EVALUATING THE ASSOCIATION BETWEEN SURROGATE ENDPOINTS AND LIVER-RELATED 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, Ankita Sood, PharmD3, Ritesh Dubey, PharmD3, Barinder Singh, RPh3;
1Gilead Sciences, Inc., Foster City, CA, USA, 2Gilead Sciences, London, United Kingdom, 3Pharmacoevidence, Mohali, India
1Gilead Sciences, Inc., Foster City, CA, USA, 2Gilead Sciences, London, United Kingdom, 3Pharmacoevidence, Mohali, India
OBJECTIVES: Primary biliary cholangitis (PBC) is a rare, autoimmune cholestatic liver disease with slow progression, complicating direct measurement of long-term outcomes. The Food and Drug Administration has recognized a composite endpoint comprising of alkaline phosphatase (ALP) and total bilirubin for accelerated approval in PBC. This systematic literature review (SLR) evaluates evidence linking ALP and total bilirubin to long-term liver outcomes (liver transplant [LT], cirrhosis, hepatocellular carcinoma [HCC], hepatic decompensation/recompensation, progression, mortality).
METHODS: A comprehensive search of Embase® and PubMed® was conducted from database inception to September 2024, following PRISMA guidelines. Meta-analysis was performed using Stata 18.5 SE software.
RESULTS: Overall, 49 studies were included, reporting an association between ALP response or normalization versus outcomes: LT, HCC, hepatic decompensation/recompensation, progression, cirrhosis, and mortality. In most of the studies, patients were treated with ursodeoxycholic acid ± off-label fibrates. ALP was evaluated as an individual surrogate endpoint in 38 studies, whereas various composite response criteria were assessed in 28 studies. Response definitions varied: Barcelona (ALP reduction ≥40%), Toronto I (ALP ≤1.67×ULN), Toronto II (ALP ≤1.76×ULN), Paris I/II, POISE, Rochester, Rotterdam for composite endpoints. Patients not achieving response based on ALP-based criteria had a significantly increased risk of adverse liver outcomes compared to responders (pooled hazard ratio [HR]: 2.50, 95% CI 1.86-3.37). Composite response showed similar trends (HR: 4.82, 3.85-6.05).
CONCLUSIONS: The study findings demonstrate the prognostic value of ALP reduction and normalization in guiding clinical decisions and monitoring treatment efficacy, both as an individual marker and within composite response definitions. These results reinforce the use ALP and total bilirubin for guiding therapy, benchmarking efficacy, and informing payer models in PBC management.
METHODS: A comprehensive search of Embase® and PubMed® was conducted from database inception to September 2024, following PRISMA guidelines. Meta-analysis was performed using Stata 18.5 SE software.
RESULTS: Overall, 49 studies were included, reporting an association between ALP response or normalization versus outcomes: LT, HCC, hepatic decompensation/recompensation, progression, cirrhosis, and mortality. In most of the studies, patients were treated with ursodeoxycholic acid ± off-label fibrates. ALP was evaluated as an individual surrogate endpoint in 38 studies, whereas various composite response criteria were assessed in 28 studies. Response definitions varied: Barcelona (ALP reduction ≥40%), Toronto I (ALP ≤1.67×ULN), Toronto II (ALP ≤1.76×ULN), Paris I/II, POISE, Rochester, Rotterdam for composite endpoints. Patients not achieving response based on ALP-based criteria had a significantly increased risk of adverse liver outcomes compared to responders (pooled hazard ratio [HR]: 2.50, 95% CI 1.86-3.37). Composite response showed similar trends (HR: 4.82, 3.85-6.05).
CONCLUSIONS: The study findings demonstrate the prognostic value of ALP reduction and normalization in guiding clinical decisions and monitoring treatment efficacy, both as an individual marker and within composite response definitions. These results reinforce the use ALP and total bilirubin for guiding therapy, benchmarking efficacy, and informing payer models in PBC management.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
CO193
Topic
Clinical Outcomes
Topic Subcategory
Relating Intermediate to Long-term Outcomes
Disease
SDC: Rare & Orphan Diseases, SDC: Systemic Disorders/Conditions (Anesthesia, Auto-Immune Disorders (n.e.c.), Hematological Disorders (non-oncologic), Pain)