MRGPRX2 Antagonist Program
EP262: Redefining the Treatment of Mast Cell-Mediated Disorders
Escient is developing EP262, an oral, once-daily, small molecule antagonist of Mas-related G protein-coupled receptor X2 (MRGPRX2) for the potential treatment of a variety of mast cell-mediated diseases, with an initial focus on chronic urticarias and atopic dermatitis.
Mast cells, which have been referred to as the leader cells of the inflammatory cascade, are a unique type of innate immune cell that reside in close proximity to sensory neurons in key barrier tissues (such as the skin, airways and GI tract) and connective tissues.
There is a large unmet need for an oral medication with a novel mechanism of action. Existing approaches, including anti-IgE therapy, antihistamines, and medications targeting other downstream mediators, have significant limitations. As many as 30-50 percent of patients with chronic urticaria are not adequately controlled with current therapies, and many mast-cell-mediated diseases have not been amenable to treatment with currently available medications.
MRGPRX2 is a mast cell receptor that is activated by numerous ligands, including many peptides released from sensory neurons (e.g. substance P, cortistatin-14, VIP) as well as other cell types (e.g. eosinophils, neutrophils, dendritic cells, and T-cells). In response to MRGPRX2 activation, mast cells release histamine, tryptase, chymase, chemokines and cytokines, which can cause itchy hives, angioedema, type 2 inflammation (through engagement of the adaptive immune system) and chronic pruritus and pain.
Small molecule MRGPRX2 antagonists efficiently inhibit agonist-induced mast cell activation and degranulation as demonstrated by single cell time-lapse confocal microscopy in primary human mast cells in the video below*.
MRGPRX2 agonists such as substance p (shown at left in video) rapidly induce calcium mobilization (in green) and release of granules (in red), which is completely inhibited upon treatment with nanomolar concentrations of MRGPRX2 antagonists (shown at right in video).
*Nadine Serhan 1, Nicolas Gaudenzio 1,2
1 Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291 – CNRS UMR5051 – University Toulouse III, France
2 Genoskin SAS, Toulouse, France
EP262 is a potent, highly-selective antagonist that blocks the activation of MRGPRX2 by various neuropeptides and other agonists. By virtue of its IgE-independent mechanism of action, EP262 holds great promise across a broad range of mast-cell-mediated diseases, both as an oral alternative or in addition to existing treatments, as a novel therapy for diseases that have not been amenable to anti-IgE therapy.