A Review of Selected Presentations From the American Association for the Study of Liver Diseases 2024 Liver Meeting
November 15-19, 2024 • San Diego, California
Efficacy and Safety of Seladelpar in Patients With Primary Biliary Cholangitis and Compensated Cirrhosis in the Phase 3 Placebo-Controlled RESPONSE Trial
Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease that primarily affects women 40 to 70 years of age.1 The current standard initial treatment of PBC is ursodeoxycholic acid (UDCA). Timely diagnosis and appropriate treatment can prevent progression of PBC to cirrhosis and liver failure. However, for patients with PBC who do not attain a complete response to UDCA or develop intolerance and for patients who progress to cirrhosis, there is a need for safe and effective second-line therapies.1
Peroxisome proliferator-activated receptor (PPAR) agonists, which signal through specific intranuclear receptors to control metabolic processes, have demonstrated activity as second-line therapies for patients with PBC.1 In August 2024, the oral selective PPAR-delta agonist seladelpar received accelerated approval from the US Food and Drug Administration (FDA) 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, based on the results of the RESPONSE study.2
The 12-month placebo-controlled phase 3 RESPONSE study compared seladelpar with placebo in patients who had an inadequate response or intolerance to UDCA. A total of 193 patients were stratified by alkaline phosphatase (ALP) level (<350 vs ≥350 U/L) and pruritus numerical rating scale (NRS) score (<4 vs ≥4) and were randomly assigned 2:1 to seladelapar 10 mg daily (n=128) or placebo (n=65).2
The study met its primary endpoint, demonstrating a significant improvement in the proportion of patients attaining a composite biochemical response, defined as an ALP level less than 1.67 × upper limit of normal (ULN), with a decrease of 15% or more from baseline, and a normal bilirubin level at 12 months (61.7% vs 20.0% with placebo; P<.001).3
At the American Association for the Study of Liver Diseases (AASLD) 2024 Liver Meeting, outcomes in the subset of patients with PBC and cirrhosis from the RESPONSE trial were presented.3 Overall, 27 patients with cirrhosis were enrolled in the trial, accounting for 14% of patients in each arm. No patients met the criteria for cirrhosis based on laboratory findings alone, and 60% of patients met at least 2 criteria. Baseline characteristics showed higher liver stiffness values in patients with cirrhosis vs those without cirrhosis, lower platelet counts, and higher ALP levels. Two patients in the seladelpar arm had a Child-Pugh score 6.
The efficacy analysis showed rapid, sustained declines in ALP with seladelpar regardless of cirrhosis status. In patients with cirrhosis, the mean change in ALP from baseline to 12 months was -121.4 U/L in the seladelpar arm and +23.2 U/L in the placebo arm (Figure 1). In patients without cirrhosis, the mean change in ALP with seladelpar and placebo was -134.8 U/L and -18.0 U/L, respectively.
Seladelpar was also associated with sustained declines in gamma-glutamyl transferase (GGT) levels. Total bilirubin measurements remained stable regardless of the presence of cirrhosis; mean international normalized ratio and Model for End-Stage Liver Disease scores were similar between groups over the 12-month period. Transient elastography showed stable liver stiffness across study groups.
The safety profile of seladelpar in patients with cirrhosis was similar to that in the overall population. In patients with cirrhosis receiving seladelpar, no adverse events (AEs) led to discontinuation of treatment. There were no treatment-related serious AEs. Two patients with cirrhosis receiving seladelpar developed liver-related AEs: 1 patient had grade 1 hepatomegaly, and 1 patient had grade 1 ascites and then experienced a serious AE of esophageal varices hemorrhage. Muscular-related AEs were mild and not associated with creatinine phosphokinase increases. Laboratory events in patients with cirrhosis included alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations in 1 patient receiving seladelpar and 2 patients receiving placebo, and total bilirubin elevations in 1 patient receiving seladelpar and 2 patients receiving placebo. The investigators concluded that seladelpar was safe and well tolerated in patients with compensated cirrhosis.
