EVO756: An emerging oral MRGPRX2 inhibitor with compelling data from early studies

Summary: Abstract Body: Chronic inflammatory diseases often involve complex neurogenic and mast cell-related pathways, with the Mas-Related G-Protein Coupled Receptor X2 (MRGPRX2) playing a pivotal role. This receptor, highly expressed on mast cells and peripheral neurons, has drawn attention for its involvement in non-IgE-driven mast cell degranulation and neurogenic inflammation, contributing to symptoms like itching, coughing, and pain. Because MRGPRX2 responds to a wide range of ligands in inflamed tissues, it is a promising target for therapeutics addressing conditions like chronic urticaria, atopic dermatitis, and severe asthma. EVO756, a novel small molecule, has emerged as a promising oral inhibitor of MRGPRX2. Preclinical data demonstrate robust inhibition of MRGPRX2-mediated responses across experimental models, such as LAD2 cells, human skin-derived mast cells, and skin explants. These findings highlight its broad activity in targeting this receptor. Initial human trials support EVO756’s potential. A Phase 1 randomized, double-blind study showed it to be well-tolerated with a dose-proportional pharmacokinetic profile. Its mechanism of action was confirmed through a skin wheal challenge with icatibant, where significant reductions in wheal size affirmed effective receptor blockade. EVO756 stands out as an innovative therapy with the potential to regulate MRGPRX2-mediated processes. Its favorable early-stage results pave the way for further investigations into its clinical utility for managing mast cell-driven and neuro-inflammatory diseases. Jamie Harden¹, Sreya Bagchi¹, Stefan Frischbutter^{2, 3}, Jorg Scheffel^{2, 3}, Han Gao^{2, 3}, Nana Shi^{2, 3}, Alexandra Pavel¹, Claudia Montlollor-Abalate¹, Andrea Kim¹, Janice Drew¹, Polina Bukshpun¹, Kelsey Santisteban¹, Dan Burge¹, Sarbjit Saini⁴, Jeegar Patel¹, Lorena Riol-Blanco¹ 1. Evommune Inc, Palo Alto, CA, United States. 2. Institute of Allergology, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany. 3. Immunology and Allergology, Fraunhofer-Institut fur Translationale Medizin und Pharmakologie ITMP, Berlin, HE, Germany. 4. School of Medicine, Division of Allergy and Immunology, Johns Hopkins University, Baltimore, MD, United States. Translational Studies: Preclinical