UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis

Background &amp; aims: thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate).Methods: this was a nationwide observational cohort study conducted from August 2017 until June 2021.Results: we accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings &gt;9.6kPa (P &lt; .05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P &lt; .001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P &lt; .001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P = .121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline.Conclusion: across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment.</p

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis

Background & Aims: Thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate). Methods: This was a nationwide observational cohort study conducted from August 2017 until June 2021. Results: We accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings >9.6kPa (P <.05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P <.001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P <.001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P =.121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline. Conclusion: Across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis

\ua9 2023 The Authors. Background &amp; Aims: Thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate). Methods: This was a nationwide observational cohort study conducted from August 2017 until June 2021. Results: We accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings &gt;9.6kPa (P &lt;.05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P &lt;.001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P &lt;.001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P =.121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline. Conclusion: Across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment

Non‐Response to Obeticholic Acid Is Associated With Heightened Risks of Developing Clinical Events in Primary Biliary Cholangitis

ABSTRACTObjectiveBiochemical non‐response to ursodeoxycholic acid, as a first‐line therapy, is associated with a heightened risk of clinical events in primary biliary cholangitis (PBC). Herein, we determine whether biochemical non‐response to second‐line therapy in obeticholic acid (OCA) is also predictive of long‐term event‐free survival.DesignData were collected from patients who initiated OCA at large, high‐volume centres in the UK, Italy, and Canada between August 2017 and 2019, with follow‐up continuing until June 2024. Biochemical non‐response was defined by POISE criteria. Clinical events were defined as hepatic decompensation, referral for transplantation, hepatocellular carcinoma, or death.ResultsOur cohort consisted of 336 patients (29% with cirrhosis), of whom n = 150 (45%) discontinued OCA over 48 months. Over 851 patient‐years of OCA use, without the addition of another PBC therapy, n = 230, n = 192, n = 158 and n = 150 patients completed 12, 24, 36 and 48 months follow‐up, respectively. Of this cohort, 37%, 48%, 63% and 55% attained biochemical response, with 7%, 14%, 25% and 19% normalising ALP (p &lt; 0.01; all comparisons vs. baseline). Over 4 years, 64 patients experienced a clinical event. Twelve‐month biochemical non‐response associated with a heightened risk of clinical events (hazard ratio [HR]: 4.50; 95% CI: 1.74–20.23), as did cirrhosis (HR: 20.24, 10.15–40.32), hyperbilirubinaemia (HR: 2.55, 1.71–3.76), hypoalbuminaemia (HR: 0.92, 0.90–0.96) and thrombocytopenia (HR: 0.99, 0.98–0.99). The prognostic utility of biochemical non‐response (HR: 3.29, 1.72–14.96) and cirrhosis (HR: 19.67, 5.09–76.08) persisted on multivariable analyses.ConclusionBiochemical response stratifies risk of clinical events in PBC patients under OCA treatment. Whilst response rates increase over time, discontinuation rates underscore the need for newer treatment paradigms.</jats:sec

Non‐Response to Obeticholic Acid Is Associated With Heightened Risks of Developing Clinical Events in Primary Biliary Cholangitis

Objective: Biochemical non‐response to ursodeoxycholic acid, as a first‐line therapy, is associated with a heightened risk of clinical events in primary biliary cholangitis (PBC). Herein, we determine whether biochemical non‐response to second‐line therapy in obeticholic acid (OCA) is also predictive of long‐term event‐free survival. Design: Data were collected from patients who initiated OCA at large, high‐volume centres in the UK, Italy, and Canada between August 2017 and 2019, with follow‐up continuing until June 2024. Biochemical non‐response was defined by POISE criteria. Clinical events were defined as hepatic decompensation, referral for transplantation, hepatocellular carcinoma, or death. Results: Our cohort consisted of 336 patients (29% with cirrhosis), of whom n = 150 (45%) discontinued OCA over 48 months. Over 851 patient‐years of OCA use, without the addition of another PBC therapy, n = 230, n = 192, n = 158 and n = 150 patients completed 12, 24, 36 and 48 months follow‐up, respectively. Of this cohort, 37%, 48%, 63% and 55% attained biochemical response, with 7%, 14%, 25% and 19% normalising ALP (p < 0.01; all comparisons vs. baseline). Over 4 years, 64 patients experienced a clinical event. Twelve‐month biochemical non‐response associated with a heightened risk of clinical events (hazard ratio [HR]: 4.50; 95% CI: 1.74–20.23), as did cirrhosis (HR: 20.24, 10.15–40.32), hyperbilirubinaemia (HR: 2.55, 1.71–3.76), hypoalbuminaemia (HR: 0.92, 0.90–0.96) and thrombocytopenia (HR: 0.99, 0.98–0.99). The prognostic utility of biochemical non‐response (HR: 3.29, 1.72–14.96) and cirrhosis (HR: 19.67, 5.09–76.08) persisted on multivariable analyses. Conclusion: Biochemical response stratifies risk of clinical events in PBC patients under OCA treatment. Whilst response rates increase over time, discontinuation rates underscore the need for newer treatment paradigms

