P28 Seladelpar treatment of patients with primary biliary cholangitis improves the GLOBE score and predicts improved transplant-free survival

<h3></h3> The GLOBE score is a validated risk-assessment tool used to estimate transplant-free survival (TFS) in patients with primary biliary cholangitis (PBC). Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated in the UK for PBC treatment including pruritus combined with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients intolerant to UDCA. This analysis evaluated the change in GLOBE score in patients with PBC on seladelpar from the placebo-controlled Phase 3 RESPONSE (NCT04620733) trial and its open-label extension (ASSURE; NCT03301506). Patients with PBC who received UDCA for ≥12 months (M) or were intolerant to UDCA, and had alkaline phosphatase (ALP) ≥1.67 × the upper limit of normal (ULN) and total bilirubin (TB) ≤2 × ULN were enrolled into RESPONSE and randomised 2:1 to daily seladelpar 10 mg or placebo. After 1 year (Y), patients were eligible for ASSURE, where patients on placebo could switch to seladelpar (crossover) and patients on seladelpar continued treatment (continuous). Change in GLOBE score, predicted TFS, and the contributions of ALP, TB, albumin, and platelets to changes in GLOBE score were evaluated. 193 patients were enrolled. Baseline characteristics were balanced between groups; 95% were female; mean (SD) age and duration of PBC were 57 (9.7) and 8 (6.6) years. Mean (SD) baseline values were 314 (120.9) U/L for ALP, 0.76 (0.31) mg/dL for TB, 4.1 (0.26) g/dL for albumin, 242 (80.6) × 103/uL for platelets, and 0.32 (0.68) for GLOBE score. Mean (SD) changes in baseline GLOBE score at 3M and 1Y for seladelpar were −0.38 (0.21) and −0.34 (0.39) vs −0.07 (0.28) and −0.01 (0.32) for placebo. At 2Y, GLOBE score changes were −0.39 (0.33) and −0.42 (0.50) for continuous or crossover seladelpar. For seladelpar, the greatest changes in GLOBE score were attributable to the ALP component (3M, −0.20; 1Y, −0.21; 2Y, −0.19), followed by the TB component (3M, −0.11; 1Y, −0.09; 2Y, −0.13). Seladelpar treatment for 3M, 1Y, and 2Y led to predicted changes in TFS with hazard ratios (HR; [95% CIs]) of 0.7 (0.7–0.7), 0.8 (0.7–0.9), and 0.7 (0.6–0.8) compared with baseline. HR (95% CIs) for placebo at 3M and 1Y were 1.0 (0.9–1.0) and 1.0 (1.0–1.1). At 2Y, crossover seladelpar had similar results to continuous seladelpar. Seladelpar resulted in an early decrease in GLOBE score for patients with PBC, which was maintained over 2Y and associated with improved predicted TFS.