Sydney Jennings

Volixibat, an investigational ileal bile acid transporter (IBAT) inhibitor, improved sleep compared with placebo in adults with 

 and cholestatic pruritus, according to new data from the phase 2b VISTAS trial.¹

Christopher Bowlus, MD, of the University of California Davis, presented the analysis at 

, hosted by the American Association for the Study of Liver Diseases (AASLD), in Denver, Colorado.

Results showed participants with a pruritus response also reported greater improvements in fatigue and sleep, regardless of treatment assignment.¹

While no therapies are currently approved for PSC, VISTAS met its primary endpoint, with a least squares (LS) mean reduction in Adult ItchRO score of 2.72 points with volixibat compared with 1.08 points with placebo (difference, −1.64; 

 < .001).² The new analysis examined whether itch relief with volixibat extends to other patient-reported symptoms.

How Did Volixibat Affect Sleep and Fatigue in VISTAS?

VISTAS is a 28-week, randomized, multicenter, double-blind, placebo-controlled phase 2b study in adults with PSC and cholestatic pruritus. The primary cohort included 111 participants with moderate to severe pruritus, randomized to volixibat 20 mg twice daily (n = 54) or placebo twice daily (n = 57). Investigators assessed fatigue and sleep through Week 28 using validated Patient-Reported Outcomes Measurement Information System (PROMIS) health-related quality of life measures, analyzed with a mixed model for repeated measures.¹

Results showed sleep improved significantly more with volixibat than with placebo, with an LS mean change of −6.47 (SE, 1.3) compared with −0.78 (SE, 1.2) (

 = .0011).¹ Negative changes in PROMIS scores indicate improvement.

In VISTAS data presented at the American College of Gastroenterology (ACG) 2026 meeting, the difference in PROMIS fatigue scores between volixibat and placebo (−2.33) did not reach statistical significance (

 = .13).² The new analysis instead examined fatigue through the lens of itch response.

Do Itch Responders See Greater Gains in Fatigue and Sleep?

Investigators compared outcomes between pruritus responders, defined as a reduction of at least 2 points in Adult ItchRO score, and nonresponders, irrespective of treatment assignment. In earlier VISTAS data, 56% of volixibat-treated participants met this threshold, compared with 26% of placebo-treated participants (P = .002).² Responders reported greater improvement than nonresponders in fatigue (mean change, −6.25 [SD, 7.8] vs −0.34 [SD, 6.3]; 

 = .0004) and sleep (−7.48 [SD, 9.5] vs 0.18 [SD, 6.6]; 

Among responders, the magnitude of improvement was larger with volixibat than with placebo. The difference reached statistical significance for sleep (−10.20 vs −2.93; P = .0165) but not for fatigue (−7.03 vs −4.95; P = .41). The authors concluded improvements in pruritus were associated with improvements in fatigue and sleep, with greater gains following volixibat treatment.¹

Across both VISTAS cohorts, diarrhea occurred in 40.3% of volixibat-treated participants vs 8.6% of placebo-treated participants, and adverse events led to discontinuation in 9.1% versus 2.5%, respectively. Elevations in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin were more frequent with volixibat.²

In August 2026, the FDA granted volixibat Breakthrough Therapy and Orphan Drug designations for cholestatic pruritus due to PSC.³ After a pre-New Drug Application (NDA) meeting in which the FDA recommended an additional phase 3 study, Mirum Pharmaceuticals said it plans further discussions with the agency and a potential NDA submission in the first half of 2027.³ Volixibat is also under evaluation in primary biliary cholangitis in the phase 2b VANTAGE trial.²

Bowlus C, Levy C, Shiffman M, et al. The impact of volixibat, an IBAT inhibitor, on fatigue and sleep for patients with primary sclerosing cholangitis: data from VISTAS. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO.

