With a potential New Drug Application (NDA) submission to the US Food and Drug Administration (FDA) on the horizon for Mirum Pharmaceuticals’ volixibat, HCPLive sat down with lead VISTAS phase 2b study investigator, Kris Kowdley, MD, for a clinical perspective on its safety profile in adults with primary sclerosing cholangitis (PSC) and cholestatic pruritus.

Managing GI Adverse Events in PSC and IBD

“It’s well known that IBAT inhibitors are associated with loose stools and sometimes diarrhea. It’s also recognized that these symptoms can be managed in the majority of patients,” explained Kowdley, director at Liver Institute Northwest and senior scientific advisor and medical director at Velocity Clinical Research. “In the patient with PSC and concomitant IBD, the clinician has to be more thorough and more careful in evaluating whether this could potentially be a superinfection with Clostridium difficile, whether this could be a flare of underlying IBD, or whether it’s just a symptom associated with IBAT therapy.”

Volixibat Meets Primary Endpoint in VISTAS

Recently, volixibat, an investigational oral ileal bile acid transporter (IBAT) inhibitor, met its primary endpoint, a statistically significant placebo-adjusted reduction in itch severity over 28 weeks.

PSC remains a disease with a major unmet need, given there are no FDA-approved therapies specifically indicated to manage pruritus in PSC, which affects up to 50% to 60% of patients. Pruritus is commonly managed with off-label approaches such as bile acid sequestrants, rifampin, opioid antagonists, and selective serotonin reuptake inhibitors, but tolerability and efficacy are variable.³

Understanding IBAT Inhibition in Cholestatic Pruritus

IBAT, also called apical sodium-dependent bile acid transporter (ASBT), is a protein predominantly located in the terminal ileum, serving as the main transporter mediating the ileal uptake of conjugated bile acids and their return to the liver through enterohepatic circulation.

Linerixibat, an IBAT inhibitor, became the first FDA-approved therapy specifically indicated for cholestatic pruritus in primary biliary cholangitis (PBC). The approval was based on the phase 3 GLISTEN trial, which showed improvement in pruritus and itch-related sleep disruption as early as 2 weeks and over 24 weeks, compared with placebo.

Monitoring Liver Safety Parameters

Other notable safety findings included elevations in liver laboratory parameters, including alanine aminotransferase (ALT) and bilirubin.

“We will be educating clinicians about how to observe patients carefully for any symptoms that might be more concerning, such as jaundice, fatigue, etc., and in that case we would obviously intervene and measure their liver tests and evaluate them clinically,” Kowdley said. “Other than that, we have not seen much in the way of safety concerns, and so far adverse events leading to discontinuation of therapy have been gratifyingly low.”

The topline results were announced on May 4, 2026, along with tentative plans to submit an NDA for volixibat in the second half of 2026.

Editor’s Note: Kowdley reports relevant disclosures with Akero, 89Bio, Boehringer Ingelheim, Boston Pharmaceuticals, Genfit, Gilead, GlaxoSmithKline, Intercept, Madrigal, Mirum, and others.

References

1. Brooks A. Volixibat Improves Pruritus in Phase 2b PSC Trial. HCPLive. Published May 4, 2026. Accessed May 14, 2026. https://www.hcplive.com/view/volixibat-improves-pruritus-in-phase-2b-psc-trial-with-gi-and-liver-safety-signa

2. Mirum Pharmaceuticals. Mirum Pharmaceuticals announces primary endpoint met in VISTAS study of volixibat in patients with primary sclerosing cholangitis. Business Wire. May 4, 2026. Accessed May 4, 2026. https://www.businesswire.com/news/home/20260504069726/en/Mirum-Pharmaceuticals-Announces-Primary-Endpoint-Met-in-VISTAS-Study-of-Volixibat-in-Patients-with-Primary-Sclerosing-Cholangitis

3. Bowlus CL, Lim JK, Lindor KD. AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review. Clinical Gastroenterology and Hepatology. 2019;17(12):2416-2422. doi:https://doi.org/10.1016/j.cgh.2019.07.011