Development of A decision-making biomarker for CRTH2 antagonism in clinical studies

Publication date: Available online 12 June 2015 Source:New Horizons in Translational Medicine Author(s): Daniel S. Strasser , Hervé Farine , Martin Holdener , Jochen Zisowsky , René Roscher , Julie Hoerner , Martine Gehin , Patricia N. Sidharta , Jasper Dingemanse , Peter M.A. Groenen Biomarkers have shown to improve success rates in the development of novel drugs, providing essential information in the early phases of clinical development for decision- making. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) is pursued as a drug target for a number of inflammatory diseases. CRTH2 antagonists block the activation and migration of key inflammatory cells such as eosinophils, basophils, and Th2 cells. The mechanism of action of CRTH2 antagonists was established in cells isolated from human blood. Biomarkers derived from these experiments were included in clinical studies to investigate the mechanism of action and potency of CRTH2 antagonists in human. For clinical phase I studies with the CRTH2 antagonist ACT-453859, a follow-up molecule of setipiprant, inclusion of the most precise and robust pharmacodynamic (PD) biomarker with a clinically relevant target effect was desired to aid phase II dose selection. Candidate biomarkers such as IL-13 secretion from Th2 cells and CRTH2, CD11b and CD203 modulation on basophils and eosinophils in whole blood were compared in terms of signal intensity and variability. Blockade of CRTH2 receptor inte...
Source: New Horizons in Translational Medicine - Category: Research Source Type: research