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. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med. 2024;390(9):783-794.
3. Villamil A, Younes Z, Bowlus CL, et al. Efficacy and safety of seladelpar in patients with primary biliary cholangitis and compensated cirrhosis in the phase 2 placebo-controlled RESPONSE trial [AASLD abstract 700]. Hepatology. 2024;80(suppl 1).
Elafibranor Long-Term Efficacy and Safety and Impact on Fatigue in Primary Biliary Cholangitis: Interim Results From the Open-Label Extension of the ELATIVE Trial Up to 3 Years
Elafibranor is an oral PPAR agonist that exerts effects on both PPAR-alpha and PPAR-gamma. In 2024, elafibranor received FDA approval for the treatment of PBC in combination with UDCA or as monotherapy for adults who have an inadequate response to UDCA or are unable to tolerate it, based on the results of the ELATIVE trial.1 In the multinational, phase 3, double-blind, placebo-controlled ELATIVE trial, elafibranor administered at 80 mg once daily was associated with significantly greater improvements in biochemical indicators of cholestasis at week 52 compared with placebo in patients with PBC with an inadequate response to or unacceptable side effects with UDCA.1
Interim results from the open-label extension (OLE) of the ELATIVE trial were presented in posters at the AASLD 2024 Liver Meeting.2,3 For patients who received placebo during the double-blind period and crossed over to elafibranor, the OLE baseline was considered the last available measurement before the first OLE elafibranor dose; data are available for this cohort with a maximum follow-up of 52 weeks.2 For patients who received elafibranor in the double-blind period, OLE baseline was defined as the time of initial randomization; data are available with up to 156 weeks of follow-up for this cohort.3
An analysis by Kowdley and colleagues reported interim results after up to 3 years in the ongoing OLE of the ELATIVE trial.2 The analysis included 138 patients of whom 45 were in the placebo arm and crossed over to elafibranor. Overall, elafibranor was associated with sustained improvements in biomarkers of cholestasis, including ALP and total bilirubin. Although mean reductions in ALP remained stable during the OLE, biochemical responses fluctuated over time. Approximately 30% of patients with a biochemical response at the beginning of the OLE had at least 1 study visit during the OLE in which they did not achieve a biochemical response, and 37% of the patients who were nonresponders at the beginning of the OLE had at least 1 study visit in which they achieved a biochemical response. Surrogates for fibrosis, including the median change in liver stiffness measurement and enhanced liver fibrosis score, were also sustained over the OLE period up to week 156. Measures of pruritus improved over time in patients who crossed over from placebo, with an improvement similar to patients initially assigned to elafibranor. No new safety findings were noted. The most frequent treatment-emergent AEs in the OLE were abdominal pain, diarrhea, nausea, and vomiting.
Given the significant impact of fatigue on patients with PBC, Swain and colleagues conducted an analysis evaluating the effects of elafibranor on fatigue-related outcome in the OLE.3 Among patients with moderate to severe fatigue or excessive sleepiness at baseline, 50% to 69% had clinically meaningful improvements in fatigue and sleep from baseline to week 104, and 50% to 78% had improvements from baseline to week 130 (Figure 2). Improvements in fatigue and sleep were also observed in the overall population but were more pronounced in those with moderate to severe fatigue or excessive sleepiness at baseline.
References
1. Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and safety of elafibranor in primary biliary cholangitis. N Engl J Med. 2024;390(9):795-805.
2. Kowdley KV, Bowlus CL, Levy C, et al. Long-term efficacy and safety of elafibranor in primary biliary cholangitis: interim results from the open-label extension of the ELATIVE trial up to 3 years [AASLD abstract 5041]. Presented at: The Liver Meeting; November 15-19, 2024; San Diego, CA.
3. Swain MG, Jones D, Levy C, et al. Impact of elafibranor on fatigue in patients with primary biliary cholangitis: interim results from the long-term open-label extension of the ELATIVE trial [AASLD abstract 5042]. Presented at: The Liver Meeting; November 15-19, 2024; San Diego, CA.
