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Targeting MRGPRX2: A Transformative Approach to Inflammatory Skin Conditions

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Authors

Sreya Bagchi, Amanda Jacobson, Alexandra Pavel, Keerthana Natarajan, Ishwarya Sankaranarayanan, Joseph B. Lesnak, Theodore J. Price, Jeegar Patel, Jamie L. Harden, Lorena Riol-Blanco*
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*Evommune Inc., Palo Alto, CA, USA
*Department of Neuroscience and Center for Advanced Pain Studies, University of Texas, Dallas, Richardson, TX, USA
*presenting author

Abstract

Mas-related G protein-coupled receptor X2 (MRGPRX2) has emerged as a potential transformative therapeutic target for inflammatory skin diseases, including chronic spontaneous urticaria (CSU) and atopic dermatitis (AD). Expressed on human skin mast cells and peripheral sensory neurons, MRGPRX2 drives neuroinflammation through activation by endogenous ligands, such as neuropeptides and antimicrobial peptides. Its synergistic interplay with FcεR and IL-33 pathways amplifies mast cell-driven inflammation, positioning it as a central player in disease pathology.

In Mrgprb2 knockout mice, the murine ortholog of MRGPRX2, mast cell activation and inflammatory itch were significantly reduced, underscoring the receptor’s therapeutic relevance. EVO756, a novel and potent small-molecule antagonist of MRGPRX2, effectively blocked mast cell degranulation, cytokine release, and neuronal activation while disrupting the synergistic effects of MRGPRX2 with IgE and IL-33. Clinically, oral EVO756 suppressed icatibant-induced wheal formation in a phase 1 trial, confirming its ability to inhibit MRGPRX2-mediated responses in humans. A phase 2a study in Chronic Inducible Urticaria further validated its potential, demonstrating significant reductions in wheals and itch.

These findings establish MRGPRX2 as a master regulator of mast cell and sensory neuron activation, driving neurogenic inflammation in CSU, AD, and beyond. EVO756 offers a potential groundbreaking therapeutic strategy, delivering multipronged benefits by targeting key pathogenic pathways across inflammatory skin diseases and other chronic inflammatory conditions.

Background

EVO756 prevents MRGPRX2-mediated mast cell degranulation and target engagement.

EVO756 inhibition of MRGPRX2-mediated (A) CD63 and (B) CD107a surface expression by flow cytometry in LAD2 cells. EVO756 inhibition of MRGPRX2-mediated (C) CD63 surface expression by flow cytometry and (D) B-hexosaminidase release by hMCs. (E) Tryptase release by hMCs upon treatment with IgE overnight followed by treatment with anti-IgE, CST-14, and SP with and without EVO756 (1 uM). Tryptase was detected using an ELISA. (F) Cytokine and chemokine release (in the absence and presence of EVO756- 5 uM) was measured by MSD from LAD2 cells following stimulation with SP. Heatmap depicts the log2 fold change of cytokines and chemokines in SP-treated versus untreated cells.

EVO756 inhibits functional MRGPRX2 activation of human sensory neurons. (A) Schematic of calcium imaging: cultured human DRG neurons were pre-loaded with Fura-2 prior to time-lapse fluorescent imaging. (B-E) Calcium imaging traces of human DRG neuron (B,D) non-responders and (C,E) responders after treatment with (B-C) icatibant alone (5 minutes, 100μM) (n=4 organ donors) and (D-E) inhibition in the presence of EVO756 (10μM) (n=5 organ donors) followed by treatment with KCl (50mM).

Phase 1 healthy volunteer skin challenge study design with oral EVO756. In brief, the wheal response in healthy volunteers was determined at baseline in response to saline, histamine, or 1, 10, and 100 ug/mL of an intradermal injection of icatibant. Healthy volunteers were given placebo, 10, 30, 100, 240 mg of EVO756 BID or 500 mg QD for 14 days. After 14 days of oral EVO756, the skin challenge was repeated as performed at baseline, and reduction in wheal size was noted. Average wheal sizes noted in this study are shown in the lower right.

Chronic Inducible Urticaria Phase 2a Results

An open-label Phase 2a study in adults with chronic inducible urticaria (symptomatic dermographism) (n=30) received either 300 mg QD or 50 mg BID for 4 weeks. Fric scores were determined at baseline and at week 4. 28/30 subjects completed the study. The primary endpoint was safety as assessed by the incidence of TEAEs. Efficacy measures included complete response, change from baseline in provocation test, change from baseline in pruritus NRS at provocation site. There were no serious adverse events, no treatment discontinuations due to adverse events, and EVO756 was generally well-tolerated.

Conclusions