80 h*µg/mL in a generally dose-proportional manner (Figure 1A). Dose-proportional plasma concentrations were also observed after repeated daily administration of AG-221 doses of 50 to 300 mg daily (n=73) in Cycle 2 (Figure 1B). AG-221 plasma exposure at the same total daily dose was comparable whether administered QD or BID. Plasma levels of AG-221 in patients receiving the 100 mg QD dose surpassed the projected efficacious concentration (15.2 h*μg/mL was associated with 97% 2-HG inhibition in preclinical models) by Cycle 1 Day 15 (Figure 2). Accumulation was observed after multiple doses, and steady state C_trough occurred at approximately mid-Cycle 1. Mean plasma half-life was >45 hrs. There was no clinically relevant impact of any patient-intrinsic factor-gender, age, weight, body surface area (BSA), or albumin levels-on clearance of AG-221.

Conclusions: AG-221 exposure is broadly dose proportional and its long plasma half-life supports QD dosing. These data suggest no initial AG-221 dose adjustment is necessary based on patient-intrinsic factors. Drug exposure is robust at steady state. The selected dose for the phase 2 expansion phase of this study is 100 mg QD, which provides AG-221 plasma exposure at levels above that determined to be efficacious.

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