Attenuation, Near Resolution, and Prevention of Pruritus in Patients With Primary Biliary Cholangitis Treated With Seladelpar: A Secondary Analysis of Patterns of Pruritus Change in the RESPONSE Trial
Cholestatic pruritus is a significant consequence of PBC, occurring in approximately 80% of patients and causing substantial reductions in quality of life (QOL).1 Cholestatic pruritus can even become an indication for liver transplant in the most severe cases.2 Off-label treatment options for cholestatic pruritus include rifampicin and fibrates, although there are limitations with these options.2 There is a need for therapies for PBC that improve both biochemical disease markers and pruritus.
In the phase 3 placebo-controlled RESPONSE trial, in which seladelpar demonstrated significant reductions in itch compared with placebo as measured by the pruritus NRS after 6 months, the secondary endpoint of PBC-40 Itch domain and the exploratory endpoint of 5-D Itch scale showed similar improvements in pruritus with seladelpar.3
In a secondary analysis from the RESPONSE trial, Kremer and colleagues reported more detailed outcomes regarding changes in pruritus and QOL.4 Among the 49 patients in the seladelpar arm with an NRS of 4 or higher at baseline, the mean itch intensity declined to a mild level (NRS score >0 to <4) by month 12. In contrast, of the 23 patients in the placebo arm with an NRS of 4 or higher at baseline, mean itch intensity remained in the moderate range (Figure 3).
Seladelpar was also associated with a higher likelihood of attaining reductions in NRS by month 12 than placebo, including reductions of at least 3 points (46.9% vs 21.7%) and reductions of at least 4 points (30.6% vs 8.7%). In the seladelpar arm, reductions in NRS to a score of 0 or 1, indicating near resolution of itch, were attained by month 12 in 26.5% of patients with moderate to severe pruritus at baseline (NRS ≥4), and 18.8% of patients with severe pruritus at baseline (NRS ≥7). No patients in the placebo arm with a baseline NRS of 4 or higher attained an NRS of 0 or 1.
Patients with severe itch at baseline also reported reductions in itch, sleep disturbance, and fatigue as assessed by the PBC-40. Among patients with clinically significant itch at baseline (defined as a PBC-40 ≥7), seladelpar was associated with improvements in itch, sleep, and fatigue. The PBC-40 was less than 7 in 40% of patients in the seladelpar arm with a PBC-40 of 7 or higher at baseline, compared with 20% of patients in the placebo arm. Finally, no new itching developed in patients in the seladelpar arm without itching at baseline, whereas 26.7% of patients in the placebo arm developed itch at 12 months. Safety analyses found no difference in the incidence of AEs based on baseline itch severity.
References
1. Mayo MJ, Carey E, Smith HT, et al. Impact of pruritus on quality of life and current treatment patterns in patients with primary biliary cholangitis [published correction appears in Dig Dis Sci. 2023;68(10):4064-4065]. Dig Dis Sci. 2023;68(3):995-1005.
2. Düll MM, Kremer AE. Evaluation and management of pruritus in primary biliary cholangitis. Clin Liver Dis. 2022;26(4):727-745.
3. Hirschfield GM, Bowlus CL, Mayo MJ, et al. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med. 2024;390(9):783-794.
4. Kremer AE, Levy C, Mayo MJ, et al. Attenuation, near resolution, and prevention of pruritus in patients with primary biliary cholangitis treated with seladelpar: a secondary analysis of patterns of pruritus change in the RESPONSE trial [AASLD abstract 703]. Hepatology. 2024;80(suppl 1).
