Volixibat Improves Itch, Fatigue in PSC, Supporting “Patient-Centered” Care

Miriam Pharmaceuticals presented late-breaking, full results from VISTAS, a phase 2b study evaluating volixibat in patients with primary sclerosing cholangitis (PSC), at the European Association for the Study of the Liver (EASL) meeting, with plans to submit a new drug application (NDA) to the US Food and Drug Administration (FDA) by the second half of summer 2026. If approved, volixibat would be the first FDA-approved therapy specifically targeting cholestatic pruritus in PSC.

Volixibat, an investigational ileal bile acid transporter (IBAT) inhibitor, was associated with statistically significant and rapid improvements in pruritus, with separation from placebo observed within 2 weeks. In the primary endpoint, patients receiving volixibat achieved a 2.72-point reduction in pruritus versus baseline and a placebo-adjusted difference of 1.64 points (P <.0001), as measured by the Adult ItchRO scale.

HCPLive spoke with Gideon Hirschfield, FRCP, PhD, Director of the Autoimmune and Rare Liver Disease Programme, to discuss the data and its implications for patient-centered care in PSC, particularly around symptom burden related to itch and fatigue.

“If I told you that you have a headache and I'm going to give you Tylenol, but you have to wait a month for the Tylenol to work, you're not going to take it,” Hirschfield said. “It's exactly the same if I tell a patient who's got cholestatic pruritus due to PSC that I have a treatment that, within 1 to 2 weeks, they'll be able to tell immediately that it's helping them. That's patient-centered care.”

VISTAS Trial Design

Pruritus is one of the most common and burdensome symptoms of PSC and is strongly associated with impaired sleep and reduced quality of life. The primary endpoint assessed change in the Adult ItchRO scale, a validated 0–10 numerical rating scale in which 0 indicates no itch and 10 indicates worst itch imaginable.

The VISTAS trial enrolled 158 patients with PSC, assigned to a primary analysis cohort (moderate-to-severe itch; n = 111) or a secondary cohort (mild itch; n = 47) based on baseline severity. Patients were randomized to volixibat 20 mg twice daily or placebo.

Itch Outcomes

A ≥2-point reduction in itch was achieved in 56% of patients receiving volixibat versus 26% with placebo (P = .0019), while a ≥3-point reduction was seen in 37% versus 11%, respectively (P = .0011).

These improvements were accompanied by reductions in serum bile acids (sBA), with a mean decrease of 33.7 µmol/L compared with a 2.1 µmol/L increase in placebo, for a placebo-adjusted difference of −35.8 µmol/L (P = .0324). Mechanistically, IBAT inhibition reduces enterohepatic circulation of bile acids, lowering systemic exposure. Bile acid accumulation is thought to contribute to cholestatic pruritus via activation of sensory pathways including MRGPRX4 and TGR5, which transmit itch signaling to the central nervous system.

Fatigue

Fatigue affects an estimated 70% to 75% of patients with PSC and is often independent of biochemical disease activity, reflecting its multifactorial pathophysiology.

“We do expect that when you improve itch, you would also have an improvement in sleep disturbance related to pruritus, and I think that’s what we see,” Hirschfield said. “We’d like to see whether or not that then translates into other symptom improvements, but at this stage it’s quite early days in terms of those analyses. Fatigue is a very complex symptom and there isn’t a complete immediate overlap between fatigue and pruritus, so it’s quite possible that drugs that improve pruritus and sleep disturbance may not directly have a quantifiable improvement in fatigue.”

Investigators reported improvements in Patient-Reported Outcomes Measurement Information System (PROMIS) sleep scores (placebo-adjusted difference −5.69; P = .0011) and numerical trends in fatigue scores (−2.33; P = .1322).

Safety

Volixibat’s safety profile was consistent with IBAT inhibition, with gastrointestinal adverse events and laboratory changes including increases in ALT, AST, ALP, and bilirubin observed versus placebo. These findings were not reported as dose-limiting but will require continued evaluation in longer-term studies.

Editors’ note: Hirschfield reports relevant disclosures with CymaBay, Ipsen, Gilead, Intercept, Mirum, Kowa, GSK, Pliant Therapeutics, and Escient.

References

1. Levy C, Hirschfield GM, Shiffman ML, et al. Efficacy and safety of volixibat, an IBAT inhibitor, in patients with primary sclerosing cholangitis and moderate-to-severe pruritus: results of the VISTAS trial. J Hepatol. 2026;84(Suppl 1):S10-S11. doi:10.1016/S0168-8278(26)00310-7.

2. Mirum Pharmaceuticals, Inc. Volixibat demonstrates statistically significant improvement in pruritus in patients with primary sclerosing cholangitis in the VISTAS phase 2b study. News release. May 4, 2026. Accessed June 30, 2026. https://ir.mirumpharma.com/news/news-details/2026/Mirum-Pharmaceuticals-Announces-Primary-Endpoint-Met-in-VISTAS-Study-of-Volixibat-in-Patients-with-Primary-Sclerosing-Cholangitis/default.asp