Background/Aims: Psoriasis plaque tests (PPTs) are important tools in the early phases of antipsoriatic drug development. Two distinct PPT design variants (open vs. occluded drug application) are commonly used, but no previous work has aimed to directly compare and contrast their performance. Methods: We compared the antipsoriatic efficacy of mapracorat 0.1% ointment and reference drugs reported in 2 separate studies, representing open and occluded PPT designs. The drug effect size was measured by sonography (mean change in echo-poor band thickness), chromametry, and standardized clinical assessment. Results: Antipsoriatic effects were detectable for the study drugs in both occluded and open PPTs. Differences between the potency of antipsoriatic drugs and vehicle were observable. The total antipsoriatic effect size appeared to be higher in the occluded PPT than the open PPT, despite the shorter treatment duration (2 vs. 4 weeks). Effect dynamics over time revealed greater differences between some study drugs in the open PPT compared to the occluded PPT. Conclusion: Taking the higher technical challenges for the open PPT into account, we recommend the occluded PPT as a standard screening setting in early drug development. In special cases, considering certain drug aspects or study objectives that would require procedural adaptations, an open PPT could be the better-suited design. Finally, both PPT models show clear advantages: classification as phase I studies, small number of psoriatic subjects, relatively short study duration, excellent discrimination between compounds and concentrations, parallel measurement of treatment response, and go/no go decisions very early in clinical development.
Psoriasis plaque test is a model that allows intra-individual comparison of multiple topical drugs and formulations, useful early in the development of topical psoriasis agents. GSK2981278 is a retinoic acid receptor-related orphan receptor gamma inverse agonist preclinically shown to inhibit the production of Th17 cytokines implicated in the pathogenesis of psoriasis. The safety, tolerability and preliminary clinical effect of GSK2981278 were evaluated in a psoriasis plaque test. In this first-inhuman , single-center, randomized, vehicle-and positive-controlled, subject-and evaluator-blind trial, 15 psoriasis patients were enrolled (Study 201465). All subjects received 6 study treatments (0%, 0.03%, 0.1%, 0.8%, and 4% GSK2981278 ointment and betamethasone valerate 0.1% cream [positive control]) each applied to one of 6 randomly assigned small test fields on stable plaque(s) once daily over 19 days. The change in inflammatory infiltrate thickness measured by sonography was the primary endpoint. Four 3 mm punch biopsies (from non-lesional skin, untreated lesion, vehicletreated lesion, and 4%-treated lesion) were collected at the end of the study in 13 consenting subjects for gene expression analysis on Th17 related cytokines. There were no safety or tolerability findings. While the positive control showed the expected reduction in infiltrate thickness, there was no reduction in infiltrate thickness with any strength of GSK2981278. No meaningful changes in IL-17 related biomarkers or psoriasis disease signature were detected. These results may be explained by several factors: GSK2981278 did not penetrate the skin and reach the target cells in the dermis; higher concentrations and/or longer treatment period were needed to induce clinical effects; this target requires a blockade of activity over the entire plaque rather than that in a small test field or systemic blockade to induce clinical effects. Further investigation is planned. 250 CADM1 is a diagnostic marker in early-stage mycosis fungoides
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