Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD

Managing GI, Liver Safety Signals With Volixibat in PSC, With Kris Kowdley, MD

With a potential New Drug Application (NDA) submission to the 

 on the horizon for Mirum Pharmaceuticals’ volixibat, 

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 

 for Part 1 where Kowdley explains VISTA’s findings!

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, 

, 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.

FDA Approves Linerixibat (Lynavoy) As First Treatment for 

Linerixibat, an IBAT inhibitor, became the

 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.

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.

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

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

Bowlus CL, Lim JK, Lindor KD. AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review. 

https://doi.org/10.1016/j.cgh.2019.07.011

Videos

GI and liver safety signals for clinicians to know from the VISTAS evaluating volixibat in PSC-associated pruritus.

Volixibat's Safety Profile Explained for PSC, With Kris Kowdley

Volixibat Shows Rapid Itch Relief in PSC, a Disease Long Undertreated for Pruritus

Cholestatic pruritus in primary sclerosing cholangitis (PSC) has historically received less attention than other complications of the disease, despite growing evidence that itch can substantially impair quality of life. New phase 2b data from the VISTAS trial suggest volixibat, an investigational ileal bile acid transporter (IBAT) inhibitor, may offer a meaningful and fast-acting treatment option for patients with few alternatives beyond off-label therapies.

, study investigator Kris Kowdley, MD, director at Liver Institute Northwest and senior scientific advisor and medical director at Velocity Clinical Research, emphasized that pruritus in PSC may be substantially more burdensome than historically appreciated.

Generally, PSC has not been viewed as a pruritus-dominant disease in the way that primary biliary cholangitis (PBC) has. Thus, emerging evidence suggests itch may be more common and clinically significant than previously appreciated. A patient-reported survey of > 400 individuals with PSC found that > 90% reported itch at some point in their lives. A separate European study using objective pruritus measures found approximately 25% of patients had moderate-to-severe itch.

Pruritus in cholestatic liver disease has been associated with impaired sleep, fatigue, reduced functional status, and social withdrawal. In PSC, symptom burden may worsen acutely during episodes of cholangitis or bile duct strictures, adding further complexity to disease management. Despite this, no therapies are currently approved in the United States specifically for PSC-associated pruritus.

VISTAS Met Primary Endpoint for PSC-Associated Pruritus

According to topline company-reported results, volixibat 20 mg twice daily produced a least squares mean change in Adult ItchRO score of −2.72 versus −1.08 with placebo, yielding a placebo-adjusted difference of −1.64 (

“The fact that this was a large study, carefully designed and adequately controlled with placebo, showing a meaningful reduction in itch score using the ItchRO assessment and associated with reduction in bile acids, all of these suggest that this may be a valuable therapy for patients with PSC to relieve symptoms,” explained Kowdley.

Safety Findings Consistent With IBAT Inhibition

Safety findings were described as generally consistent with IBAT inhibition. Across study cohorts, treatment-emergent adverse events occurred in 93.5% of patients receiving volixibat and 84.0% receiving placebo. Diarrhea-related discontinuation occurred in 3.9% versus 1.2%, respectively, and the company also reported elevations in alanine aminotransferase and bilirubin.

Tolerability may be particularly relevant in PSC, where many patients also have inflammatory bowel disease, and gastrointestinal adverse events may carry additional clinical implications.

Rapid Symptom Relief May Carry Particular Importance in PSC

The company reported improvements in pruritus within 2 weeks of treatment initiation, although detailed time-course data have not yet been presented publicly.

Rapid symptom improvement is especially meaningful in PSC, where disease-modifying therapies remain limited and chronic itch can substantially impair quality of life.

“For patients that have been suffering from cholestatic pruritus for months or years, it’s very gratifying to see this prompt symptom relief,” Kowdley said.

Full results from VISTAS are expected at the European Association for the Study of the Liver International Liver Congress on May 30, 2026.

 Mirum said a pre–new drug application meeting with the FDA is planned for summer 2026, with a potential submission in the second half of the year.

Mirum Pharmaceuticals. Mirum Pharmaceuticals announces primary endpoint met in VISTAS study of volixibat in patients with primary sclerosing cholangitis. News release. May 4, 2026. Accessed May 13, 2026. 

