| In Vitro |
In vitroactivity: BMS-986205 is a novel, potent, orally bioactive and selective inhibitor of IDO (indoleamine 2,3-dioxygenase 1) with potential anticancer activities. It is licensed by Flexus Inc. to Bristol-Myers Squibb for clinical development. This compound appears to act as an irreversible inhibitor of high potency (~2 nmol/L) with superior pharmacokinetics relative to epacadostat and navoximod. In 2015, BMS-986205 entered a phase I/II study in melanoma patients as monotherapy and in combination with nivolumab (NCT02658890). An interim report noted the compound was well tolerated in patients. A second phase I study of the same combination is being conducted in various other types of advanced cancer patients (NCT03192943).
Kinase Assay: In vitrocharacteristics included potent inhibition of kynurenine (kyn) production in IDO1-HEK293 cells (IC50= 1.1 nM) but not in TDO-HEK293 cells, sustained inhibition in IDO1 cell-based assays after washout, and single-digit nM potency in human tolerogenic MLR assays. |
| In Vivo |
Based on preclinical data, a 150 mg QD human dose was projected to maximally inhibit IDO1. In the ongoing clinical study, 42 pts have been treated. All treatment-related adverse events were grade 1/2 except three grade 3 toxicities (autoimmune hepatitis [dose limiting; BMS-986205 100 mg/nivo 240 mg], rash, and asymptomatic hypophosphatemia). Day 14 individual trough concentrations began exceeding the human whole blood IC50 starting with 25 mg QD, and the IC90 starting with 50 mg QD; all pts treated at 200 mg QD exceeded the IC90. Serum kyn was substantially reduced at all doses (> 45% mean reduction at each dose), with> 60% mean reduction at the 100 and 200 mg QD doses. Importantly, intratumoral kyn was reduced up to 90% in evaluable paired pre- and on-treatment samples. |
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