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

Elafibranor normalized alkaline phosphatase (ALP) in 85.3% of participants with 

 and mildly elevated ALP despite ursodeoxycholic acid (UDCA), compared with 23.3% receiving placebo, according to late-breaking  data from the 

“This entire population had a very good rate of response,” presenting author Kris Kowdley, Director at Liver Institute Northwest, told 

. Findings come the phase 3 ESPIRE clinical trial. 

Elafibranor Normalizes ALP in PBC:  ELSPIRE Trial Results

ELSPIRE: Elafibranor Normalizes ALP in PBC Below the 1.67 Threshold

Global PBC Study Group data show 10-year survival of 93.2% among participants with normal ALP, compared with 86.1% among those with ALP between 1 and 1.67 times the upper limit of normal (ULN).

 Yet participants in that range have generally been excluded from registrational trials. 

 (Iqirvo), a peroxisome proliferator-activated receptor (PPAR)-α/δ agonist, was approved as second-line therapy based on the phase 3 ELATIVE trial, which enrolled participants with ALP of 1.67 times ULN or higher. In ELATIVE, 51% of participants receiving elafibranor achieved the composite biochemical response vs 4% receiving placebo, but only 15% normalized ALP.

Kowdley and colleagues randomized 92 participants with ALP between 1 and 1.67 times ULN to either elafibranor 80 mg or placebo.

 Response was consistent whether baseline ALP was 1.33 times ULN or lower (80.4% vs 26.1%) or higher (87.5% vs 14.3%), and 64.3% of participants receiving elafibranor achieved complete biochemical response vs 16.7% receiving placebo.

Adverse events were mostly mild or moderate, with no new safety signals.

 Kowdley notes slightly more fractures and weight gain with elafibranor, consistent with ELATIVE, and says the findings reinforce the need to monitor bone health in this population.

Watch the full interview to hear Kowdley explain why the treatment goal in PBC is shifting, how ELSPIRE compares with ELATIVE, and what the safety findings mean for counseling participants. 

Murillo Perez CF, Harms MH, Lindor KD, et al; Global PBC Study Group. Goals of treatment for improved survival in primary biliary cholangitis: treatment target should be bilirubin within the normal range and normalization of alkaline phosphatase. 

. 2020;115(7):1066-1074. doi:10.14309/ajg.0000000000000557

Kowdley K, Lawitz E, Bowlus C, et al. Elafibranor to normalize alkaline phosphatase in patients with primary biliary cholangitis and incomplete response to ursodeoxycholic acid: results from the phase III randomized controlled ELSPIRE trial. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO.

Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and safety of elafibranor in primary biliary cholangitis. 

. 2024;390(9):795-805. doi:10.1056/NEJMoa2306185

Videos

Late-breaking ELSPIRE data show elafibranor normalized ALP in 85% of patients with PBC and ALP below 1.67 times ULN despite UDCA, vs 23% with placebo.

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

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

Articles