Journal Article

Latent Variable Indirect Response Modeling of Cendakimab Exposure–Response for Longitudinal Dysphagia Days Using a Combined Uniform‐Binomial Likelihood Framework

Wojciechowski, Jessica, Shen, Jun, Zhang, Peijin, Kondic, Anna, Hu, Chuanpu, Du, Shengnan, Aras, Urvi, Murthy, Bindu

2026

Overview

To characterize the relationship between cendakimab exposure and the longitudinal efficacy endpoint dysphagia days (DD), E–R analyses were performed using data from the EE‐001 study (N = 427) with eosinophilic esophagitis. DD—a bounded, discrete endpoint assessed over 14‐day period via modified daily symptom diary (mDSD)—was modeled using a latent variable indirect response (IDR) model coupled with a combined uniform‐binomial (CUB) distribution. The latent variable, representing the underlying disease status, was dynamically modulated by placebo and drug effects (a function of individual‐predicted exposure) to govern the binomial probability of DD, while the uniform component captured the residual variability in patient‐reported outcomes. Inter‐individual variability was estimated for baseline DD, maximum placebo effect, and maximum drug effect. Covariates, including steroid inadequate response or intolerance (Steroid IR/I) status and baseline DD, were incorporated in the final model based on the clinical relevance. The estimated placebo half‐life was 28 weeks, estimated EC50 was 76.5 μg/mL, corresponding to an EC90 of 688 μg/mL, indicating steepness of the Emax curve. Model‐based simulations showed that both 360 mg QW and QW‐to‐Q2W regimens reduced DD compared to placebo at Week 48, with mean reductions of 1.65 and 1.36 days, respectively. Covariate‐stratified simulations suggested consistent responses across sex, age, and race. Steroid IR/I and baseline DD influenced treatment response magnitude but did not warrant dose modification. These findings support QW‐to‐Q2W as an effective maintenance posology and the utility of latent variable IDR models with appropriate likelihoods for modeling bounded, discrete longitudinal endpoints in E–R analyses. Study Highlights What is the current knowledge on the topic? ○Cendakimab is an anti–IL‐13 monoclonal antibody that has demonstrated dose‐dependent efficacy in reducing histologic and symptomatic burden in eosinophilic esophagitis (EoE). What question did this study address? ○This study evaluated the E–R relationship between cendakimab exposure and the longitudinal Dysphagia Days (DD) in EoE patients from the Phase 3 EE‐001 trial. Simulation supported QW‐to‐Q2W as an effective regimen, with comparable DD improvement to QW at Week 48 compared. What does this study add to our knowledge? ○A latent variable indirect response model with a combined uniform‐binomial likelihood was developed to characterize the bounded, discrete DD endpoints, offering a flexible and clinically interpretable framework for modeling endpoints like patient reported outcomes (PROs). How might this change drug discovery, development, and/or therapeutics? ○This model approach provides a robust framework for analyzing discrete, longitudinal PROs, supporting data‐driven dose selection and optimization in therapeutic areas where symptom‐based endpoints are pivotal.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Adult / Aged / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - pharmacokinetics / Antibodies, Monoclonal, Humanized - therapeutic use / Binomial distribution / cendakimab / Clinical trials / Deglutition Disorders - drug therapy / Diaries / Dose-Response Relationship, Drug / Double-Blind Method / Drug dosages / Dysphagia / Endoscopy / eosinophilic esophagitis / Eosinophilic Esophagitis - complications / Eosinophilic Esophagitis - drug therapy / Esophagus / exposure response / Female / Generalized linear models / Humans / latent variable indirect response modeling / Likelihood Functions / longitudinal / Longitudinal Studies / Male / Middle Aged / Parameter estimation / Steroids / Treatment Outcome