MRGPRX4 Antagonist Program
EP547: A Potent, Highly-selective MRGPRX4 Antagonist for Cholestatic and Uremic Pruritus
Escient is developing EP547, an oral, once-daily, small molecule antagonist of Mas-related G protein-coupled receptor X4 (MRGPRX4) for the potential treatment of cholestatic and uremic pruritus.
Cholestatic and uremic pruritus are common, often unrelenting and debilitating conditions characterized by very itchy skin in patients with cholestatic liver diseases (CLD) and chronic kidney disease (CKD), respectively. This form of pruritus is often not relieved by scratching and not responsive to anti-histamines or other currently available medications, which are non-specific and associated with significant side effects. There is a large unmet need for a more targeted medication that can effectively treat cholestatic and uremic pruritus without undue safety and tolerability concerns.
MRGPRX4, a receptor expressed on a subset of pruriceptive neurons in the dorsal root ganglia (DRG) innervating the skin, is specifically activated by bile acids, bilirubin, and urobilin that may accumulate in the skin and plasma of patients with CLD and CKD, making it a promising therapeutic target.
EP547 is a potent, highly-selective antagonist that blocks the activation of MRGPRX4 by various bile acids, bilirubin and urobilin. By virtue of this disease-specific mechanism of action, EP547 has the potential to be a highly targeted and efficacious treatment for cholestatic and uremic pruritus.