A Review of Selected Presentations From the American Association for the Study of Liver Diseases 2025 Liver Meeting
November 7-11, 2025 • Washington, DC
Seladelpar Is Associated With a Sustained Reduction in Cholestatic Markers and a Consistent Safety Profile in Patients With PBC Treated Up to 48 Months in the Ongoing, Open-Label ASSURE Study
Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease that typically affects women older than 40 years.1 PBC can cause liver injury and fibrosis and can progress to cirrhosis. The standard first-line treatment of PBC is ursodeoxycholic acid (UDCA). However, intolerance and insufficient responses can limit the use of UDCA.
Seladelpar is a selective peroxisome proliferator-activated receptor (PPARδ) that has demonstrated improvements in cholestasis, anti-inflammatory effects, and reductions in pruritus in patients with PBC.1,2 The US Food and Drug Administration (FDA) has approved seladelpar for the treatment of PBC in combination with UDCA in adults with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA. The approval of seladelpar was based on results of the 12-month placebo-controlled phase 3 RESPONSE study, which demonstrated significant improvements in cholestatic biomarkers and pruritus compared with placebo in this population.2 The long-term efficacy and safety of seladelpar are being evaluated in the open-label phase 3 ASSURE trial, which includes patients from the RESPONSE trial and other seladelpar trials.3
Pratt and colleagues presented results of additional follow-up, through 36 months for efficacy and 48 months for safety, from the ASSURE trial.4 Of 337 patients in the trial, 179 patients are from legacy studies, including 104 patients from the seladelpar arm and 54 patients who crossed over to seladelpar from the placebo arm in the RESPONSE trial. The mean age of enrolled patients was 58.1 years; 94% were female and 16% had cirrhosis.
Composite biochemical response (defined as alkaline phosphatase [ALP] <1.67 × upper limit of normal [ULN], ALP decrease ≥15% from baseline, and total bilirubin normalization) was attained by the majority of patients at each time point tested (Figure 1). The composite biochemical response rate was 70.2% at 24 months (181 of 258) and 67.2% at 36 months (82 of 122). Approximately one-third of patients attained ALP normalization during treatment, including 29.6% at 3 months and 33.6% at 36 months. Total bilirubin levels remained stable through treatment, with approximately 90% of patients attaining total bilirubin normalization at each time point (rates ranging between 91.3% at 6 months and 87.3% at 30 months). Approximately one-third of patients (32.8% at 36 months) achieved a deep response, defined as normalization of both ALP and total bilirubin. Among patients with elevated alanine aminotransferase (ALT) at baseline, 62.3% (33 of 53) attained ALT normalization at 36 months. GLOBE scores, which account for age at UCDA initiation, total bilirubin, ALP, albumin, and platelet count, improved with seladelpar, which investigators noted may indicate improved prognosis.
Among 107 patients with moderate to severe pruritus at baseline, seladelpar was associated with rapid and sustained improvements in pruritus, with the mean change in the Pruritus numeric rating scale (NRS) crossing the threshold of clinically meaningful changes at 6 months and remaining for the duration.
After up to 4 years of treatment, no serious adverse events (AEs) or fatal events related to seladelpar were noted, and rates of AEs remained stable over time. Of patients who stopped treatment, 13 (3.9%) discontinued because of a liver-related AE, although no events were considered related to seladelpar, and 1 discontinued because of myalgia. Seladelpar continues to show durable improvements in biochemical markers of cholestasis after up to 3 years of use and a favorable safety profile after up to 4 years.
References
1. Tanaka A, Ma X, Takahashi A, Vierling JM. Primary biliary cholangitis. Lancet. 2024;404(10457):1053-1066.
2. Hirschfield GM, Bowlus CL, Mayo MJ, et al; RESPONSE Study Group. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med. 2024;390(9):783-794.