Hov JR, Boberg KM, Karlsen TH. Health-related quality of life in primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol. 2012;36(1):40-47. doi:10.1016/j.clinre.2011.08.007

Benito de Valle M, Rahman M, Lindkvist B, et al. Factors associated with pruritus in patients with primary sclerosing cholangitis. Liver Int. 2021;41(12):2896-2904. doi:10.1111/liv.15044

Bowlus CL, Lim JK, Lindor KD. AGA clinical practice update on surveillance for hepatobiliary cancers in primary sclerosing cholangitis: expert review. Gastroenterology. 2019;157(3):769-775. doi:10.1053/j.gastro.2019.07.055

Gunaydin M, Bozkurt Y, Demirci H, et al. Ileal bile acid transporter inhibitors in cholestatic pruritus and cholestatic liver disease: current evidence and future directions. Clin Res Hepatol Gastroenterol. 2024;48(1):102271. doi:10.1016/j.clinre.2023.102271


Kowdley explains phase 2b VISTAS data suggesting volixibat rapidly reduced PSC-associated pruritus in adults with limited treatment options.

Volixibat Shows Rapid Itch Relief in PSC in Phase 2b VISTAS, With Kris Kowdley, MD

Liver Lineup: Innovations in Cholestatic Disease Management, With Kris Kowdley, MD

Liver Lineup: Updates & Unfiltered Insights

, Nancy Reau, MD, sits down with Kris Kowdley, MD, to discuss evolving approaches in cholestatic liver disease, with a particular focus on 

The conversation begins with how treatment goals have shifted from partial biochemical response to striving for full normalization of alkaline phosphatase and bilirubin, changes supported by recent global data showing improved long-term outcomes when patients achieve complete biochemical remission.

Kowdley highlights how these evolving targets are shaping clinical practice and guideline development, including the growing push to evaluate UDCA response at 6 months rather than 1 year, potentially expediting decisions about second-line therapy. The discussion also underscores the importance of incorporating staging tools such as transient elastography, which has shown promise as a biomarker and surrogate endpoint for predicting clinical outcomes in PBC.

The duo highlights the recent voluntary withdrawal of obeticholic acid from the US market as another major inflection point for clinicians, raising questions about how to manage patients who had been stable on the therapy. Kowdley reviews available alternatives, including fibrates and recently approved peroxisome proliferator-activated receptor (PPAR) agonists elafibranor and seladelpar, and addresses practical considerations when transitioning patients to new regimens. Importantly, he notes the potential of combination or even triple therapy strategies to help more patients achieve complete biochemical response.

Beyond laboratory targets, the conversation emphasizes patient-centered outcomes such as fatigue and pruritus, symptoms that often have a profound impact on quality of life but have historically lacked effective treatment. The emerging role of ileal bile acid transporter (IBAT) inhibitors represents an encouraging step forward, offering rapid relief of pruritus in PBC and other cholestatic diseases, with clinical trials underway to expand their use.

The pair also discuss diagnosis, particularly in challenging AMA-negative cases. Kowdley shares insights on when to use biopsy, how transient elastography fits into the workup, and the emerging role of genetic testing for patients with atypical presentations or suspected hereditary cholestatic syndromes.

The episode closes with reminders about comprehensive management, including monitoring bone health and tailoring therapy to the individual patient’s disease stage, biochemical profile, and quality-of-life concerns.

 has relevant disclosures with AbbVie, Gilead, Salix, Arbutus, and VIR. 

has relevant disclosures with CymaBay, Genfit, Gilead, Intercept, Ipsen, Madrigal, Mirum, Pfizer, NovoNordisk, 89Bio, AbbVie, and others.

Brooks A. Intercept Voluntarily Withdraws Obeticholic Acid (Ocaliva) for PBC From US Market. HCPLive. September 11, 2025. Accessed September 18, 2025. 

https://www.hcplive.com/view/intercept-voluntarily-withdrawals-obeticholic-acid-ocaliva-for-pbc-from-us-market

Brooks, A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed September 18, 2025. 

https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc

Brooks, A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. August 14, 2024. Accessed September 18, 2025. 

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

Podcasts

Kowdley joins Liver Lineup to discuss evolving approaches in cholestatic liver disease and recent progress in PBC.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: 

We’re comingto the end of this discussion, but I want to talk about unmet needs in PBC [primary biliary cholangitis]. What are some unmet needs? I’m going to have everyone comment, but I’m going to start with you, David.

This was a lead-in to say that transplantation for patients with PBC is an unmet need. They’re not well served by our current allocation system, and I’ve implored some of our UNOS [United Network for Organ Sharing] colleagues to consider itching in the malignant, life-altering aspect of pruritis to be something that we incentivize for transplant. Transplant is supposed to make your life longer and better, and many of these patients with recalcitrant pruritus from PBC deserve quality therapy. That’s where I see the biggest unmet need. I don’t think we do great in our transplant world. That’s a bigger question to answer. I’m hopeful that these new therapies and some of the emerging therapies may be able to treat some of our patients who aren’t candidates for obeticholic acid or second-line therapy as we try to prevent them from progressing to such a stage.

