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P638 BMS-986165, an oral selective tyrosine kinase 2 (TYK2) inhibitor, does not affect the pharmacokinetics of methotrexate in healthy subjects

A. Chimalakonda*1, J. Jones III2, R. Dockens1, J. Throup1, S. Banerjee1, I. Girgis1

1Bristol-Myers Squibb, Princeton, United States, 2PRA Health Sciences, Blue Bell, United States

Background

Methotrexate (MTX), a substrate of organic anion transporter 1 and 3, is an immunosuppressive agent recommended for the treatment of steroid-dependent ulcerative colitis and active/relapsing Crohn’s disease.1,2 BMS-986165, an oral selective TYK2 inhibitor, has demonstrated efficacy and acceptable safety in patients with moderate to severe plaque psoriasis,3 and is under investigation in moderate to severe Crohn’s disease (LATTICE; NCT03599622), among other chronic autoimmune diseases. There is a potential for co-administration of BMS-986165 with MTX in many of these diseases. The objectives of this study were to evaluate the effects of BMS-986165 on the pharmacokinetics (PK; primary objective) and safety and tolerability (secondary objective) of MTX on co-administration.

Methods

This was a Phase 1, open-label, single-sequence study in healthy male volunteers. Subjects aged 18–50 years with a body mass index (BMI) of 18–32 kg/m2 received a single oral (po) dose of MTX 7.5 mg on Day (D) 1 and D12 and BMS-986165 12 mg po from D8 to D14. Blood samples were collected after each treatment to determine the PK of MTX and BMS-986165. Safety evaluations (adverse events [AEs], physical and skin examinations, vital signs, electrocardiograms, laboratory tests) were performed during the course of the study.

Results

Overall, 10 subjects were treated (mean [standard deviation] age 33.6 [7.06] years, BMI 24.9 [2.31] kg/m2), all of whom completed the study. Following co-administration of MTX + BMS-986165, MTX geometric mean maximum concentration (Cmax) and total exposure (area under the curve extrapolated to infinity [AUCINF]) increased by ~11% and 4%, respectively, compared with MTX alone (Table). The 90% confidence intervals (CIs) for the geometric least-square mean ratios for Cmax and AUCINF were contained within the no-effect boundary of 0.80–1.25. There were no serious AEs, deaths, or AEs leading to discontinuation. All treatment-emergent AEs were mild and resolved spontaneously.

Table. PK parameters for MTX and MTX + BMS-986165.

Conclusion

BMS-986165 at steady state had no clinically meaningful effect on the PK of a single dose of MTX. MTX alone or in combination with BMS986165 was safe and well tolerated in this study.

Reference

1. Harbord M, et al. (2017) J Crohn’s Colitis.

2. Gomollón F, et al. (2017) J Crohn’s Colitis.

3. Papp K, et al. (2018) N Engl J Med.