3. Levy C, Trivedi PJ, Kowdley KV, et al; ASSURE Investigators. Long-term efficacy and safety of selective PPARδ agonist seladelpar in primary biliary cholangitis: ASSURE interim study results [published online June 24, 2025]. Am J Gastroenterol. doi:10.14309/ajg.0000000000003603.
4. Pratt D, Lawitz EJ, Bowlus CL, et al. Seladelpar is associated with a sustained reduction in cholestatic markers and a consistent safety profile in patients with PBC treated up to 48 months in the ongoing, open-label ASSURE study. Abstract 0213. Presented at: AASLD 2025 Liver Meeting; November 7-11, 2025; Washington, DC.
Long-term Treatment With Elafibranor Leads to Biochemical and Symptomatic Improvements for at Least 3 Years in Patients With PBC
Elafibranor is an oral PPARα and PPARγ agonist that was FDA-approved for the treatment of PBC following the results of the multinational phase 3 double-blind placebo-controlled ELATIVE trial.1 In this trial, elafibranor administered at 80 mg once daily was associated with significantly greater improvements in biochemical indicators of cholestasis, fatigue, and pruritus at week 52 compared with placebo in patients with PBC who had an inadequate response to or unacceptable side effects with UDCA.2
Levy and colleagues presented long-term efficacy and safety data with elafibranor from the ELATIVE open-label extension (OLE) trial, in which patients completing the double-blind period could continue to receive elafibranor 80 mg for a treatment period of up to 5 years.2 The cohort included 93 patients receiving continuous elafibranor and 45 patients crossing over from the placebo arm in the double-blind period to elafibranor at the OLE entry. The mean age of patients at entry to the OLE was 58.2 years, and the median time since PBC diagnosis was 9.3 years. Mean ALP was 192.5 U/L in the continuous elafibranor group and 335.8 U/L in the crossover group. Mean ALT was 40.7 U/L and 53.1 U/L, respectively, and mean gamma-glutamyl transferase (GGT) was 159.7 U/L and 229.2 U/L, respectively.
Elafibranor was associated with sustained, rapid biochemical responses, which occurred in 56% of patients at week 52, 59% at week 104, 67% at week 156, and 72% at week 182. Rates of ALP normalization were 18% at week 52, 17% at week 104, 27% at week 156, and 19% at week 182. Elafibranor was also associated with reduction or stabilization of disease progression as assessed by total bilirubin, ALT, and GGT, and stabilization or reduction of multiple markers of liver fibrosis, including liver stiffness measurement (LSM), enhanced liver fibrosis, and N-terminal propeptide of type III collagen. Among patients with moderate to severe fatigue (n=45) and pruritus (n=41) at baseline, elafibranor was associated with clinically meaningful improvements in fatigue and pruritus, respectively, out to 156 weeks (Figure 2).
The safety analysis after up to 4.5 years of treatment showed a similar toxicity profile with elafibranor in the OLE as previously reported in the double-blind period. The most frequent treatment-emergent AEs were abnormal weight gain, reported in 16.7% of patients, urinary tract infection (13.0%), and pruritus (10.1%). The rate of severe treatment-emergent AEs was 7.2%; no treatment-related AEs of special interest, such as creatine phosphokinase elevation, myalgia, and rhabdomyolysis, were reported in the OLE.
References
1. Kowdley KV, Bowlus CL, Levy C, et al; ELATIVE Study Investigators’ Group. Efficacy and safety of elafibranor in primary biliary cholangitis. N Engl J Med. 2024;390(9):795-805.
2. Levy C, Akarca U, Alvares-da-Silva MR, et al. Long-term treatment with elafibranor leads to biochemical and symptomatic improvements for at least 3 years in patients with PBC. Abstract 5016. Presented at: AASLD 2025 Liver Meeting; November 7-11, 2025; Washington, DC.
