Affiliations 

  • 1 Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
  • 2 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA. Electronic address: sudha.visvanathan@boehringer-ingelheim.com
  • 3 Service de Dermatologie, Assistance Publique-Hôpitaux de Paris Hôpital Saint-Louis, and INSERM Unité 1163, Imagine Institute of Genetic Diseases, Université Paris Cité, France
  • 4 Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
  • 5 Icahn School of Medicine at Mount Sinai, New York, New York, USA
  • 6 St John's Institute of Dermatology, King's College London, London, UK
  • 7 Jeffrey Cheah School of Medicine and Health Sciences, Clinical School Johor Bahru, Monash University Malaysia, Johor Bahru, Malaysia
  • 8 School of Infection and Immunity, University of Glasgow, Glasgow, UK
  • 9 Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
  • 10 Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, USA
J Invest Dermatol, 2024 Jul 12.
PMID: 39004117 DOI: 10.1016/j.jid.2024.05.034

Abstract

EFFISAYIL® 1 was a randomized, placebo-controlled study of spesolimab, an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis (GPP) flare. Treatment with spesolimab led to more rapid pustular and skin clearance versus placebo in approximately half of the patients. Here we present histologic, transcriptomic, and proteomic analyses of lesional and non-lesional skin, and whole-blood samples collected from EFFISAYIL® 1. Treatment with spesolimab led to a transition toward a non-lesional profile, with a downregulation of gene expression in the skin of IL-36 transcripts (IL-36α, IL-36β, IL-36γ) and those associated with neutrophil recruitment (CXCL1, CXCL6, CXCL8), proinflammatory cytokines (IL-6, IL-19, IL-20), and skin inflammation (DEFB4A, S100A7, S100A8). Changes were manifest at Week 1 and sustained to Week 8. At the systemic level, reductions in serum biomarkers of inflammation (IL-17, IL-8, IL-6) were sustained until 12 weeks post-spesolimab treatment. Considerable overlap was observed in the spesolimab-induced changes in gene and protein expression from skin and blood samples, demonstrating the molecular basis of the effects of spesolimab on controlling local and systemic inflammation. Data are consistent with the mode of action of spesolimab, whereby inhibition of the IL-36 pathway leads to subsequent reductions in the key local and systemic pathologic events associated with acute GPP flares.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.