That’s a good point. There’s concern about patients who have decompensated liver disease. Obviously, they can’t receive obeticholic acid. With fibrates, there are some concerns and warnings about liver or kidney toxicity. Clearly, that’s the population where there’s a big need. I’ve had 3 patients in my career who I was able to get either prior to MELD [model for end-stage liver disease] and requiring exception points or during MELD with exception points for refractory life-threatening pruritis, 2 of whom were considering suicide. Those patients would not be eligible for exception points in this era. It’s uncommon, but it’s a huge unmet need. Ed, what do you think are the unmet needs in this disease?

Something we looked at in our clinic is ethnic disparities in PBC. We found that our Latino population who had PBC came at a much later stage of disease. Most of them have cirrhosis. David, you mentioned patients with PBC languishing in clinics. Increasing awareness of PBC and screening using the antimitochondrial antibody in certain ethnic groups or communities would be of value.

Like many things in liver disease, Kris, they’re all out of unmet needs. First, there’s an unmet need regarding the education of practitioners in how to diagnose this early. There’s an unmet need in terms of having more effective primary therapy in the first place for patients with PBC. There’s an unmet need for the treatment of the profound fatigue that some patients have with this disease. Even if they don’t have cirrhosis, it’s a major quality-of-life issue for them. There’s an unmet medical need for the pruritis. The pruritis doesn’t always correlate with the advance, with the stage of the disease. That’s also a misunderstanding. Patients can have moderate pruritis, which does affect their quality of life, but it’s not enough to need a transplant, and their liver disease isn’t so advanced. We know we could do better with therapy. So, there are a lot of unmet needs in PBC.

I agree, and your point about pruritis and symptoms not being correlated with disease severity is important to recognize. Some patients, as they start having more symptoms, are petrified, and their fatigue is getting worse. They think they need to get on a liver transplant list.

For patients with PBC, 1 of the extrahepatic manifestations is they can have very profound and aggressive osteoporosis. The guidance documents are clear that patients should have periodic bone densitometry when they have PBC. This, too, doesn’t correlate necessarily with the stage of their liver disease, and you can’t wait until patients are having spontaneous pathological fractures to identify this. The audience should also know in a patient with PBC that they are or should be recommending periodic bone densitometry to look for osteoporosis or even osteopenia.

At a minimum, your patient with PBC who comes into the office every 6 months or 1 year should have a vitamin D test with their standard labs. That’s a guidance, but it’s often not done. We added it to our standard order set for patients with cholestatic liver disease, so other providers would do it. That’s the best and easiest screening tool to identify higher-risk patients.

That’s an excellent point. Fractal vitamin deficiency isn’t necessarily seen only in patients with jaundice, so we do that routinely when we first see the patient. Sonal, you get the last word on unmet needs for education and for patients or clinicians.

I’ll piggyback on what Steve said. As physicians, we focus on normalization of the alkalis or goals of preventing and disease prevention, which are understandable and obviously important. But from a patient perspective, what affects their day to day is their quality of life. If we can improve that, in combination with these new therapies, that will prevent disease progression. That will be huge.

That’s great. That hour and a half went by fast. I appreciate the chance to share thoughts and clinical experience. Thanks to all of you for this rich and informative discussion. Before we conclude, I’d like to get some final thoughts. Everybody gets 30 seconds. Let’s start with you, Steve.

The practitioners in the audience should understand that although this is an uncommon disease, it’s not so uncommon that you won’t see it. You will, and you need to know how to diagnose it and be comfortable about the diagnosis. Be aggressive in your therapy, even in patients who are asymptomatic. Follow their fibrosis scores, and don’t forget these extrahepatic manifestations, which are more prominent than any of the others in liver disease: osteoporosis, hyperlipidemia, pruritis. Become comfortable with it, understand it, and follow the patients aggressively because you’ll help them.

Steve summed it up well. Disease awareness is a big deal in PBC. Although this is a rare disease, it’s not something you’ll see once in your lifetime or never see. It’s important for practitioners to be aware that this disease exists and recognize that it’s an exciting time for patients with PBC. We have good therapies already in existence but even more exciting therapies in development.

I agree with what everyone said. But let’s not let these patients languish in our clinics. Let’s follow that alkaline phosphatase, and let’s get that alkaline phosphatase to normal.

Having the last name Victor puts me at the end of this. Our panelists have hit on all the issues. To the providers and practitioners watching this, go through your clinic and make sure you’ve optimized the patients you have to make sure they don’t see me for transplant.

That’s very well summed up. Thank you again. To our viewing audience, I hope this 

 discussion was useful and informative. If you enjoyed the content, please subscribe to our e-newsletters to receive 

Experts in hepatology review the unmet needs in primary biliary cholangitis, commenting on liver transplant, ethnic disparities, management of pruritis, as well as other symptoms.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD

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