2. Academic Validation
  3. Pharmacology of orismilast, a potent and selective PDE4 inhibitor

Pharmacology of orismilast, a potent and selective PDE4 inhibitor

  • J Eur Acad Dermatol Venereol. 2023 Apr;37(4):721-729. doi: 10.1111/jdv.18818.
Jonathan I Silverberg 1,  Lars E French 2,  Richard B Warren 3,  Bruce Strober 4,  Kim Kjøller 5,  Morten O A Sommer 5 6,  Philippe Andres 5,  Jakob Felding 5,  Anne Weiss 5,  Deniz Tutkunkardas 5,  Tine Skak-Nielsen 7,  Emma Guttman 8
Affiliations

Affiliations

  • 1 George Washington University School of Medicine and Health Sciences, District of Columbia, Washington, USA.
  • 2 Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University (LMU) Munich, Munich, Germany. Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Florida, Miami, USA.
  • 3 Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, The University of Manchester, Manchester, UK.
  • 4 Yale University and Central Connecticut Dermatology, Connecticut, Cromwell, USA.
  • 5 UNION therapeutics, A/S, Hellerup, Denmark.
  • 6 Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark (DTU), Kongens Lyngby, Denmark.
  • 7 LEO Pharma A/S, Ballerup, Denmark.
  • 8 Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
PMID: 36527389 DOI: 10.1111/jdv.18818
Abstract

Background: There remains an unmet need for oral medications that are safe and efficacious for long-term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro-inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 Inhibitor in clinical development for CISD treatment.

Objectives: The objective of this study was to examine the PDE4 enzymatic activity and anti-inflammatory effects of orismilast in vitro, ex vivo, and in vivo.

Methods: The PDE1-11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone-induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed.

Results: Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T-helper (Th)1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) related cytokines in PBMC. In vivo, 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (p < 0.0001, respectively).

Conclusion: Orismilast displayed selective and potent PDE4 inhibition and broad-spectrum anti-inflammatory activity in several pre-clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.

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