Background Aberrant toll-like receptor (TLR) 7/8 activation is thought to be involved in both lupus pathogenesis and glucocorticoid resistance. Enpatoran, a selective and potent dual inhibitor of TLR7/8 that is in development for cutaneous and systemic lupus erythematosus (CLE/SLE), was well tolerated by healthy participants and patients hospitalized with COVID-19 pneumonia. We report evaluation of the glucocorticoid-sparing effect of enpatoran and a trial design to assess its efficacy and safety in patients with SLE and/or CLE.
Methods Cytokine concentrations and gene expression changes were measured in stimulated human peripheral blood mononuclear cells (PBMCs) from healthy donors after treatment with dexamethasone, TLR7/8 inhibitor, or both. A Phase II basket design, proof-of-concept, dose-finding, randomized, double-blind, placebo-controlled 24-week study in patients with SLE and/or CLE (WILLOW; NCT05162586), which will also assess glucocorticoid sparing, was designed.
Results In healthy donor PBMCs, synergy was observed between TLR7/8 inhibitor and dexamethasone. Combination treatment inhibited cytokine release (interleukin-6) with greater potency than either treatment alone and reduced the expression of nuclear factor-kappa B and interferon-regulated genes. Glucocorticoid sparing will be evaluated by a mandatory tapering schedule in the WILLOW study, which has two cohorts (figure 1). Cohort A will enroll patients with CLE or SLE with predominantly active lupus rash. Cohort B, in two parts, will enroll SLE patients with moderate-to-severe systemic disease activity; Part 1 will assess clinical signal and Part 2 may be adapted to improve dose finding. The primary objectives are to evaluate the dose-response relationship of enpatoran in reducing disease activity based on CLASI-A or BICLA. The secondary objectives include evaluating effects on disease control and clinically meaningful glucocorticoid reduction.
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