Sustained and Clinically Meaningful Improvements in Moderate to Severe Pruritus Patients With PBC Treated With Seladelpar: Results From the ASSURE Study Up to 30 Months
Cholestatic pruritus is common in PBC, occurring in up to 80% of patients. This pruritus is often debilitating and negatively affects quality of life. Current treatment options for cholestatic pruritus, including bile acid sequestrants, antihistamines, and off-label rifampin, have limited efficacy or challenges with toxicity.1 In the RESPONSE and ASSURE trials, seladelpar demonstrated significant improvements in biochemical markers and pruritus in patients with PBC.2,3 Among patients with a baseline moderate to severe pruritus (NRS ≥4) in the RESPONSE trial, seladelpar 10 mg (n=49) was associated with significant improvements in itch over placebo (n=23), with differences that reached statistical significance at 6 months (P<.005) and were sustained at 12 months (P<.005). In the overall patient population in RESPONSE (n=193), seladelpar was associated with a significant benefit over placebo in itch reduction starting at 1 month (P<.05) that was maintained over 12 months.2 In the ASSURE trial, declines in pruritus initially observed in the RESPONSE trial were maintained after 6 additional months of treatment. Patients who entered the ASSURE OLE from legacy trials also showed similar declines in itching as assessed by NRS.3
Hirschfield and colleagues presented updated interim long-term results related to pruritus outcomes in the ASSURE trial among patients initially in the RESPONSE study.4 Baseline characteristics for the subset of patients with moderate to severe pruritus (NRS ≥4) were balanced between the seladelpar 10 mg arm (n=49) and the placebo arm (n=23), with mean pruritus NRS scores of 6.1 and 6.6, respectively, mean 5-D Itch total scores of 16.2 and 16.4, respectively, and mean PBC-40 itch domain scores of 8.7 and 9.6, respectively.
Assessments of NRS scores over time found clinically meaningful changes in pruritus NRS scores among patients receiving seladelpar. These improvements were sustained with a follow-up of up to 30 months in the ASSURE trial (Figure 3). In this cohort of patients (with a baseline pruritus NRS ≥4), more than half attained clinically meaningful improvements in pruritus (defined as an NRS improvement of ≥3 points), including 56% of patients in both the continuous seladelpar arm and the crossover arm at 30 months. Seladelpar was also associated with durable improvements in pruritus in patients with moderate to severe pruritus as assessed by the 5-D Itch total score and the PBC-40 itch score.
Investigators also assessed the comparability of single-visit pruritus NRS compared with weekly averaged NRS outcomes in the ASSURE trial. A regression analysis found that both methods of assessing pruritus were comparable, with an r value of 0.93 (95% CI, 0.90-0.95), and a plot of mean NRS over time with single-visit vs weekly average scores yielded similar outcomes. The results demonstrated sustained clinically relevant improvements in pruritus with seladelpar after up to 30 months of treatment in the ASSURE study. More than half of patients with moderate to severe itch attained meaningful improvements in pruritus NRS, 5-D itch, and PBC-40 itch domain scores.
References
1. Ebhohon E, Chung RT. Systematic review: efficacy of therapies for cholestatic pruritus. Therap Adv Gastroenterol. 2023;16:17562848231172829.
2. Hirschfield GM, Bowlus CL, Mayo MJ, et al; RESPONSE Study Group. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med. 2024;390(9):783-794.
3. Levy C, Trivedi PJ, Kowdley KV, et al; ASSURE Investigators. Long-term efficacy and safety of selective PPARδ agonist seladelpar in primary biliary cholangitis: ASSURE interim study results [published online June 24, 2025]. Am J Gastroenterol. doi:10.14309/ajg.0000000000003603.
4. Hirschfield GM, Kremer AE, Leby C, et al. Sustained and clinically meaningful improvements in moderate to severe pruritus patients with PBC treated with seladelpar: results from the ASSURE study up to 30 months. Abstract 5015. Presented at: AASLD 2025 Liver Meeting; November 7-11, 2025; Washington, DC.