A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA

\ua9 2021 European Association for the Study of the Liver. Background &amp; Aims: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC. Methods: This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108). Results: At 12 weeks, ALP was reduced by -48.3\ub114.8% in the elafibranor 80 mg group (p &lt;0.001 vs. placebo) and by -40.6\ub117.4% in the elafibranor 120 mg group (p &lt;0.001) compared to a +3.2\ub114.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP &gt;15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0\ub125.5% in the elafibranor 80 mg group (p &lt;0.001) and 40.0\ub124.1% in the elafibranor 120 mg group (p &lt;0.01) compared to no change (+0.2\ub126.0%) in the placebo group. Levels of disease markers such as IgM, 5’-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate. Conclusion: In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid. Lay summary: Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy. Clinical trial registration number: Clinical Trials.gov NCT0312410

Prognostic Factors for Transplant-Free Survival and Validation of Prognostic Models in Chinese Patients with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid

OBJECTIVES: We aimed to validate the prognostic models for primary biliary cholangitis (PBC) in Chinese patients receiving ursodeoxycholic acid (UCDA), and to compare their performances in predicting the long-term survival. METHODS: Chinese patients with PBC from a tertiary center were identified via electronic search of hospital medical registry. Risk factors associated with adverse events (liver transplantation or death from liver-related causes including hepatocellular carcinoma (HCC) and liver decompensation) were determined. Transplant-free survival was defined as survival free of liver-related death or transplantation. RESULTS: Of the 144 patients, 41 (28.5%) had baseline cirrhosis. The median age at diagnosis was 57.8 years. During a median follow-up of 7.0 years, 40 patients died (21 liver-related; 19 non-liver-related), 12 developed HCC, and 10 underwent transplantations. The 5-, 10-, and 15-year transplant-free survival probabilities were 91.0%, 78.1%, and 58.9%, respectively. Independent risk factors for adverse events were increasing age (hazard ratio (HR) 1.05), cirrhosis (HR 8.53), and suboptimal treatment response (HR 3.06). Aspartate aminotransferase/platelet ratio index at 1 year (APRI-r1) in combination with treatment response optimized the risk stratification. The performances of the GLOBE, UK-PBC scores, Rotterdam criteria, and APRI-r1 were comparable in predicting adverse events. The area under receiver operating curves within 5, 10, and 15 years were as follows-GLOBE score: 0.83, 0.85, and 0.85, respectively; UK-PBC score: 0.89, 0.83, and 0.79, respectively; Rotterdam criteria: 0.82, 0.76, and 0.80, respectively; APRI-r1: 0.80, 0.83, and 0.77, respectively. CONCLUSIONS: The UK-PBC, GLOBE scores, Rotterdam criteria, and APRI-r1 had good and comparable prognostic prediction values for Chinese PBC patients receiving UCDA.published_or_final_versio

Non-Response to Obeticholic Acid Is Associated With Heightened Risks of Developing Clinical Events in Primary Biliary Cholangitis