Brooks A. Volixibat reduces PSC-related pruritus in phase 2b VISTAS trial. HCPLive. Published October 12, 2026. Accessed November 5, 2026. 

https://www.hcplive.com/view/volixibat-reduces-psc-related-pruritus-in-phase-2b-vistas-trial

Hillenbrand A. FDA grants volixibat Breakthrough Therapy, Orphan designations for PSC. HCPLive. Published August 10, 2026. Accessed November 5, 2026. 

https://www.hcplive.com/view/fda-grants-volixibat-breakthrough-therapy-orphan-designations-for-psc

Articles

In the phase 2b VISTAS trial, volixibat improved sleep vs placebo in PSC with cholestatic pruritus, and itch responders saw greater fatigue and sleep gains.

Itch Relief With Volixibat Tied to Better Sleep, Fatigue in PSC

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

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

 whose ALP remained above the upper limit of normal (ULN) but below 1.67× ULN despite ursodeoxycholic acid (UDCA), compared with 23.3% of patients receiving placebo, according to results from the 

The findings will also be presented as a late-breaking abstract at 

, hosted by the American Association for the Study of Liver Diseases (AASLD), November 5–9 in Denver, Colorado.²

“While traditional measures of treatment response have focused on reducing ALP below 1.67 times the upper limit of normal, growing evidence suggests that achieving normal ALP levels may be associated with better long-term outcomes,” Kris V. Kowdley, MD, of Liver Institute Northwest, Velocity Clinical Research, and Washington State University, said in a statement. “The results of this study demonstrate that ALP normalization is an achievable goal for a substantial proportion of patients receiving [elafibranor], even among those with moderately elevated ALP levels.”²

PBC is a chronic, immune-mediated cholestatic liver disease that destroys intrahepatic bile ducts and can progress to fibrosis, cirrhosis, and liver failure.¹ In a large analysis of US health systems, PBC prevalence was estimated at 29.3 per 100,000 persons, with the highest rates among women (42.8 per 100,000).³ UDCA remains first-line therapy, but up to 40% of patients have an inadequate response, according to the ELSPIRE investigators.¹

Most phase 3 trials of second-line PBC therapies have enrolled patients with ALP of at least 1.67× ULN. That threshold comes from the POISE response criteria, so patients with milder elevations have gone largely unstudied. Elevated ALP above the ULN has nonetheless been associated with shorter transplant-free survival. The investigators noted that updated clinical guidelines increasingly emphasize ALP normalization as a treatment target.¹

The oral peroxisome proliferator-activated receptor (PPAR)-α/δ agonist received US Food and Drug Administration (FDA) accelerated approval in June 2024 for adults with PBC with an inadequate response or intolerance to UDCA.⁴ The approval was based on the phase 3 ELATIVE trial, in which 51% of patients receiving 

 achieved a biochemical response compared with 4% receiving placebo. ALP normalized in 15% of patients on elafibranor and none on placebo.⁴,⁵ ELSPIRE results also arrive alongside phase 3 IDEAL data for seladelpar, a PPAR-δ agonist, in a similar ALP range.⁶

How Did Elafibranor Perform in the ELSPIRE Trial?

ELSPIRE (NCT06383403) randomly assigned 92 adults in a 2:1 ratio to elafibranor 80 mg once daily (n = 62) or placebo (n = 30) for 52 weeks. Enrollment ran from July 2024 through May 2025 at sites in 10 countries. Eligible patients had ALP >1 to <1.67× ULN after at least 12 months of UDCA, or were intolerant to UDCA. Randomization was stratified by ALP of >1 to ≤1.33× ULN or >1.33 to <1.67× ULN.¹

Median age was 61 years, 92.4% of patients were female, and 96.7% were receiving concurrent UDCA, for a median of approximately 5 years. The primary endpoint was ALP normalization, defined as ALP ≤120 U/L, at week 52 without rescue therapy, a liver-related event, or death.¹

The trial met its primary endpoint (treatment difference, 62.0%; 95% CI, 44.3%–79.7%; 

 < .0001). Results were consistent across strata. In the lower stratum, 80.4% of patients on elafibranor vs 26.1% on placebo achieved normalization. In the higher stratum, the rates were 87.5% vs 14.3%.¹

