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.