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Abstract Number: 1771

First-in-Human Safety, Pharmacokinetic and Pharmacodynamic Study of Escalating Single- and Multiple-Doses of BMS-986256, a Novel, Potent, Oral Inhibitor of TLR7 and TLR8

Melanie Harrison1, Manoj Chiney1, Diane Shevell2, Lixian Dong3, Michelle Dawes1 and Ihab Girgis3, 1Bristol Myers Squibb, Lawrenceville, NJ, 2Bristol Myers Squibb, Lawrenceville, 3Bristol Myers Squibb, Princeton, NJ

Meeting: ACR Convergence 2021

Keywords: autoimmune diseases, Biomarkers, clinical trial, cytokines, Systemic lupus erythematosus (SLE)

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Session Information

Date: Tuesday, November 9, 2021

Title: SLE – Treatment Poster (1732–1772)

Session Type: Poster Session D

Session Time: 8:30AM-10:30AM

Background/Purpose: Toll-like receptor (TLR)7 and TLR8 are endosomal receptors that are normally activated by pathogen-associated RNA. They are also activated by self-RNA as part of the pathophysiology of systemic lupus erythematosus (SLE) and related autoimmune diseases. Inhibition of TLR7 and TLR8 may be effective in the treatment of these diseases. BMS-986256 is an oral, potent and selective TLR7 and TLR8 inhibitor. It demonstrates robust pharmacodynamic (PD) activity and efficacy in multiple mouse models of lupus. The objective of this first-in-human, single ascending dose (SAD) and multiple ascending dose (MAD) study was to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-986256 in healthy volunteers (HV)

Methods: Each of the SAD and MAD parts of the study were randomized, double-blind, placebo-controlled trials in which HV were randomized 3:1 (BMS-986256:placebo) within each dose cohort. In the SAD part of the study, a total of 48 HV were enrolled across 6 dose cohorts (1mg through 120mg) of 8 participants each and followed for up to 28 days. In the first of two MAD parts of the study, 24 non-Japanese HV were enrolled across 4 dose cohorts (once daily 3mg through 60mg) for up to 21 days and followed for up to 42 days. A second MAD part (J-MAD) enrolled 24 Japanese HV across 3 dose cohorts, (once daily 10mg through 60mg) for up to 21 days and followed for up to 42 days. Safety, tolerability, PK and PD were assessed throughout the study and reviewed following each dose level prior to initiation of successive dose escalation cohorts.

Results: Across all cohorts, the frequency of treatment emergent adverse events (TEAEs) was low and the majority were unrelated to BMS-986256. There were no serious adverse events and all TEAEs were classified as mild except for 2 moderate TEAEs (viral upper respiratory infection and tooth fracture), both unrelated to BMS-986256. One participant in the J-MAD part of the study discontinued BMs-986256 for asymptomatic, elevated ALT, which then resolved. BMS-986256 has linear PK over the dose range evaluated in SAD and MAD parts. It has a long half-life of approximately 80 hours to support once daily dosing. BMS-986256 has low inter-individual variability in exposures and low level of single circulating metabolite (< 2 % of parent). An ex vivo assay that measured BMS-986256 inhibition of TLR7-agonist or TLR8-agonist induced IL-6 production showed rapid target engagement at all doses tested in the SAD and MAD parts. The effect was dose-dependent and durable, reaching >90% target engagement. BMS-986256 also exhibited dose dependent, robust effects in 2 other ex vivo assays that measured TLR7-agonist stimulation of CD69 expression on B cells and TLR8-agonist stimulated CD319 expression on monocytes, using flow cytometry.

Conclusion: BMS-986256 was generally safe and well-tolerated following single and multiple doses administered across the dose range studied. It has favorable PK properties. These findings along with its robust biomarker response support its further development as a treatment for SLE and related autoimmune diseases.


Disclosures: M. Harrison, Bristol-Myers Squibb, 3, Pfizer, 12, Stock holder, Pfizer, 3; M. Chiney, Bristol Myers Squibb, 3; D. Shevell, Bristol Myers Squibb, 3; L. Dong, Bristol-Myers Squibb, 3; M. Dawes, None; I. Girgis, Bristol Myers Squibb, 3, 11.

To cite this abstract in AMA style:

Harrison M, Chiney M, Shevell D, Dong L, Dawes M, Girgis I. First-in-Human Safety, Pharmacokinetic and Pharmacodynamic Study of Escalating Single- and Multiple-Doses of BMS-986256, a Novel, Potent, Oral Inhibitor of TLR7 and TLR8 [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/first-in-human-safety-pharmacokinetic-and-pharmacodynamic-study-of-escalating-single-and-multiple-doses-of-bms-986256-a-novel-potent-oral-inhibitor-of-tlr7-and-tlr8/. Accessed .
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