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