Fibrate-OCA (Fi-OCA) Study – A Global Snapshot of PBC Practice Around the Globe
Until 2023, the main options for the second-line treatment of PBC after first-line UDCA were obeticholic acid (OCA) and bezafibrate. OCA was evaluated in the randomized, placebo-controlled, phase 3 POISE trial, demonstrating improvements in ALP and total bilirubin at 12 months.1 Bezafibrate was evaluated in combination with UDCA as second-line therapy in the BEZURSO trial, demonstrating higher complete biochemical response rates over placebo plus UDCA.2
Use of these second-line therapies is limited by differential access worldwide, a lack of real-world data
regarding outcomes with these therapies, and a lack of tools to effectively individualize therapy. To better understand the use of current second-line therapies worldwide, Ronca and colleagues with the Global PBC Study Group conducted a retrospective multicenter cohort study evaluating real-world use of these agents as second-line therapy worldwide in patients with PBC.3
Centers from the United States, Canada, Argentina, Europe, Israel, and Japan enrolled patients with PBC with at least 12 months of follow-up on second-line treatment with fenofibrate, bezafibrate, or OCA. Patients with overlap syndromes with autoimmune hepatitis or concomitant chronic liver disease were excluded.
The analysis included 1825 patients, of whom 887 received fibrates and 938 received OCA. Overall, the median age was 49.0 years at the time of diagnosis and 56.6 years at the time of second-line treatment. Males accounted for 11.6% of the population. Cirrhosis was present at diagnosis in 25.5% of patients and present at the time of second-line treatment in 25.2%. Second-line treatment changes included switching agents in 7.6% and adding treatment in 8.7%. The median time from second-line to third-line treatment was 24.0 months. Orthotopic liver transplant was performed in 4.6% of patients, and 4.6% of patients had died at the time of analysis.
Compared with patients receiving fibrates (n=887), patients receiving OCA (n=938) had higher rates of cirrhosis at baseline (30% vs 12.4%; P<.001) and at the time of second-line treatment (28.4% vs 19.5%; P<.0001), higher rates of switching second-line treatment (9.8% vs 5.4%) or adding treatment (14.4% vs 3.0%) (P<.001), a shorter median time before stopping treatment (18.0 vs 26.0 months; P=.012), a shorter time from first-line to second-line treatment (72.0 vs 51.0 months; P<.001), and shorter follow-up on second-line treatment (P<.001).
An analysis of cohort features found geographic differences based on whether patients were in America (n=432), Europe (n=1143), or Japan (n=214). Patients in Japan tended to be older (P<.001) and had a higher proportion of males (24.3% vs 6.7% in America and 10.9% in Europe) (P<.001). Patients in America were significantly more likely than patients in Europe to change treatment (P<.001). Rates of pruritus and fatigue were higher in American and European patients than in Japanese patients.
A comparison of clinical features in patients receiving bezafibrate (n=500) or fenofibrate (n=175) found no significant differences in choice of fibrate based on age, rate of cirrhosis, liver transplant, and death. The patients on fenofibrate had a longer time before starting the second-line treatment, 77 months compared with 41 months on bezafibrate, and also had a higher rate of switching treatment to bezafibrate or to OCA.
In an analysis of treatment sequences, 852 patients started on OCA, 17 started on OCA plus fibrates, and 834 started on fibrates. By the end of follow-up, 550 patients were receiving OCA, including 40 who switched from fibrates, 141 were receiving combination (12 who started double treatment, 105 who added a fibrate, and 24 who added OCA), 289 had stopped treatment (including 151 patients who had started with OCA), and 713 were still receiving fibrates (including 81 patients who switched from OCA to fibrates) (Figure 4).
The most frequent reasons for interrupting OCA were pruritus (31.8%), hepatic events (9.6%), gastrointestinal symptoms (6.3%), insufficient response (5%), and an FDA warning (2.9%). The most frequent reasons for interrupting fibrates were high transaminases (17.5%), renal dysfunction (9.8%), muscle pain (7.6%), gastrointestinal symptoms (7%), insufficient response (6.0%), and hepatic events (5.6%).
The investigators concluded that differences in access to therapy and selection of therapy yield differences in treatment pictures geographically. The high rate of treatment changes and discontinuation suggest suboptimal treatment selection. A more granular definition of international cohorts could provide greater information on patients’ treatment trajectories, which could enable the development of treatment allocation tools.
References
1. Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-643.
