ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 514

BMS-986195, a Novel, Rapidly Acting, Covalent Inhibitor of Bruton’s Tyrosine Kinase: Safety, Pharmacokinetic and Pharmacodynamic Profiles in Healthy Participants

IM Catlett, L Wei, N Zheng, A Liu, B He, I Girgis and M Nowak, Bristol-Myers Squibb, Princeton, NJ

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: , , ,

Session Information

Date: Sunday, November 5, 2017

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy Poster I: Comorbidities and Adverse Events; Efficacy and Safety of Small Molecules

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Bruton’s tyrosine kinase (BTK) is an attractive, novel therapeutic target for autoimmune disease, as it is required for signal transduction and activation via B-cell receptor, Fc receptor and RANKL pathways.1 Due to the relatively slow turnover of BTK, a covalently bound inhibitor with a short pharmacokinetic (PK) half-life can lead to prolonged pharmacodynamic (PD) effects. BMS-986195 is being developed for the treatment of autoimmune diseases. This study assessed the safety, tolerability, PK and PD of BMS-986195 following oral administration in healthy participants. Methods: Healthy participants (18–50 years) were randomized in a 3:1 ratio to receive a single dose (0.3–30 mg BMS-986195 or placebo; n=30) or multiple doses (0.3–10 mg BMS-986195 or placebo once daily for 14 days; n=24). Safety and tolerability were assessed by physical examinations, vital sign measurements, 12-lead electrocardiograms and clinical laboratory evaluations. Plasma concentrations of BMS-986195 were measured using a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay at various time points. BTK occupied by BMS-986195 was measured using a novel LC-MS assay, as a PD and target engagement marker. Results: BMS-986195 was well tolerated in the single- and multiple ascending dose study. No drug-related serious adverse events were observed. BMS-986195 was rapidly absorbed with peak concentrations occurring in <1 hour and eliminated with a half-life of <2 hours across all dose levels tested. Increases in the PK exposure (area under the curve and maximum serum concentration) were dose proportional. No time-dependent changes in PK were observed following the multiple-dose administration of BMS-986195. BTK occupancy increased in a dose-dependent manner following single-dose administration of BMS-986195. The mean (SD) peak BTK occupancy following a single dose was 19% (3%) at 0.3 mg, and 100% (0%) at ≥10 mg. 100% BTK occupancy was sustained for up to 24 hours. BTK occupancy returned towards baseline over the following 6 days (Figure). Total BTK levels did not vary over time or by dose group. With multiple-dose administration, 100% BTK occupancy was reached at ≥3 mg once daily, and drug-occupied BTK exhibited similar kinetics to that observed following a single-dose administration. Additional PD and safety results from the multiple ascending dose study will be presented. Conclusion: BMS-986195 was well tolerated at the doses tested in healthy participants. It showed a favorable PK/PD profile with a rapid elimination of the compound and sustained PD activity, due to the relatively slow turnover of BTK and covalent binding of BMS-986195. 100% BTK occupancy over the entire daily dosing interval was observed. Overall results suggest that BMS-986195 is an attractive candidate for further clinical development. 1. Whang JA, et al. Drug Discov Today 2014;19:1200–4.

Disclosure: I. Catlett, Bristol-Myers Squibb, 3; L. Wei, Bristol-Myers Squibb, 3; N. Zheng, Bristol-Myers Squibb, 3; A. Liu, Bristol-Myers Squibb, 3; B. He, Bristol-Myers Squibb, 3; I. Girgis, Bristol-Myers Squibb, 3; M. Nowak, Bristol-Myers Squibb, 3.

To cite this abstract in AMA style:

Catlett I, Wei L, Zheng N, Liu A, He B, Girgis I, Nowak M. BMS-986195, a Novel, Rapidly Acting, Covalent Inhibitor of Bruton’s Tyrosine Kinase: Safety, Pharmacokinetic and Pharmacodynamic Profiles in Healthy Participants [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/bms-986195-a-novel-rapidly-acting-covalent-inhibitor-of-brutons-tyrosine-kinase-safety-pharmacokinetic-and-pharmacodynamic-profiles-in-healthy-participants/. Accessed .

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