S1549 Baseline Characteristics and Risk Profiles of 1111 Patients with Primary Biliary Cholangitis (PBC) in Need of Second-Line Therapy

Introduction: Ursodexoxycholic acid (UDCA) is the first-line treatment for primary biliary cholangitis (PBC). Up to 40% of patients receiving UDCA have an alkaline phosphatase (ALP) ≥ 1.67×ULN and are usually considered for second-line therapy to prevent progression. Cohort studies confirm that targeting normal ALP and bilirubin are better treatment goals. We examined patients who screen failed due to elevated ALP < 1.67xULN to further characterize this population, including presence of additional risk factors for progression. Methods: In 4 clinical trials with seladelpar from 2015 – 2022, 1111 patients with PBC were screened at 197 clinical sites in 27 countries after treatment with UDCA for ≥12 months, or intolerance to UDCA. ALP levels of ≥ 1.67×ULN were required for enrollment. We compared the baseline characteristics and risk profiles of patients enrolled (ALP ≥ 1.67×ULN) to those who screen failed due to ALP³ ULN, but < 1.67×ULN. We stratified using proportions with Enhanced Liver Fibrosis (ELF) values ≥ 10.0 or bilirubin levels > 0.6×ULN. The relationship of ELF and liver stiffness assessed with FibroScan® was confirmed when available. Results: The 1111 screened patients were predominantly female (94%) with a mean (SD) age of 57±9.5 years. Studies enrolled 54% of screened patients (n=603) (EN cohort) with a duration of PBC of 8±6.5 years and on a UDCA dose of 15±3.9 mg/kg/day (92% were on UDCA). Overall, 26% of patients (n=284) screen failed due to ALP > ULN, but < 1.67×ULN (SF Cohort). The most common reasons for screen failure in the remaining 20% of patients were ALT and AST >3xULN, ALP< 1xULN, and EGFR < 60. Meaningful differences in baseline values in the EN and SF cohorts were in ALP, GGT and ALT. Higher-risk bilirubin levels were present in 51.1% and 42.0% of EN and SF cohorts, respectively. Elevated risk based on ELF was identified in 43.2% of the EN and 27.2% of the SF cohorts. Liver stiffness was assessed in 66% of EN patients, and a mean liver stiffness of 9.7 kPa correlated with ELF (r = 0.50, P < 0.001). Conclusion: We found that in this large international cohort of UDCA treated PBC patients, clinical risk factors for disease progression were common in patients achieving ALP levels > ULN, but < 1.67×ULN. Consideration should be given to including this population in clinical research of second-line therapies with a goal of normalization of ALP (Figure 1).Figure 1.: Baseline characteristics.

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