Impact of Linerixibat on Pharmacodynamic Biomarkers and Mediators of Cholestatic Pruritus in PBC in the Phase 3 GLISTEN Study
Bile acids are considered to be a key driver of cholestatic pruritus. Bile acid synthesis occurs when cholesterol is converted to bile acid intermediates which are then converted into cholic acid and chenodeoxycholic acid. These acids are secreted into the intestines and converted by bacteria into secondary bile acids that are reabsorbed in the distal ileum and transported to the liver.1 In patients with cholestasis, accumulation of bile acids may contribute to pruritus, suggesting that bile acids could be a therapeutic target.2
Linerixibat is a novel orally administered minimally absorbed inhibitor of ileal bile acid transporter (IBAT) being evaluated for the treatment of cholestatic pruritus.2 By inhibiting bile acid reabsorption from the small bowel and promoting fecal bile acid excretion, linerixibat may alter mediators of cholestatic pruritus. In the phase 2b dose-escalation GLIMMER trial in 147 patients with PBC and moderate to severe pruritus, linerixibat was not associated with a significant improvement in pruritus compared with placebo in the intent-to-treat population but did demonstrate a dose-dependent reduction in pruritus in the per-protocol population, leading to the phase 3 GLISTEN trial.3
The GLISTEN trial enrolled 238 patients with PBC and moderate to severe pruritus (worst itch NRS [WI-NRS] ≥4) who were randomly assigned to linerixibat 40 mg twice daily (n=119) or placebo (n=119) for 24 weeks, followed by an 8-week blinded crossover period. Investigators noted that baseline characteristics were well balanced and representative of current practice.
The trial met its primary endpoint, demonstrating a significant improvement in change from baseline in monthly itch score on the WI-NRS scale over 24 weeks, with a least squares mean change from baseline of -2.86 in the linerixibat arm compared with -2.15 on the placebo arm (a difference of 0.72; P=.001). Linerixibat was also associated with significant changes in levels of C4 and FGF-19, biomarkers of bile acid synthesis and reabsorption, and in potential mediators of cholestatic pruritus, including TSBA, ATX, and IL-31 (Figure 4). Specifically, over the 24-week treatment period, serum concentrations of C4 increased significantly with linerixibat vs placebo, and levels of FGF-19, TSBA, ATX, and IL-31 decreased significantly (P<.001). These changes were evident by week 4 and were sustained during treatment, although the difference in IL-31 did not reach statistical significance at week 24. Switching treatment arms during the crossover period led to corresponding changes in these biomarkers.
An analysis of biomarkers with clinical outcomes found that reductions in TSBA and IL-31 levels in patients receiving linerixibat were significantly correlated with reductions in pruritus starting at week 4. Over the 24-week treatment period, reductions in FGF-19, TSBA, ATX, and IL-31 and increases in C4 correlated with improvements in pruritus in patients receiving linerixibat. However, correlations between each individual biomarker change and improvements in pruritus were weak (r values ≤0.3), suggesting that linerixibat may exert effects through multiple mediators. Changes in 3 biomarkers—TSBA, ATX, and IL-31—were significantly associated with responses to linerixibat (P<.001 for each).
References
1. Kode V, Yuimam KK. Cholestatic pruritus: pathophysiology, current management approach, and emerging therapies. Curr Hepatol Rep. 2024;23:123-136.
2. Levy C, Kendrick S, Bowlus CL, et al; GLIMMER Study Group. GLIMMER: a randomized phase 2b dose-ranging trial of linerixibat in primary biliary cholangitis patients with pruritus. Clin Gastroenterol Hepatol. 2023;21(7):1902-1912.e13.
3. Kremer AE, Bowlus C, Lennie J, et al. Impact of linerixibat on pharmacodynamic biomarkers and mediators of cholestatic pruritus in PBC in the phase 3 GLISTEN study. Abstract 0214. Presented at: AASLD 2025 Liver Meeting; November 7-11, 2025; Washington, DC.
