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LP-183 Enpatoran: preclinical evidence supporting glucocorticoid dose reduction and phase II study design in patients with SLE and/or CLE (WILLOW)
  1. Eric F Morand1,
  2. Victoria P Werth2,
  3. Andrew Bender3,
  4. Aditee Deshpande3,
  5. Ankita Deshmukh3,
  6. Bharat Vaidyanathan3,
  7. Cristina Vazquez-mateo4,
  8. Melinda Przetak3,
  9. Flavie Moreau5,
  10. Mukhy Khursheed6,
  11. Sanjeev Roy7 and
  12. David R Pearson8
  1. 1Centre for Inflammatory Disease, Monash University, Melbourne, Australia
  2. 2Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  3. 3Research Unit – Neuroscience and Immunology, EMD Serono Research and Development institute, Inc., an affiliate of Merck KGaA, Billerica, MA, USA
  4. 4Global Clinical Development, EMD Serono Research and Development institute, Inc., an affiliate of Merck KGaA, Billerica, MA, USA
  5. 5Global Biostatistics, EMD Serono Research and Development institute, Inc., an affiliate of Merck KGaA, Billerica, MA, USA
  6. 6Global Patient Safety, Merck Serono Ltd., an affiliate of Merck KGaA, Feltham, UK
  7. 7Global Clinical Development, Ares Trading SA, an affiliate of Merck KGaA, Eysins, Switzerland
  8. 8Department of Dermatology, University of Minnesota, Minneapolis, MN, USA


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.

Conclusions Enpatoran is a novel TLR7/8 inhibitor and may enable glucocorticoid dose reduction in patients with SLE and CLE. The WILLOW study incorporates multiple novel elements including a basket design and evaluation of glucocorticoid sparing.

Abstract LP-183 Figure 1

WILLOW study design

  • Lupus
  • Enpatoran
  • Glucocorticoids

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