FDA approves linerixibat for cholestatic pruritus in PBC

The FDA has approved linerixibat (Lynavoy), the first therapy in the US specifically indicated for cholestatic pruritus in adults with primary biliary cholangitis (PBC), addressing a long-standing gap in symptom management.

Cholestatic pruritus affects up to 89% of patients with PBC and can be severe and persistent. It frequently disrupts sleep, exacerbates fatigue, and significantly impairs quality of life. In some cases, patients pursue liver transplantation primarily due to intractable itching rather than liver failure. Until now, the absence of approved targeted therapies has led clinicians to rely on off-label or variably effective treatments.

Linerixibat is an oral ileal bile acid transporter (IBAT) inhibitor that reduces circulating bile acids, which are thought to contribute to pruritus in cholestatic liver disease. By inhibiting bile acid reuptake in the gut, it targets a key mechanistic pathway underlying itch in PBC.

Approval was based on results from the phase III GLISTEN trial, a randomized, placebo-controlled study demonstrating statistically significant improvements in itch severity and itch-related sleep interference. Reductions in worst itch scores were observed as early as 2 weeks and were sustained through 24 weeks. The findings suggest the treatment works quickly, which may be important for patients with severe symptoms that haven’t improved with other treatments.

Although absolute reductions in itch scores were modest on a numerical rating scale, they were associated with clinically meaningful patient-reported improvements, including better sleep. For hepatologists and gastroenterologists, these quality-of-life gains are particularly relevant given the substantial burden of pruritus.

The most common adverse events in GLISTEN were gastrointestinal, including diarrhea (61%) and abdominal pain (18%), typically mild to moderate in severity. Approximately 4% of patients discontinued treatment because of diarrhea. According to a GSK media release, patient counseling regarding tolerability will be important in clinical use.

Linerixibat’s mechanism also highlights the broader role of bile acid signaling in symptom generation and raises the possibility of similar approaches in other cholestatic conditions. Regulatory reviews are ongoing in multiple regions, suggesting potential expansion into global practice.

In an interview with GI & Hepatology News, Don C. Rockey, MD, a gastroenterologist who chairs the Department of Medicine at the Medical University of South Carolina (MUSC), Charleston, characterized the approval of linerixibat as “a significant advance” for PBC patients with severe pruritus.

“Right now, we throw sort of the kitchen sink at these patients,” said Dr. Rockey, who is also Vice Chair of AGA Institute Council Liver & Bilary Section. “They might get Benadryl or an SSRI. Sometimes that works and sometimes it doesn't. So, I think this is going to be targeted to patients with moderate-to-severe, and especially, I think, severe pruritus.”

Linerixibat “is an added therapy that's mechanistically different from what we have, and therefore I think that it's going to be used,” he noted. “It will be important to see what the cost is going to be.”

Dr. Rockey disclosed that he has conducted clinical trials on behalf of the MUSC for several pharmaceutical companies, including GSK.