36 Months of Treatment With Seladelpar Is Associated With Stable or Improved Liver Stiffness in Patients With PBC
In patients with PBC with advanced fibrosis or cirrhosis, progression of liver stiffness can be observed even with standard first-line UDCA treatment.1 Elevated LSM by vibration-controlled transient elastography (VCTE) has been shown to predict poor clinical outcomes in PBC.2 Although seladelpar has demonstrated improvements in markers of cholestasis in patients with PBC, its effect on liver stiffness has not been assessed.
Bowlus and colleagues presented an analysis of longitudinal trends in LSMs in patients receiving seladelpar in the open-label phase 3 ASSURE trial.3 In the trial, LSM was assessed locally at screening and every 12 months using VCTE. At baseline, patients were categorized into LSM groups based on established thresholds for fibrosis in PBC: 73.0% (n=227) were in the low-LSM group (LSM <10.7 kilopascals [kPa], indicating F0-F2 fibrosis); 16.4% (n=51) were in the intermediate-LSM group (LSM ≥10.7 to <16.9 kPa, indicating F3 fibrosis); and 10.6% were in the high-LSM group (LSM ≥16.9 kPa, indicating F4 fibrosis). Confirmed cirrhosis was present at baseline in 4% of the low-LSM group, 27% of the intermediate-LSM group, and 79% of the high-LSM group.
Over the 36-month seladelpar treatment period, LSM remained stable in the overall population, with a median change from baseline of -0.2 kPa (-2.9%). In a subgroup analysis, LSM also remained stable in the low-LSM subset (median change, 0.1 kPa; 2.0%) and in the intermediate-LSM subset (median change, -0.9 kPa; -7.4%); however, there was a trend toward improved LSM over time in the subset of patients with an LSM of 16.9 kPa or more (median change, -5.2 kPa; -29.7%).
Investigators also evaluated patterns of change in patients with worsening or improvement (of >30% for each) in liver stiffness with seladelpar treatment. Among 25 patients with an LSM worsening of greater than 30%, 20 patients (80%) were in the low-LSM category at baseline, and half of these patients remained in this category at 36 months. Among 19 patients with an LSM improvement of greater than 30% (including 11 with LSM <10.7 kPa, 3 with LSM ≥10.7 to <16.9 kPa, and 5 with LSM ≥16.9 kPa), 17 (89%) were in the low-LSM group (<10.7 kPa) at 36 months (Figure 5).
Overall, 85% of patients (97/114) remained in the same LSM category or improved LSM categories at 36 months. Among patients in the high-LSM baseline cohort (n=11), 3 (27%) shifted to the low group, 4 (36%) shifted to the intermediate group, and 4 (36%) remained in the high group. In the intermediate-LSM baseline cohort of patients (n=14), 5 (36%) shifted to the low group, 5 (36%) remained in the intermediate group, and 4 (29%) shifted to the high group. In the low-LSM baseline cohort of patients (n=89), 76 (85%) remained in the low group, 11 (12%) shifted to the intermediate group, and 2 (2%) shifted to the high group.
In an analysis of baseline characteristics associated with worsening of LSM, younger age at seladelpar initiation and higher baseline ALP category were both significantly associated with developing greater than 30% worsening of liver stiffness at 36 months (P=.0275 and P=.0122, respectively).
Seladelpar treatment was generally associated with stability of LSMs over time in patients with PBC, although there was a trend toward improvement in LSM for patients in the highest LSM group at baseline (≥16.9 kPa).
References
1. Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 2012;56(1):198-208.
2. Corpechot C, Carrat F, Gaouar F, et al; Global & ERN Rare-Liver PBC Study Groups. Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis. J Hepatol. 2022;77(6):1545-1553.
