Eliminating a liver disease treatment’s itchy side effect

By visualizing how analogs of bile acids bind to mas-related G-protein coupled receptor member X4 (MRGPRX4) , scientists think they may have discovered the molecular mechanism that causes itchy side effects in people who take the drug obeticholic acid. The researchers propose that a small molecular change could eliminate the itch (Cell 2024, DOI: 10.1016/j.cell.2024.10.001).

Obeticholic acid, which is marketed as Ocaliva as a treatment for a type of liver disease known as primary biliary cholangitis, has come under scrutiny recently. Although the US Food and Drug Administration approved obeticholic acid in 2016 under its accelerated pathway, the agency restricted the drug’s use in 2021, and an FDA advisory committee voted not to extend full approval to the drug in September 2024. The committee found that data don’t demonstrate clinical benefit, and the drug doesn’t have a favorable risk-benefit profile. The FDA doesn’t have to follow the advisory committee’s recommendations but usually does.

“Why obeticholic has chronic itch side effects has become a mystery and a billion-dollar question,” Peking University’s Xiaoguang Lei, who led the study, says in an email.

Certain bile acids are known to cause itchiness in people with liver disease, and Lei and coworkers previously identified MRGPRX4 as the receptor that may be mediating this effect. In the recent work, the team solved the cryo-electron microscopy (cryo-EM) structure of MRGPRX4 bound to a bile acid analog that had a phosphate at a key position—called the 3 position—on its molecular skeleton. The cryo-EM results suggest that a polar group, such as a hydroxy or sulfate, at the 3 position is critical for binding to MRGPRX4.

Because obeticholic acid has a chemical structure that’s similar to those of bile acids, Lei and coworkers suspected that it might cause itching by binding to MRGPRX4. They prepared an obeticholic analog called C7 that’s missing the hydroxy group at the 3 position. C7 alleviated liver injury and fibrosis in rodent studies without causing itching.

Christa E. Müller, a scientist at the University of Bonn who studies the receptors that cause itch, says the research provides exciting data about MRGPRX4, which has received scant attention until now. She says the cryo-EM structure will support drug development efforts.