Population Pharmacokinetic-Pharmacodynamic (popPK/PD) Relationship of Orismilast, A Potent and Selective PDE4B/D Inhibitor, in Atopic Dermatitis

Richard B Warren; Anne Weiss; Jakob Felding; Morten O A Sommer

doi:10.1007/s13555-025-01371-9

Population Pharmacokinetic-Pharmacodynamic (popPK/PD) Relationship of Orismilast, A Potent and Selective PDE4B/D Inhibitor, in Atopic Dermatitis

Dermatol Ther (Heidelb). 2025 Apr;15(4):831-839. doi: 10.1007/s13555-025-01371-9. Epub 2025 Mar 5.

Authors

Richard B Warren¹, Anne Weiss², Jakob Felding², Morten O A Sommer^{2

3}

Affiliations

¹ Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, The University of Manchester, Salford, Manchester, M6 8HD, UK. richard.warren@manchester.ac.uk.
² UNION Therapeutics A/S, Hellerup, Denmark.
³ Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark (DTU), Lyngby, Denmark.

Abstract

Introduction: Orismilast is a novel oral selective inhibitor of phosphodiesterase 4B and 4D subtypes (PDE4B/D) in clinical development for treatment of atopic dermatitis (AD) and other inflammatory skin conditions. Herein, we describe a pharmacokinetic/pharmacodynamic (PK/PD) analysis comparing predicted exposure data of orismilast and apremilast in AD patients and place these data in the context of their IL-13 secretion data generated in a human whole-blood assay.

Methods: A PK/PD assessment of orismilast and apremilast in AD was performed. In a human whole blood assay, the levels needed to inhibit IL-13 production were measured for orismilast and apremilast head-to-head. These data were then contextualized with simulated exposure of clinically relevant doses of the two drugs.

Results: The analysis shows that orismilast has potential to significantly inhibit IL-13 production at all three clinical doses trialed in AD (20 mg bid, 30 mg bid, and 40 mg bid) as the drug has a predicted C_average plasma concentration exceeding the IL-13 IC₉₀ value of the human whole-blood assay and a predicted C_min above the IL-13 IC₅₀ value. Apremilast, in contrast, is predicted to reach C_average plasma concentrations below the IL-13 IC₅₀ value for both doses (30 mg bid and 40 mg bid) and only exceeding the IL-13 IC₅₀ value at peak concentrations for the highest dose.

Conclusion: The outcome of the analysis supports the observed clinical effect of orismilast in patients with AD and could explain the lack of efficacy of apremilast in the same indication.

Keywords: Atopic dermatitis; Orismilast; PDE4; Pharmacodynamics; Pharmacokinetics.

Plain language summary

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that negatively impacts AD patients’ quality of life. Various drugs are used for treatment of AD; however, a safe and effective oral treatment is still an important unmet need. Orismilast is an orally available PDE4B/D selective inhibitor in clinical development that has demonstrated improved effect in pre-clinical models and clinical studies compared to apremilast. This analysis compared predicted exposures of orismilast and apremilast in relation to data from a human whole-blood assay measuring IL-13 release. The authors reported that orismilast has potential to block IL-13 secretion more efficiently compared to apremilast at therapeutically relevant doses, supporting the observed clinical effect of orismilast in patients with AD and lack of efficacy of apremilast in the same indication. It highlights the strength of using drug exposure in relation to whole-blood derived data when performing pharmacokinetic/pharmacodynamic (PK/PD) assessments instead of comparing dose and biochemical data.