Feasibility Assessment of an Indirect Treatment Comparison of Seladelpar vs. Elafibranor in Patients With Primary Biliary Cholangitis
Author(s)
David E. Jones, MD1, Robert G. Gish, MD2, Gideon M. Hirschfield, FRCP, PhD3, Cynthia Levy, MD4, Howard Thom, MSc, PhD5, Gianluca Baio, PhD6, Marvin Rock, DrPH, MPH7, Chong H Kim, MPH, MS, PhD7, Mirko von Hein, MSc8, Ryan Thaliffdeen, PharmD, MS7, Oskar Eklund, MSc9, Barinder Singh, RPh10, Akanksha Sharma, MSc10, Dilip Makhija, MS7.
1Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle Upon Tyne, United Kingdom, 2Robert G. Gish Consultants, LLC, San Diego, CA, USA and Hepatitis B Foundation, Doylestown, PA, USA, 3Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada, 4University of Miami Miller School of Medicine, Miami, FL, USA, 5Bristol Medical School, University of Bristol, Bristol, United Kingdom, 6University College London, London, United Kingdom, 7Gilead Sciences, Inc., Foster City, CA, USA, 8Gilead Sciences, London, United Kingdom, 9Gilead Sciences AB, Solna, Sweden, 10Pharmacoevidence, Mohali, India.
1Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle Upon Tyne, United Kingdom, 2Robert G. Gish Consultants, LLC, San Diego, CA, USA and Hepatitis B Foundation, Doylestown, PA, USA, 3Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada, 4University of Miami Miller School of Medicine, Miami, FL, USA, 5Bristol Medical School, University of Bristol, Bristol, United Kingdom, 6University College London, London, United Kingdom, 7Gilead Sciences, Inc., Foster City, CA, USA, 8Gilead Sciences, London, United Kingdom, 9Gilead Sciences AB, Solna, Sweden, 10Pharmacoevidence, Mohali, India.
OBJECTIVES: Seladelpar and Elafibranor are two recently approved novel therapies for the second-line treatment of primary biliary cholangitis (PBC). In the absence of direct head-to-head comparisons, this study aims to evaluate the feasibility of conducting an indirect treatment comparison (ITC) using Bayesian network meta-analysis (NMA), or population-adjusted methods, such as matching-adjusted indirect comparisons (MAIC), to assess their relative efficacy and safety.
METHODS: A systematic literature review (SLR) was conducted to identify randomized controlled trials (RCTs) assessing seladelpar and elafibranor in PBC. The validity of ITC relies on the transitivity assumption, which requires similarity of RCT designs and balance in baseline effect modifiers, as outlined in NICE Technical Support Document 2 and 18. Following the construction of network geometry, a feasibility assessment was conducted to evaluate heterogeneity in RCT design, outcome definitions, population characteristics, and placebo response. Treatment effect modifiers compared between RCTs at baseline included age, alkaline phosphatase (ALP) levels, bilirubin levels, and the percentage of patients with cirrhosis.
RESULTS: The SLR identified two RCTs, RESPONSE and ELATIVE, which evaluated the efficacy and safety of seladelpar and elafibranor at 52 weeks. RESPONSE and ELATIVE exhibited differences in effect modifiers, including baseline bilirubin (12.9 vs. 9.6 μmol/liter, respectively) and the proportion of patients with cirrhosis. Additionally, the designs differed in the cut-off values for the upper limit of normal (ULN) for ALP and bilirubin. Placebo effects varied significantly for the composite primary endpoint (ALP<1.67xULN, >=15% decrease from baseline, and bilirubin <ULN), with the ELATIVE’s placebo showing the lowest composite response rate (3.8%) compared to other large Phase 3 trials (RESPONSE: 20%; POISE: 9.6%), complicating ITC for this outcome.
CONCLUSIONS: The observed heterogeneity in effect modifiers and RCT designs suggests a potential violation of the transitivity assumption, rendering conventional NMA unsuitable. In such cases, population-adjusted ITC, like MAIC, provides a more appropriate approach for robust comparisons.
METHODS: A systematic literature review (SLR) was conducted to identify randomized controlled trials (RCTs) assessing seladelpar and elafibranor in PBC. The validity of ITC relies on the transitivity assumption, which requires similarity of RCT designs and balance in baseline effect modifiers, as outlined in NICE Technical Support Document 2 and 18. Following the construction of network geometry, a feasibility assessment was conducted to evaluate heterogeneity in RCT design, outcome definitions, population characteristics, and placebo response. Treatment effect modifiers compared between RCTs at baseline included age, alkaline phosphatase (ALP) levels, bilirubin levels, and the percentage of patients with cirrhosis.
RESULTS: The SLR identified two RCTs, RESPONSE and ELATIVE, which evaluated the efficacy and safety of seladelpar and elafibranor at 52 weeks. RESPONSE and ELATIVE exhibited differences in effect modifiers, including baseline bilirubin (12.9 vs. 9.6 μmol/liter, respectively) and the proportion of patients with cirrhosis. Additionally, the designs differed in the cut-off values for the upper limit of normal (ULN) for ALP and bilirubin. Placebo effects varied significantly for the composite primary endpoint (ALP<1.67xULN, >=15% decrease from baseline, and bilirubin <ULN), with the ELATIVE’s placebo showing the lowest composite response rate (3.8%) compared to other large Phase 3 trials (RESPONSE: 20%; POISE: 9.6%), complicating ITC for this outcome.
CONCLUSIONS: The observed heterogeneity in effect modifiers and RCT designs suggests a potential violation of the transitivity assumption, rendering conventional NMA unsuitable. In such cases, population-adjusted ITC, like MAIC, provides a more appropriate approach for robust comparisons.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
MSR108
Topic
Clinical Outcomes, Methodological & Statistical Research, Study Approaches
Disease
Rare & Orphan Diseases, Systemic Disorders/Conditions (Anesthesia, Auto-Immune Disorders (n.e.c.), Hematological Disorders (non-oncologic), Pain)