POS0672 ASSESSMENT OF THE DRUG-DRUG INTERACTION POTENTIAL OF BRANEBRUTINIB (BMS-986195), A HIGHLY POTENT AND SELECTIVE IRREVERSIBLE COVALENT INHIBITOR OF BRUTON'S TYROSINE KINASE, IN HEALTHY PARTICIPANTS

Abstract

Background: Branebrutinib (BMS-986195) is a highly potent and selective irreversible small-molecule covalent inhibitor of Bruton's tyrosine kinase (BTK),1 a non-receptor tyrosine kinase involved in the pathophysiology of immune-mediated diseases. Branebrutinib has the potential to be best in its class, as it achieves ~100% BTK occupancy in humans, sustained over a 24-hour dosing interval at low doses (≤ 10 mg once daily [QD]) despite its short half-life (≤ 2 hours),2 and demonstrates potent efficacy in murine models of immune-mediated diseases.1 Branebrutinib is under clinical study in multiple autoimmune infammatory disorders such as RA, systemic lupus erythematosus, primary Sjögren's syndrome, and atopic dermatitis. In vitro drug-drug interaction (DDI) studies with branebruti-nib predicted pharmacokinetic DDI potential with substrates of cytochrome P450 (CYP)3A4 and the breast cancer resistant protein drug transporter. Objectives: To assess the DDI potential of branebrutinib when co-administered with potential concomitant medications and probe substrates of major drug-metabolizing enzymes (DMEs) and drug transporters. Methods: DDI risk with branebrutinib was assessed in 3 single-sequence, cross-over clinical studies in healthy participants. In the frst 2-part study, MTX was administered alone or with steady-state (SS) branebrutinib (10 mg QD) in part 1; in part 2, caffeine, montelukast, furbiprofen, omeprazole, midazolam, digoxin, and pravastatin were taken with or without SS branebrutinib (9 mg QD). In the second study, rosuvastatin was taken alone or with SS branebrutinib (9 mg QD). In cycle 1 of the third study, the oral contraceptive (OC) loestrin (1.5 mg norethindrone/30 μg ethinyl estradiol) was taken alone; in cycle 2, SS branebrutinib (9 mg QD) was taken alone or with the OC. Results: Weak DDI with montelukast (CYP2C8) was observed, leading to a mild increase in montelukast exposure (max concentration [Cmax], 56%; area under the curve [AUC], 27%). A mild increase in digoxin exposure (P-glycoprotein [P-gp] substrates; Cmax, 57%; AUC, 21%) was also observed. There was no potential DDI with MTX (Table 1). No other clinically relevant DDIs with branebrutinib were observed. No serious AEs or other signifcant AEs occurred during these studies. All AEs were mild to moderate in intensity. Conclusion: In all 3 studies, co-administration of SS branebrutinib was generally well tolerated. The only potentially signifcant DDIs with substrates of major DMEs or transporters were mild increases in montelukast (CYP2C8) and digoxin (P-gp) exposures.