P1754 - Effect of Obeticholic Acid on Reduction and Normalization of Alanine Aminotransferase and Aspartate Aminotransferase in the Phase 3 POISE Trial in Primary Biliary Cholangitis

Robert G. Gish, MD¹, Darren Wheeler, PhD², Jing Li, PhD², Christopher Gasink, MD², David W. Victor, MD^3
1Robert G. Gish Consultants, LLC, San Diego, CA; ²Intercept Pharmaceuticals, Inc., Morristown, NJ; ³Houston Methodist Hospital, Houston, TX

Introduction: Obeticholic acid (OCA) received accelerated approval for primary biliary cholangitis (PBC) based on improvements in alkaline phosphatase (ALP) and total bilirubin levels in the phase 3 POISE study. Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are linked to an increased risk of negative outcomes in patients with PBC. We evaluated the effect of OCA on ALT and AST, including the proportion of patients normalizing these levels (ALT ≤ 41 U/L and AST ≤ 34 U/L) from abnormal baseline (BL) values.

Methods: In POISE, PBC patients with inadequate response or intolerance to ursodeoxycholic acid were randomized 1:1:1 to receive placebo (PBO), OCA titration (OCA 5 mg with option to titrate to 10 mg at month 6), or OCA 10 mg for 12 months. The Cochran–Mantel–Haenszel method was used to assess the association between OCA treatment and ALT or AST normalization among patients with elevated BL levels.

Results: In the intention-to-treat (ITT) population, mean BL ALT values were 56.0 U/L for PBO, 61.6 U/L for OCA titration, and 56.3 U/L for OCA 10 mg. Baseline AST levels were 48.8, 52.3, and 50.5 U/L for PBO, OCA titration, and OCA 10 mg, respectively. Among patients with ALT > 41 U/L at BL (61%), 16% (7/45) on PBO normalized at month 6 vs 55% (26/47) on OCA 5 mg and 53% (21/40) on OCA 10 mg (p ≤ 0.001 for both; Fig. 1A). By 2 weeks, 3 to 4 times more patients in both OCA groups normalized ALT (both p< 0.01 vs PBO). Among patients with AST > 34 U/L at BL (71%), normalization rates at month 6 were 12% (6/51) on PBO, 30% (16/53) on OCA 5 mg, and 31% (15/49) on OCA 10 mg (p < 0.05 for both; Fig. 1B). The proportions of patients normalizing ALT and AST on OCA were similar at month 12. In the ITT population, ALT and AST reductions were significant for both OCA groups vs PBO at all visits (all p < 0.001) as early as week 2. Least-squares mean changes from BL for ALT were −6.6 U/L (PBO), −18.9 U/L (OCA 5 mg), and −22.0 U/L (OCA 10 mg), and −3.8 U/L, −10.6 U/L, and −12.2 U/L for AST, respectively.

Discussion: OCA significantly reduced ALT and AST as early as week 2 in both OCA treatment groups. By month 6, ALT normalized in > 50% and AST in nearly 33% of patients with elevated BL levels. These data suggest that OCA meaningfully reduces ALT and AST to levels indicative of improved clinical outcomes. Further research is needed to understand how measuring ALT and AST levels can enhance the assessment of PBC treatment response and minimize the risk of disease progression.



Disclosures:


Robert G. Gish, MD¹, Darren Wheeler, PhD², Jing Li, PhD², Christopher Gasink, MD², David W. Victor, MD³. P1754 - Effect of Obeticholic Acid on Reduction and Normalization of Alanine Aminotransferase and Aspartate Aminotransferase in the Phase 3 POISE Trial in Primary Biliary Cholangitis, ACG 2024 Annual Scientific Meeting Abstracts. Philadelphia, PA: American College of Gastroenterology.