2. Corpechot C, Chazouillères O, Rousseau A, et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018;378(23):2171-2181.
3. Ronca V, De Vincentis A, Ferraciani F, et al. Fibrate-OCA (Fi-OCA) – a global snapshot of PBC practice around the globe [AASLD abstract 724]. Hepatology. 2024;80(suppl 1).
Long-Term Efficacy and Safety of Open-Label Seladelpar Treatment in Patients With Primary Biliary Cholangitis: Pooled Interim Results for Up to 3 Years From the ASSURE Study
The ongoing open-label phase 3 ASSURE trial is evaluating the long-term efficacy and safety of seladelpar 10 mg in patients with PBC who had received seladelpar in the placebo-controlled RESPONSE trial or in other earlier seladelpar trials.1
A total of 337 patients have been enrolled in the ASSURE study, including 179 patients from legacy studies, 104 patients from the seladelpar arm of the RESPONSE trial, and 54 patients from the placebo arm of the RESPONSE trial. As of the data cutoff, 124 patients had at least 24 months of seladelpar exposure. The mean age of patients at baseline was 58.1 years; 94% of patients were female and 16% had cirrhosis.
Interim results reported by Lawitz and colleagues show that the composite biochemical response endpoint (defined as an ALP <1.67 × ULN, an ALP decrease ≥15%, and a normal total bilirubin level) was met in 73% of patients at month 12, 73% of patients at week 24, and 81% of patients at month 30 (Figure 5). The ALP normalization rate at month 30 was 41% (15 of 37). At month 30, ALT had normalized in 90% (17 of 19) of patients with elevated ALT at baseline. Among 37 patients with month 30 data, the mean percentage change from baseline in ALT, total bilirubin, and GGT was -29%, -5%, and -42%, respectively. Among 99 patients with moderate to severe pruritus at baseline, the mean change in pruritus NRS from baseline to 6 months was -3.3.
No new safety issues or changes in AE frequency were observed after up to 3 years of treatment. The most common AEs were COVID-19, pruritus, and nausea; most AEs of interest were grade 1 or 2 in severity. No serious treatment-related AEs were reported. One death caused by autoimmune hemolytic anemia was considered unrelated to seladelpar use. Rates of exposure-adjusted liver, muscle, and renal AEs were stable or decreased over the 3-year period.
Reference
1. Lawitz EJ, Trivedi PJ, Kowdley KV, et al. Long-term efficacy and safety of open-label seladelpar treatment in patients with primary biliary cholangitis: pooled interim results for up to 3 years from the ASSURE study [AASLD abstract 5044]. Presented at: The Liver Meeting; November 15-19, 2024; San Diego, CA.
One-Year Treatment With Elafibranor in the Phase 3 ELATIVE Trial Improves GLOBE and UK-PBC Prognostic Scores
The GLOBE and UK-PBC are scoring systems that were developed and validated independently to predict outcomes in patients with PBC.1,2 The GLOBE formula incorporates age, total bilirubin, ALP, albumin, and platelet count, whereas the UK-PBC formula incorporates ALP, ALT or AST, total bilirubin, albumin, and platelet count.1,2
The GLOBE and UK-PBC models were developed in patients receiving UDCA but have demonstrated utility in patients receiving OCA.3 The models demonstrate greater prognostic value than dichotomous response criteria.3 Kowdley and colleagues reported outcomes of an analysis evaluating GLOBE and UK-PBC scores in patients receiving elafibranor or placebo in the phase 3 ELATIVE trial.4
Overall, baseline demographics and clinical and laboratory parameters that contribute to the GLOBE and UK-PBC scores were well balanced between the elafibranor and placebo arms. Both scores improved after 4 weeks in the elafibranor arm and continued to improve through 52 weeks (Figure 6). During the 52-week period, changes in all contributing laboratory parameters were observed in the elafibranor arm, including mean ALP (-117.7 U/L), mean total bilirubin (-0.04 mg/dL), mean AST (-2.5 U/L), mean ALT (-9.7 U/L), mean albumin (0.10 g/dL), and mean platelet count (7.5 × 109/L).
