Gideon Hirschfield, PhD, MB BChir

Volixibat Improves Itch, Fatigue in PSC, Supporting “Patient-Centered” Care, With Gideon Hirschfield, FRCP, PhD

Mirum Pharmaceuticals presented late-breaking, full results from VISTAS, a phase 2b study evaluating volixibat in patients with 

, at the European Association for the Study of the Liver (EASL) meeting, with plans to submit a new drug application (NDA) to the 

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.

 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.”

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.

A ≥2-point reduction in itch was achieved in 56% of patients receiving volixibat versus 26% with placebo (

 = .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 (

 = .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 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;

= .0011) and numerical trends in fatigue scores (−2.33; 

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.

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. 

 2026;84(Suppl 1):S10-S11. doi:10.1016/S0168-8278(26)00310-7.

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

Videos

Gideon Hirschfield, FRCP, PhD, discusses phase 2b results from VISTAs, evaluating volixibat in PSC


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

Seladelpar’s Long-Term Benefit for Pruritus in PBC, With Gideon Hirschfield, FRCP, PhD

In primary biliary cholangitis (PBC), care is evolving beyond just controlling biochemical markers of disease activity. Now, symptom management is widely viewed as equally important, among the most burdensome being pruritus.

Despite affecting the majority of patients with PBC and having a well-documented negative impact on quality of life, itch often goes underrecognized and undertreated in clinical practice. However, last year’s introduction of seladelpar (Livdelzi) to the PBC treatment landscape may offer clinicians and patients alike a much-needed tool for addressing pruritus.

American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025

, Gideon Hirschfield, FRCP, PhD, director of The Autoimmune and Rare Liver Disease Programme and the Lily and Terry Horner Chair in Autoimmune Liver Disease Research in the division of gastroenterology and hepatology at Toronto General Hospital, presented long-term pruritus outcomes from the RESPONSE study of seladelpar in adults with PBC and interim results from its ongoing open-label extension study, ASSURE, demonstrating sustained, clinically meaningful improvement in itch among patients with moderate to severe pruritus.

“The toolbox for looking after patients has really been augmented over time, far beyond UDCA,” Hirschfield told 

. “Having this choice of drugs, including seladelpar, where there's evidence for biochemical efficacy and there's evidence for pruritus efficacy, really raises the gain for our patients.”

In RESPONSE, pruritus NRS was collected daily for 6 months, then weekly for one week each month through 12 months. Upon rollover to ASSURE, NRS was collected daily for 6 months and then at scheduled clinic visits. Other measures included the 5-D Itch and PBC-40.

Patients with moderate to severe pruritus (NRS ≥4) at baseline were analyzed based on randomization to seladelpar 10 mg or placebo in RESPONSE and reported as continuous or crossover seladelpar 10 mg groups in ASSURE.

Overall, there were 49 seladelpar and 23 placebo patients with pruritus at baseline in RESPONSE. Among them, 33 seladelpar and 17 placebo patients rolled over to ASSURE, and 27 and 16 patients reached 30 months.

Results showed daily NRS was strongly correlated with weekly NRS (r, 0.93; 95% CI, 0.90 to 0.95). Of note, reduction in pruritus with seladelpar in RESPONSE was maintained in ASSURE up to 30 months, with clinically meaningful NRS improvement observed in ≥50% of patients upon seladelpar initiation for crossover patients in ASSURE from 15 months through 30 months.

Mean 5-D Itch total and PBC-40 Itch domain scores were reduced from baseline in continuous seladelpar (−4.6; SE, 0.7; −3.3; SE, 0.7) and crossover seladelpar (−5.8; SE, 1.1; −4.3; SE, 1.0) patients.

“What this presentation does is demonstrate the durability and impact of the improvement of pruritus from seladelpar to be clear and overt and for patients and providers to have a real sense of surety that seladelpar is going to help the patients who are itchy,” Hirschfield said, adding that the data also validates some of the different tools used to measure itch. “We have the tools to assess itch, and now we have the tools to treat it.”

Hirschfield G, Kremer A, Levy C, et al. Sustained and Clinically Meaningful Improvements in Moderate to Severe Pruritus Patients With Primary Biliary Cholangitis Treated With Seladelpar: Results From the ASSURE Study up to 30 Months. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

Brooks A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. 