ALP fell rapidly, with a least squares (LS) mean reduction of 31.9% by week 4. At week 52, the LS mean change from baseline was −36.5% with elafibranor vs −4.2% with placebo.¹

Elafibranor also outperformed placebo on composite secondary endpoints¹:

ALP normalization with a reduction of at least 15% from baseline: 84.5% vs 20.0%

Complete biochemical response, defined as normal ALP, total bilirubin, transaminases, albumin, and international normalized ratio (INR): 64.3% vs 16.7%

The LS mean difference in total bilirubin change favored elafibranor by 15.0% (95% CI, −28.2% to −1.8%). Formal significance testing applied only to the primary endpoint, so 

 values for secondary and exploratory outcomes were descriptive.¹

What Safety Findings Were Reported With Elafibranor?

Treatment-emergent adverse events (TEAEs) occurred in 79.0% of patients receiving elafibranor and 70.0% of those receiving placebo, and most were mild or moderate. Serious TEAEs occurred in 4.8% and 13.3% of patients, respectively, and none were considered treatment related. TEAEs led to discontinuation in 4.8% and 3.3% of patients, respectively. The 1 death, from traumatic intracranial hemorrhage, occurred in the placebo arm.¹

Weight gain of more than 5% from baseline was reported in 22.6% of patients receiving elafibranor vs 6.7% receiving placebo. Mean weight change at week 52 was 1.4 kg vs 0.1 kg. Bone fractures occurred in 8.1% vs 3.3% of patients. All fractures were traumatic, and none were considered treatment related. Investigators observed no cases of drug-induced liver injury, transaminase elevations of at least 3× ULN, or creatine phosphokinase elevations above 3× ULN.¹

“These results underscore the potential of [elafibranor] to raise the standard of biochemical response in PBC,” Naga P. Chalasani, MD, incoming co-editor-in-chief of 

What Questions Remain for Elafibranor in Lower-ALP PBC?

The investigators acknowledged several limitations¹:

 too few patients had moderate-to-severe pruritus or fatigue at baseline for formal analysis.

 most participants did not have cirrhosis or advanced fibrosis.

 83.7% of patients were White and 16.3% were Asian, with no patients of other races.

 UK-PBC and GLOBE scores improved with elafibranor, but the authors cautioned that these projection models were developed for use after first-line UDCA.

The trial was funded by Ipsen. Under its accelerated approval, elafibranor has not demonstrated improved survival or prevention of liver decompensation.⁴ The ongoing placebo-controlled phase 3 ELFIDENCE trial (NCT06016842) is evaluating its effect on long-term clinical outcomes.¹

Kowdley KV, Lawitz E, Bowlus CL, et al. Treatment with 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. 

. Published online ahead of print. doi:10.1097/HEP.0000000000001906

American Association for the Study of Liver Diseases. Phase III ELSPIRE trial results published in HEPATOLOGY demonstrates elafibranor achieves ALP normalization in more than 85% of patients with primary biliary cholangitis. Published November 5, 2026. Accessed November 5, 2026. 

https://www.aasld.org/phase-iii-elspire-trial-results-published-hepatology-demonstrates-elafibranor-achieves-alp

Lu M, Li J, Haller IV, et al. Factors associated with prevalence and treatment of primary biliary cholangitis in United States health systems. 

Ipsen. Ipsen’s Iqirvo receives U.S. FDA accelerated approval as a first-in-class PPAR treatment for primary biliary cholangitis. Published June 10, 2024. Accessed November 5, 2026. 

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

Brooks A. IDEAL: seladelpar achieves ALP normalization in second-line PBC. HCPLive. Published November 5, 2026. Accessed November 5, 2026. 

https://www.hcplive.com/view/ideal-seladelpar-achieves-alp-normalization-in-second-line-pbc

In the phase 3 ELSPIRE trial, 85.3% of patients with PBC and ALP below 1.67× ULN reached ALP normalization on elafibranor at 52 weeks vs 23.3% on placebo.