In the elafibranor arm, estimated transplant-free survival rates as calculated with the GLOBE score improved from baseline to week 52 by 2.9% at 10 years (from 91.2% to 94.1%) and by 4.9% at 20 years (from 84.8% to 89.7%). In the placebo arm, estimated transplant-free survival rates improved from baseline to week 52 by 0.4% at 10 years (from 92.2% to 92.6%) and by 0.7% at 20 years (from 86.5% to 87.2%). Similarly, estimated transplant-free survival rates based on UK-PBC scores at week 52 improved by 0.9% at 10 years and 1.6% at 15 years in the elafibranor arm, and decreased by 0.2% at 10 years and 0.4% at 15 years in the placebo arm. The improvement on estimated transplant-free survival based on the GLOBE score was observed regardless of disease stage (early vs advanced based on liver stiffness or histology) or biochemical response.
The investigators concluded that elafibranor was associated with greater improvements than placebo in GLOBE and UK-PBC prognostic scores, with improvements observed as early as week 4. These improvements translated to higher estimated transplant-free survival rates including in patients with advanced disease and those without a biochemical response.
References
1. Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149(7):1804-1812.e4.
2. Carbone M, Sharp SJ, Flack S, et al. The UK-PBC risk scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016;63(3):930-950.
3. Carbone M, Harms MH, Lammers WJ, et al. Clinical application of the GLOBE and United Kingdom-primary biliary cholangitis risk scores in a trial cohort of patients with primary biliary cholangitis. Hepatol Commun. 2018;2(6):683-692.
4. Kowdley KV, Lawitz E, Sonderup M, et al. One-year treatment with elafibranor in the phase III ELATIVE trial improves GLOBE and UK-PBC prognostic scores [AASLD abstract 2371]. Hepatology. 2024;80(suppl 1).
Disparities in Primary Biliary Cholangitis: A Retrospective Study Using Real-World Data From a Single Hepatology Clinic in the Greater Los Angeles Area
Rates of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are higher in Hispanic adults in the United States than in non-Hispanic adults, and MASH is associated with a poorer prognosis in patients with PBC.1,2
Disparities in PBC severity in Hispanic/Latino adults have not been well characterized, particularly in a real-world setting. Alff and colleagues conducted a retrospective study evaluating demographic, clinical, and laboratory characteristics of patients with PBC receiving care at a nonacademic hepatology clinic in the Los Angeles area.2
The cohort included 184 patients with PBC for whom ethnic data were available, of whom 49.5% (n=91) were Hispanic/Latino and 50.5% (n=93) were non-Hispanic/Latino. Hispanic/Latino patients identified as White, whereas non-Hispanic/Latinos identified as White (56.5%), Asian (39.1%), and Black (4.4%). The median age of the cohort was 62 years (range, 20-90), and 83% were female.
Analyses using the Area Deprivation Index (ADI) showed significantly more disadvantage for Hispanic/Latinos than non-Hispanic/Latinos according to continuous and categorical ADI scores. White Hispanic/Latinos were significantly more likely to be in the 7-to-10 ADI category than Black non-Hispanic/Latinos (25.0%), White non-Hispanic/Latinos (14.6%), and Asian non-Hispanic/Latinos (9.1%).
Median body mass index (BMI) was significantly higher in Hispanic/Latinos than in non-Hispanic/Latinos (26.7 vs 22.4; P=.0025), and 22.4% of patients had a history of type 2 diabetes mellitus. In an assessment of PBC, MASLD, and autoimmune hepatitis, Hispanic/Latinos were significantly more likely than non-Hispanic/Latinos to have MASLD (45.6% vs 19.4%; P=.0001) and to have all 3 associated conditions (12.1% vs 2.2%; P=.0011). They were significantly less likely than non-Hispanic/Latinos to have only 1 liver condition (40.7% vs 63.4%; P =.0011).