. August 14, 2024. Accessed November 8, 2025. 

https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis

Hirschfield describes the burden of pruritus in PBC and reviews late-breaking ASSURE data on seladelpar’s long-term impact on itch presented at AASLD The Liver Meeting.

In this video segment, Reau, Trivedi, and Hirschfield discuss pipeline developments and other advances in primary biliary cholangitis they are most looking forward to.

The Future of PBC Management, Pipeline Developments

In recognition of the US Food and Drug Administration accelerated approval of Gilead's seladelpar (Livdelzi) and other recent evolutions in 

 Special Report spotlights a conversation between a trio of subject matter experts on the latest advancements in PBC and their implications for disease management.

A chronic and progressive autoimmune liver disease affecting intrahepatic bile ducts, common symptoms of PBC include ​​jaundice, pruritus, and fatigue. Ursodeoxycholic acid (UDCA) has long been the mainstay of treatment for PBC and continues to be the only first-line therapy. However, many patients do not respond to or are unable to tolerate UDCA, underscoring the need for more treatment options to prevent progression to cirrhosis and eventual liver failure as well as to improve symptoms most negatively impacting patients. In the past 3 months alone, the PBC treatment landscape has seen the addition of 2 new therapeutic options with the accelerated approvals of seladelpar and elafibranor, both of which are proliferator-activated receptor agonists shown to reduce alkaline phosphatase.

In the final segment of our 6-part HCPLive Special Report on the evolving landscape of PBC management, moderator Nancy Reau, MD, asks Palak Trivedi, MD, PhD, and Gideon Hirschfield, PhD, MB BChir, about pipeline developments they are most looking forward to. Hirschfield answers first, describing his excitement at the prospect of having new on-label options for his patients that he feels he can use safely and effectively. Specifically, he mentions the potential he sees in ileal bile acid transporter (IBAT) inhibitors and their impact on pruritus. Trivedi points to the development of clinical trials assessing what he deems to be more complex facets of PBC and symptoms that are more difficult to manage, including fatigue and cognitive impairment.

Reau concludes the discussion by saying she hopes it helps clinicians understand how their cholestatic toolbox is “rapidly filling” and ways in which they can leverage these new tools to help their patients achieve “remarkable results,” a sentiment Hirschfield and Trivedi both echoed.

Check out the other segments in this series:

Shifting Treatment Goals, Timelines in PBC

Assessing PBC Treatment Options, Sequencing

Considerations for Treatment Sequencing in PBC

Impact of Next-Generation PPAR Agonists on PBC Management

: associate director of solid organ transplantation and section chief of hepatology at Rush University Medical Center

 associate professor and honorary consultant hepatologist and clinical research director for industry engagement at the University of Birmingham

 director of the Autoimmune Liver Disease Program at University Health Network’s Francis Family Liver Clinic and Toronto Centre for Liver Disease and Lily and Terry Horner Chair in Autoimmune Liver Disease Research at the University of Toronto

Relevant disclosures for Reau include Eiger, Gilead, AbbVie, Salix, and Intercept. Relevant disclosures for Trivedi include Bristol Myers Squibb, Gilead, Intercept, CymbaBay, and others. Relevant disclosures for Hirschfield include CymaBay, Escient, Gilead, GSK, HighTide, Intercept, Ipsen, Mirum, and Pliant.

In this video segment, Reau, Trivedi, and Hirschfield discuss how the emergence of second-generation PPAR agonists like seladelpar and elafibranor impact PBC management.

In recognition of the US Food and Drug Administration accelerated approval of seladelpar (Livdelzi) and other recent evolutions in 

 Special Report on the evolving landscape of PBC management, moderator Nancy Reau, MD, asks Palak Trivedi, MD, PhD, and Gideon Hirschfield, PhD, MB BChir, about how the emergence of second-generation PPAR agonists impacts the management of patients with PBC, especially those experiencing pruritus. Trivedi describes his own practice in the United Kingdom and says that although he does not anticipate it will have an immediate major impact on patients he currently treats with obeticholic acid because he believes they will still benefit from that treatment, he also acknowledges that his perspective may change with time.

Hirschfield describes excitement for patients who now have more than one drug label to read. He also mentions the conservative nature of the US Food and Drug Administration and the significance of their recognition of pruritus improvement with seladelpar. Although he believes the future will include combination therapies and their exploration in clinical trials, for now, Hirschfield says he believes providers are going to look at labels and try to make decisions that will benefit patients most.

Gideon Hirschfield, PhD, MB BChir

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