HMN 2026: What is the first-in-class drug candidate for chronic itch

Chronic itch is often described as an “invisible torment.” It can persist for weeks or months, severely affecting sleep, mental health, and quality of life. In patients with cholestatic liver disease, chronic itch remains a major clinical challenge, and current treatments often provide limited relief.

A team led by PKU’s Professor Lei Xiaoguang, together with Hepai-Tech Biopharma Technology and collaborators from the University of Science and Technology of China (USTC) and the Hefei Comprehensive National Science Center, has developed HEP-50768, a potent and selective small-molecule inverse agonist targeting the itch receptor MRGPRX4. The study is published in Nature Chemical Biology.

Chronic itch remains difficult to treat because it often does not respond well to conventional allergy medications such as antihistamines or corticosteroids. Existing therapies, including ursodeoxycholic acid, maralixibat, and rifampin, may offer only limited relief. This study introduces a potentially more precise strategy for treating cholestatic itch and other forms of chronic itch.

Previous research by Lei Xiaoguang’s team and collaborators found that 3-hydroxyl-sulfated bile acids can activate MRGPRX4, an itch receptor linked to cholestasis-related itching. This discovery clarified an important disease mechanism and laid the foundation for targeted drug development. Building on this work, the team aimed to develop a clinically viable compound that could block MRGPRX4 activity and relieve cholestatic itch.

The researchers tested more than 100,000 small molecules to find one that could act on MRGPRX4, the itch-related receptor. After further optimization, they developed HEP-50768, a strong and selective drug candidate. HEP-50768 was able to block the activation of MRGPRX4 caused by bile acids. It also reduced the receptor’s natural activity, indicating that it acts as an inverse agonist.

The team then used cryo-electron microscopy and computer simulations to understand how HEP-50768 blocks the receptor at the molecular level. In animal studies, the compound greatly reduced scratching behavior in humanized MRGPRX4 rats. It also showed good drug-like properties and a favorable safety profile in rats and rhesus monkeys.

HEP-50768 shows a compelling preclinical profile, combining mechanistic precision, efficacy, and safety. With the Investigational New Drug filing completed and Phase I trials planned, it represents a promising clinical candidate for cholestatic itch and potentially other chronic itch conditions.

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