An analysis of PBC severity showed higher degrees of fibrosis in Hispanic/Latinos vs non-Hispanic/Latinos as assessed by Scheuer stage (P=.0059), METAVIR stage (P=.0207), and FibroScan stiffness (10.1 vs 7.5 kPa; P=.0249) (Table), and by composite fibrosis score distribution (P=.0105) and prevalence of F2 to F4 disease (P=.0012).
In a multivariate analysis, being Hispanic/Latino, single, male, older, and having low plasma albumin levels was independently associated with F2 to F4 disease. Compared with having just PBC, having PBC plus either autoimmune hepatitis overlap or MASLD was associated with a significantly increased risk of having F2 to F4 fibrosis (odds ratio, 2.91; 95% CI, 1.23-7.16; P=.0143), and having all 3 conditions further increased the risk over having 2 conditions.
References
1. Tesfai K, Pace J, El-Newihi N, Martinez ME, Tincopa M, Loomba R. Disparities for Hispanic adults with metabolic dysfunction-associated steatotic liver disease in the United States: a systematic review and meta-analysis [published online July 16, 2024]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2024.06.038.
2. Alff S, Ventura OE, Love Foster-Malave T, Mendler M, Mena E. Examining disparities in primary biliary cholangitis: a retrospective study using real-world data from a single hepatology clinic in the greater Los Angeles area [AASLD abstract 907]. Hepatology. 2024;80(suppl 1).
The Effect of Obeticholic Acid on Inflammatory Markers and Fibrosis Scores in POISE Incomplete Responders: A Retrospective Review of POISE, a Phase 3 Trial of Obeticholic Acid for the Treatment of Primary Biliary Cholangitis
OCA received FDA approval for the treatment of PBC based on results from the randomized, double-blind, phase 3 POISE trial, in which OCA was associated with significantly greater reductions in ALP and total bilirubin from baseline than placebo.1 At 12 months, the proportion of patients achieving the composite endpoint (defined as an ALP <1.67 × ULN, with a reduction of ≥15% from baseline and normal total bilirubin) was significantly higher with either of the OCA doses evaluated (46% with 5-10 mg and 47% with 10 mg) than with placebo (10%; P<.001 for both).
Victor and colleagues reported results from a post-hoc analysis evaluating other outcomes, including markers of farnesoid X receptor (FXR) activation, inflammation, hepatocyte injury, and hepatic fibrosis, in patients without an incomplete response to OCA in the POISE trial.2 Of the 217 patients randomized in the trial, 70 were assigned to OCA 5-10 mg, 73 were assigned to OCA 10 mg, and 73 were assigned to placebo. Incomplete responses occurred in 54.3% of patients receiving OCA titration, 53.4% receiving OCA 10 mg, and 90.4% of patients receiving placebo.
Among the patients with an incomplete response, OCA was associated with a significant difference over placebo in the median percentage change from baseline in fibroblast growth factor 19 (FGF19), a marker of FXR activation. The difference in percentage change from baseline in FGF19 with OCA vs placebo was statistically significant at 12 months whether patients received OCA titration (52%) or OCA 10 mg (94%) (Figure 7). Differences were also observed for reductions in the immune-mediated inflammatory markers C-reactive protein, immunoglobulin M, and cytokeratin 18.
Finally, noninvasive estimates of hepatic fibrosis (Fibrosis-4 and AST to Platelet Ratio Index) indicated lower fibrosis scores in patients with incomplete responses to OCA compared with placebo. Investigators concluded that patients who did not achieve the composite endpoint of response assessed by ALP and bilirubin may still gain benefits from OCA as assessed by reductions in inflammation that could translate to reduced progression of fibrosis.
References
1. Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-643.
2. Victor D, Li J, Nair R, Wheeler D, Kowdley K. The effect of obeticholic acid on inflammatory markers and fibrosis scores in POISE incomplete responders: a retrospective review of POISE, a phase 3 trial of obeticholic acid for the treatment of primary biliary cholangitis [AASLD abstract 949]. Hepatology. 2024;80(suppl 1).