3. Bowlus CL, Hirschfield GM, Villamil AM, et al. 36 months of treatment with seladelpar is associated with stable or improved liver stiffness in patients with PBC. Abstract 5031. Presented at: AASLD Liver Meeting; November 7-11, 2025; Washington, DC.
Volixibat Leads to Improvements in Fatigue and Sleep for Adults With PBC: Data From VANTAGE
Volixibat is a novel minimally absorbed IBAT inhibitor being evaluated for the treatment of cholestatic pruritus in adults with PBC in the randomized multicenter double-blind placebo-controlled phase 2b VANTAGE trial.1 In part 1 of the trial, 31 patients with PBC and chronic pruritus were randomly assigned to volixibat 20 mg (n=10), volixibat 80 mg (n=10), or placebo (n=11) twice daily for 28 weeks. The trial met its primary endpoint, with volixibat demonstrating rapid, significant reductions in pruritus from baseline to week 28. On the adult Itch Reported Outcome (ItchRO) scale, which measures itch severity from 0 to 10, volixibat was associated with a change from baseline of -3.7 points (P<.0001) and a placebo-adjusted response of -2.4 (P=.0039) with volixibat 20 mg. Changes from baseline to week 28 were similar with volixibat 20 mg and volixibat 80 mg. In the ongoing part 2 of the trial, patients are being randomly assigned to the selected dose of volixibat 20 mg or placebo twice daily for 28 weeks.
Kowdley and colleagues presented additional analysis from part 1 of the VANTAGE trial, reporting on the efficacy of volixibat against fatigue and sleep disturbances, which are also symptoms associated with cholestasis.2 The analysis included 20 patients from the combined volixibat 20-mg and 80-mg arms and 11 patients from the placebo arm. At baseline, the mean Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue and Sleep scores among 27 assessed patients were 57.6 and 57.8, respectively.
Improvements in both fatigue and sleep were reported at week 28 in patients receiving volixibat. The least squares mean change from baseline to week 28 in the PROMIS Fatigue Score was -3.8 with volixibat (n=14) and -1.0 with placebo (n=6); 57.1% and 16.7% of patients, respectively, attained a minimum clinically important difference (MCID = ≥3-point decrease from baseline). In regard to sleep, the least squares mean change from baseline to week 28 in the PROMIS Sleep score was -4.3 with volixibat (n=14) and -1.0 with placebo (n=6), with 42.9% and 16.7% of patients, respectively, attaining a MCID at week 28.
At baseline, 28.6% of patients in the combined volixibat arm reported PROMIS fatigue scores in the normal range; this increased to 42.9% at week 28. In contrast, the proportion of patients reporting normal PROMIS fatigue scores in the placebo arm was 33.3% at both baseline and at week 28. The proportion of patients reporting normal PROMIS Sleep scores increased from 50.0% at baseline to 64.3% at week 28 in the combined volixibat group but declined from 66.7% to 50.0% in the placebo group.
PROMIS Fatigue and Sleep scores correlated significantly with pruritus outcomes assessed by the average weekly ItchRO score, with the correlation reaching significance at week 16 for fatigue (correlation coefficient, 0.66; P=.004) and sleep (correlation coefficient, 0.51; P=.037). The results suggest that improvements in pruritus attained with volixibat in patients with PBC may also yield improvements in sleep and fatigue.
References
1. Heneghan M, Shiffman M, Weinstein D, et al. Volixibat for the treatment of cholestatic pruritus in primary biliary cholangitis: an adaptive, randomized, placebo-controlled phase 2b trial (VANTAGE): 28-week interim results. Abstract OS-059. Presented at: EASL Congress 2025; May 7-10, 2025; Amsterdam, the Netherlands.
2. Kowdley KV, Shiffman ML, Weinstein D, et al. Volixibat leads to improvements in fatigue and sleep for adults with PBC: data from VANTAGE. Abstract 2015. Presented at: AASLD 2025 Liver Meeting; November 7-11, 2025; Washington, DC.