Investigating Composite Response Definitions Based on Key Surrogate Markers for Predicting Clinical Outcomes in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis
Author(s)
Dilip Makhija, MS1, Marvin Rock, MPH, DrPH1, Chong H Kim, MPH, MS, PhD1, Mirko von Hein, M.Sc.2, Ryan Thaliffdeen, BS, MS, PharmD1, Oskar Eklund, MSc3, Pankaj Rai, MS4, Ritesh Dubey, PharmD4, Howard Thom, MSc, PhD5, Gianluca Baio, PhD6, Barinder Singh, RPh4.
1Gilead Sciences, Inc., Foster City, CA, USA, 2Gilead Sciences, London, United Kingdom, 3Gilead Sciences AB, Solna, Sweden, 4Pharmacoevidence, Mohali, India, 5University of Bristol, Bristol, United Kingdom, 6University College London, London, United Kingdom.
1Gilead Sciences, Inc., Foster City, CA, USA, 2Gilead Sciences, London, United Kingdom, 3Gilead Sciences AB, Solna, Sweden, 4Pharmacoevidence, Mohali, India, 5University of Bristol, Bristol, United Kingdom, 6University College London, London, United Kingdom.
Presentation Documents
OBJECTIVES: Primary biliary cholangitis (PBC) is a rare, chronic autoimmune liver disease with slow progression, making it challenging to assess long-term clinical outcomes like liver transplantation (LT) and death. Our previous systematic literature review (SLR) demonstrated a significant association between alkaline phosphatase (ALP), ALP normalization, and improved long-term clinical outcomes in PBC. This follow-up SLR further evaluates the association between composite response-based surrogate endpoints incorporating ALP, total bilirubin, or other liver parameters on long-term clinical outcomes in PBC.
METHODS: A comprehensive search of Embase®, PubMed®, and Cochrane was conducted from inception to September 2024 following PRISMA guidelines. Meta-analysis was performed using Stata 17 software.
RESULTS: Overall, 28 studies reporting an association between composite response defined by key biomarkers and clinical outcomes were included. Death and LT were the most frequently reported clinical endpoints (n=15). Commonly applied composite response criteria included Paris I (ALP ≤3×ULN, AST ≤2×ULN and normal bilirubin; n=22), Paris II (ALP and AST ≤1.5×ULN and normal bilirubin; n=15), and Rotterdam (bilirubin ≤ 1×ULN and/or albumin ≥LLN; n=13) with some studies using Rochester (n=3) and POISE (n=2) criteria. Patients not achieving response had a significantly increased risk of LT or death compared to responders (Hazard ratio: 5.06, 95%CI: 3.69-6.95). Notably, the two most recent studies that used POISE criteria (defined as ALP <1.67×ULN, ≥15% ALP reduction, and bilirubin ≤1×ULN) found significantly worse clinical outcomes for non-responders compared to responders.
CONCLUSIONS: Key disease markers of ALP and total bilirubin show a strong association with long-term clinical outcomes in PBC when incorporated into composite response definitions. This aligns with our previous evidence that links ALP decline to improved clinical outcomes, such as LT and death. These findings support their use in guiding treatment decisions, evaluating therapeutic efficacy, and reinforcing the value of biomarker-driven strategies in PBC management and reducing patient burden.
METHODS: A comprehensive search of Embase®, PubMed®, and Cochrane was conducted from inception to September 2024 following PRISMA guidelines. Meta-analysis was performed using Stata 17 software.
RESULTS: Overall, 28 studies reporting an association between composite response defined by key biomarkers and clinical outcomes were included. Death and LT were the most frequently reported clinical endpoints (n=15). Commonly applied composite response criteria included Paris I (ALP ≤3×ULN, AST ≤2×ULN and normal bilirubin; n=22), Paris II (ALP and AST ≤1.5×ULN and normal bilirubin; n=15), and Rotterdam (bilirubin ≤ 1×ULN and/or albumin ≥LLN; n=13) with some studies using Rochester (n=3) and POISE (n=2) criteria. Patients not achieving response had a significantly increased risk of LT or death compared to responders (Hazard ratio: 5.06, 95%CI: 3.69-6.95). Notably, the two most recent studies that used POISE criteria (defined as ALP <1.67×ULN, ≥15% ALP reduction, and bilirubin ≤1×ULN) found significantly worse clinical outcomes for non-responders compared to responders.
CONCLUSIONS: Key disease markers of ALP and total bilirubin show a strong association with long-term clinical outcomes in PBC when incorporated into composite response definitions. This aligns with our previous evidence that links ALP decline to improved clinical outcomes, such as LT and death. These findings support their use in guiding treatment decisions, evaluating therapeutic efficacy, and reinforcing the value of biomarker-driven strategies in PBC management and reducing patient burden.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
CO156
Topic
Clinical Outcomes
Topic Subcategory
Relating Intermediate to Long-term Outcomes
Disease
Rare & Orphan Diseases, Systemic Disorders/Conditions (Anesthesia, Auto-Immune Disorders (n.e.c.), Hematological Disorders (non-oncologic), Pain)