\ua9 2025 The Author(s). Alimentary Pharmacology &amp; Therapeutics published by John Wiley &amp; Sons Ltd.Objective: Biochemical non-response to ursodeoxycholic acid, as a first-line therapy, is associated with a heightened risk of clinical events in primary biliary cholangitis (PBC). Herein, we determine whether biochemical non-response to second-line therapy in obeticholic acid (OCA) is also predictive of long-term event-free survival. Design: Data were collected from patients who initiated OCA at large, high-volume centres in the UK, Italy, and Canada between August 2017 and 2019, with follow-up continuing until June 2024. Biochemical non-response was defined by POISE criteria. Clinical events were defined as hepatic decompensation, referral for transplantation, hepatocellular carcinoma, or death. Results: Our cohort consisted of 336 patients (29% with cirrhosis), of whom n = 150 (45%) discontinued OCA over 48 months. Over 851 patient-years of OCA use, without the addition of another PBC therapy, n = 230, n = 192, n = 158 and n = 150 patients completed 12, 24, 36 and 48 months follow-up, respectively. Of this cohort, 37%, 48%, 63% and 55% attained biochemical response, with 7%, 14%, 25% and 19% normalising ALP (p &lt; 0.01; all comparisons vs. baseline). Over 4 years, 64 patients experienced a clinical event. Twelve-month biochemical non-response associated with a heightened risk of clinical events (hazard ratio [HR]: 4.50; 95% CI: 1.74–20.23), as did cirrhosis (HR: 20.24, 10.15–40.32), hyperbilirubinaemia (HR: 2.55, 1.71–3.76), hypoalbuminaemia (HR: 0.92, 0.90–0.96) and thrombocytopenia (HR: 0.99, 0.98–0.99). The prognostic utility of biochemical non-response (HR: 3.29, 1.72–14.96) and cirrhosis (HR: 19.67, 5.09–76.08) persisted on multivariable analyses. Conclusion: Biochemical response stratifies risk of clinical events in PBC patients under OCA treatment. Whilst response rates increase over time, discontinuation rates underscore the need for newer treatment paradigms

The diagnosis and treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a slowly progressive cholestatic liver disease of autoimmune etiology. The initial presentation of PBC is various from asymptomatic, abnormal liver biochemical tests to overt cirrhosis. The diagnosis of PBC is based on cholestatic biochemical liver tests, presence of antimitochondrial antibody and histologic findings of nonsuppurative destructive cholangitis. Although the diagnosis is straightforward, it could be underdiagnosed because of its asymptomatic presentation, or underrecognition of the disease. UDCA in a dose of 13-15 mg/kg is the widely approved therapy which can improve the prognosis of patients with PBC. However, one-third of patients does not respond to UDCA therapy and may require liver transplantation. Every effort to diagnose PBC in earlier stage and to develop new therapeutic drugs and clinical trials should be made

Critical shortfalls in the management of PBC:Results of a UK-wide, population-based evaluation of care delivery

BACKGROUND &amp; AIMS: Guidelines for the management of primary biliary cholangitis (PBC) were published by the British Society of Gastroenterology in 2018. In this study, we assessed adherence to these guidelines in the UK National Health Service (NHS).METHODS: All NHS acute trusts were invited to contribute data between 1 January 2021 and 31 March 2022, assessing clinical care delivered to patients with PBC in the UK.RESULTS: We obtained data for 8,968 patients with PBC and identified substantial gaps in care across all guideline domains. Ursodeoxycholic acid (UDCA) was used as first-line treatment in 88% of patients (n = 7,864) but was under-dosed in one-third (n = 1,964). Twenty percent of patients who were UDCA-untreated (202/998) and 50% of patients with inadequate UDCA response (1,074/2,102) received second-line treatment. More than one-third of patients were not assessed for fatigue (43%; n = 3,885) or pruritus (38%; n = 3,415) in the previous 2 years. Fifty percent of all patients with evidence of hepatic decompensation were discussed with a liver transplant centre (222/443). Appropriate use of second-line treatment and referral for liver transplantation was significantly better in specialist PBC treatment centres compared with non-specialist centres (p &lt;0.001).CONCLUSIONS: Poor adherence to guidelines exists across all domains of PBC care in the NHS. Although specialist PBC treatment centres had greater adherence to guidelines, no single centre met all quality standards. Nationwide improvement in the delivery of PBC-related healthcare is required.IMPACT AND IMPLICATIONS: This population-based evaluation of primary biliary cholangitis, spanning four nations of the UK, highlights critical shortfalls in care delivery when measured across all guideline domains. These include the use of liver biopsy in diagnosis; referral practice for second-line treatment and/or liver transplant assessment; and the evaluation of symptoms, extrahepatic manifestations, and complications of cirrhosis. The authors therefore propose implementation of a dedicated primary biliary cholangitis care bundle that aims to minimise heterogeneity in clinical practice and maximise adherence to key guideline standards.</p