Evommune has dosed the first patient in its Phase 2b trial of EVO756, an oral MRGPRX2 antagonist being evaluated as a novel preventive treatment for migraine.
Written By: Amit Kumar Bharati, BPharm
Reviewed By: Pharmacally Editorial Team
Evommune announced that the first patient has been dosed in its global Phase 2b clinical trial (NCT07616128) evaluating EVO756, an investigational oral small-molecule antagonist of Mas-related G protein-coupled receptor X2 (MRGPRX2), for the prophylactic treatment of migraine.
The study marks an important milestone in the company’s clinical development program and is designed to evaluate whether targeting MRGPRX2 can provide a differentiated oral preventive therapy for patients who remain inadequately controlled with currently available treatments. Topline results are expected in 2027.
Novel MRGPRX2-targeted approach aims to broaden migraine prevention
Unlike currently approved preventive therapies that primarily target a single biological pathway, EVO756 is designed to inhibit MRGPRX2-mediated signaling triggered by three migraine-associated neuropeptides: pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), and Substance P.
MRGPRX2 is expressed in human trigeminal neurons and meningeal mast cells, two key disease-relevant tissues involved in migraine biology. According to Evommune, targeting this receptor may provide broader mechanistic coverage by simultaneously addressing neuronal signaling and mast cell activation implicated in migraine pathophysiology.
The company believes this differentiated mechanism could potentially benefit a broad range of patients, including those who have experienced an inadequate response to calcitonin gene-related peptide (CGRP) inhibitors, although this remains to be demonstrated in clinical studies.
Phase 2b study evaluates efficacy in refractory migraine
The ongoing Phase 2b study is a global, randomized, double-blind, placebo-controlled, dose-ranging trial evaluating EVO756 in adults with refractory migraine who experience six or more migraine days per month.
Approximately 330 participants will be randomized to two active treatment arms or placebo and receive 12 weeks of oral treatment. The study is evaluating daily doses of up to 100 mg.
The primary endpoint is the mean change from baseline in monthly migraine days (MMD). Key secondary endpoints include the proportion of participants achieving at least 50% and 75% reductions in monthly migraine days, changes in monthly headache days, and reductions in acute migraine medication use.
Exploratory endpoints include patient subtyping, migraine-related biomarkers, and migraine-specific quality-of-life measures, which may provide additional insights into treatment response and disease biology.
Migraine continues to present a significant unmet clinical need
Migraine affects more than 40 million people in the United States and more than 10% of the global population, making it one of the leading causes of neurological disability worldwide.
More than 10 million Americans are considered eligible for preventive therapy. However, currently available preventive treatments provide only modest improvements, reducing migraine frequency by approximately two additional migraine days per month compared with placebo.
Nearly half of patients do not achieve a meaningful reduction in migraine frequency, while more than 80% discontinue traditional preventive therapies within one year. These limitations highlight the need for new treatment approaches with differentiated mechanisms of action.
Executives and investigators highlight the potential of MRGPRX2 inhibition
Commenting on the trial initiation, Evommune President and Chief Executive Officer Luis Peña said that meaningful unmet need remains despite advances in migraine prevention. He noted that EVO756’s dual-action biology, multi-neuropeptide coverage, and mechanistic breadth could potentially benefit a wide range of patients, including those who have not responded adequately to CGRP inhibitors.
Stewart Tepper, M.D., Vice President of the New England Institute for Neurology and Headache and a clinical trial investigator, said migraine remains one of the most disabling neurological disorders worldwide and emphasized the need for additional targeted oral preventive therapies. He described MRGPRX2 as a compelling therapeutic target and said he looks forward to the data generated by the Phase 2b study.
EVO756 expands Evommune’s MRGPRX2 development strategy
EVO756 is a first-in-class, highly selective oral small-molecule antagonist of MRGPRX2, a receptor predominantly expressed on mast cells and peripheral sensory neurons.
Beyond migraine, Evommune is investigating the therapeutic potential of MRGPRX2 inhibition in other chronic inflammatory diseases, including atopic dermatitis, reflecting the broader role of mast cell activation in inflammatory disorders.
The initiation of the Phase 2b migraine trial expands the clinical development of EVO756 beyond inflammatory skin diseases and represents an important advancement in the company’s pipeline. If the study demonstrates favorable efficacy and safety, EVO756 could emerge as a novel oral preventive therapy targeting MRGPRX2, offering an alternative mechanism for patients with migraine who remain inadequately controlled on existing preventive treatments.
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About the Writer
Amit Kumar Bharti (LinkedIn) is a pharmacy graduate from DPSRU, Delhi and healthcare writer with a strong interest in pharmaceutical research, medical writing, and evidence-based healthcare communication. He is passionate about translating complex scientific and medical information into clear, accurate, and engaging content for healthcare professionals and the pharmaceutical industry. His focus includes emerging therapies, clinical research, and recent advances in medicine.