Safety, pharmacokinetics, and pharmacodynamics in first-in-human study of a novel compound E6742, a Toll-like receptor 7 and 8 antagonist

[Speaker] Kenya Nakai:1
[Co-author] Sanae Yasuda:1, Min-Kun Chang:2, Mark Matijevic:2, Shannon Mcgrath:2, Hua Yang:2, Nancy Hall:2, Jagadeesh Aluri:2, Robert Lai:3, Sally Ishizaka:2
1:Eisai Co., Ltd., Japan, 2:Eisai Inc., USA, 3:Eisai Ltd., UK

E6742 is a novel investigational molecule which blocks the activation of Toll-like receptor (TLR) 7 and 8. E6742 is in development for the treatment of systemic lupus erythematosus (SLE). In mouse models of lupus, E6742 blocks the progression of nephritis, significantly slowing the advance of proteinuria, kidney histopathology, and associated mortality. In mouse models, E6742 down regulates a set of interferon-regulated genes in peripheral blood. Based on the genetic and preclinical evidence, targeting TLR7 and 8 may have a unique disease modifying impact in systemic lupus.

This was a single-center, single ascending oral dose, placebo-controlled, randomized, double-blind study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of E6742 in healthy subjects. Eight subjects were administered either E6742 (6 subjects) or matching placebo (2 subjects) at each 10, 25, 50, 100, 200, 400, and 800 mg dose group. As pharmacodynamic parameters, multiple cytokines (IL-1beta, IL-6, IFN-alpha, IFN-gamma, and TNF-alpha) using an ex vivo challenge assay in whole blood were assessed. The relationship between plasma E6742 concentration and placebo-corrected change from baseline for QT interval was analyzed using a mixed effects modeling approach.

There were no clinically significant adverse events for any subjects. There was no safety related findings in any vital signs, electrocardiograms, physical examinations, or clinical laboratory tests. E6742 was rapidly absorbed with tmax less than 2.5 hours. The mean half-life ranged between 2.38 to 12.7 hours across dose groups. Up to 400 mg, Cmax and AUC(0-t) were almost dose proportional, however, they were slightly less than dose proportional between 400 and 800 mg. Regarding the pharmacodynamics, the expression of multiple cytokines in response to TLR7/8 agonists was suppressed with dose increase.

Overall, E6742 was well tolerated up to 800 mg and the results demonstrated that E6742 has a low risk of QT prolongation at predicted therapeutic and supratherapeutic exposures. Pharmacodynamic assessments of ex vivo challenge assay demonstrated proof of mechanism of E6742.
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