Background BTK is an attractive, novel therapeutic target for autoimmune disease, based on the established mechanistic data via B cell receptor (BCR)-dependent and Fc receptors (FcR)-dependent pathways (Whang et al. Drug Discov Today, 2014;19:1200–4). BMS-986142, a new small molecule reversible inhibitor of BTK, is being developed for the treatment of rheumatoid arthritis (RA) and auto-immune diseases. To support clinical development of BMS-986142, it is important to demonstrate sufficient pharmacodynamic (PD) activity, acceptable pharmacokinetic (PK) profile, and low drug-drug interaction potential with methotrexate (MTX) prior to testing in patients.
Objectives Here we present the outcomes from two phase 1 studies investigating safety, tolerability, PK, PD, and its effect on MTX PK following oral administration of BMS-986142 in healthy subjects.
Methods In Study 1, healthy volunteers (18–50 y) were randomized to receive single doses of BMS-986142 (5 to 900 mg or placebo) or multiple doses of BMS-986142 (25 to 350 mg or placebo once daily [QD] for 14 days) to assess the safety, tolerability, PK, and PD (as measured by CD69 inhibition). In Study 2, safety and tolerability was assessed in healthy males (18–50 y) receiving single doses of MTX alone (7.5 mg) and in combination with BMS-986142 (350 mg QD) while assessing the effect of BMS-986142 on the PK of MTX.
Results BMS-986142 was well tolerated in both studies. In Study 1, a grade 3 SAE (psychosis, 75 mg BMS-986142) not related to study drug was reported in 1 subject; 1 grade 3 AE (blood creatinine phosphokinase elevation, placebo) was also reported. Three drug related grade 1 AEs (headache-SAD, 900mg; back pain-MAD, 200 mg; cough-MAD, placebo) were reported in Study 1. There were no grade 3 AEs reported in Study 2. AEs reported at least twice among all dosing groups are presented in the table. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 hours and gradually eliminated with a half-life of up to 11 hours, enabling QD dosing in the patient studies. BMS-986142 showed linear PK following either a single- or multiple-dose administration. A dose- and concentration-dependent decrease in CD69 expression was observed following the administration of BMS-986142. Daily administration at 350 mg led to near complete coverage above the IC50 for CD69 inhibition throughout the dosing interval without time-dependent changes. BMS-986142 did not affect the PK of MTX, as the peak concentrations and total exposure were comparable when administered with and without BMS-986142 (adjusted geometric mean ratios [90% CI]: Cmax, 1.046 [0.910, 1.202]; AUC(0-T), 1.041 [0.950, 1.139]).
Conclusions BMS-986142 was found to be safe and well tolerated at the doses tested in two phase 1 studies in healthy subjects. It showed favorable PK/PD profile including lack of interaction with MTX and can be safely administered in RA patients that are on background MTX. Overall, BMS-986142 has the potential to show clinical activity in treating autoimmune diseases.
Disclosure of Interest S. K. Lee Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, J. Xing Employee of: Bristol-Myers Squibb Company, I. Catlett Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, R. Adamczyk Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, A. Griffies Employee of: Bristol-Myers Squibb Company, A. Liu Employee of: Bristol-Myers Squibb Company, B. Murthy Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, M. Nowak Employee of: Bristol-Myers Squibb Company
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