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.

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ACR Meeting Abstracts - 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/