Modeling clinical efficacy of the SIP receptor modulator ponesimod in psoriasis

Background: Ponesimod is currently the only SIP receptor modulator studied in psoriasis. In a dose finding study, the active doses showed similar efficacy. Objective: Prediction of efficacy at lower doses to aid clinical phase 3 planning with respect to dose selection, duration of treatment, and patient inclusion criteria based on pharma-co-kinetic/pharmacodynamic (PK/PD) modeling and simulation. Methods: The dose-finding study treated 326 patients (67 on placebo, 126 on 20 mg, and 133 on 40 mg) over 16 weeks. PK/PD modeling of steady-state trough concentrations and longitudinal PASI scores was employed to characterize data and simulate scenarios. Results: PASI score continually decreased with time on ponesimod treatment, reaching a plateau at 16 weeks. Absolute and relative (percent) PASI score change was larger in patients with higher PASI score at baseline. Doses below 10 mg were predicted to show lower efficacy than doses of 10 mg and higher. Conclusion: Concentration-response modeling was able to predict the efficacy of doses that were not studied. In psoriasis patients, a dose of 10 mg (not administered in the study) was predicted to show efficacy similar to 20 mg. Disease status (PASI score at baseline) as study inclusion criterion has pronounced influence on study outcome. (C) 2017 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.