An anti-IL-13 antibody reverses epithelial-mesenchymal transition biomarkers in eosinophilic esophagitis: Phase 2 trial results.

BACKGROUND: Fibrostenosis, the most serious eosinophilic esophagitis (EoE) complication, is mediated by epithelial-mesenchymal transition (EMT). Transitioned cells contribute to pathogenesis by overproducing extracellular matrix. OBJECTIVE: Our aim was to determine whether RPC4046 (anti‒IL-13 mAb) modulates EMT biomarkers in biopsy samples from adults with active EoE in a substudy of a double-blind, placebo-controlled phase 2 trial. METHODS: Baseline and week 16 esophageal biopsy samples were taken from 69 patients who were randomized to weekly treatment with subcutaneous RPC4046, 180 mg (n = 19), 360 mg (n = 26), or placebo (n = 24). Duplex immunofluorescence slides stained for E-cadherin and vimentin were digitally analyzed by mapping each epithelial cell and recording fluorescence intensities. End points included change from baseline to week 16 in percentage of vimentin-positive epithelial cells (primary), total E-cadherin expression, and vimentin-to-E-cadherin ratio per cell (an average of 47,000 cells per biopsy sample analyzed). RESULTS: The mean percentage of vimentin-positive cells decreased by 0.94%, 2.75%, and 4.24% in the placebo, low-dose, and high-dose groups, respectively (P =.032 for the high-dose vs placebo group). Mean E-cadherin expression per cell increased 5.6-fold in both dose groups versus in the placebo group (high-dose group P = .047). The increases in E-cadherin expression per cell from baseline to week 16 were correlated with improvements in histology, eosinophil counts, endoscopic findings, and symptoms. CONCLUSION: RPC4046 significantly reduced EMT markers in adults with active EoE, with greater effects at 360 mg. Together with results for eosinophil density and clinical end points from the main trial, these data support the hypothesis that pharmacologic IL-13 inhibition ameliorates both inflammatory and remodeling pathways and could potentially reduce the risk of fibrostenotic complications.

Inference of equivalence for the ratio of two normal means with unspecified variances.

Equivalence trials aim to demonstrate that new and standard treatments are equivalent within predefined clinically relevant limits. We focus on when inference of equivalence is made in terms of the ratio of two normal means. In the presence of unspecified variances, methods such as the likelihood-ratio test use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit the knowledge on the extent to which equivalence is affected by variability of the parameter of interest. In this article, we propose a likelihood approach that retains the unspecified variances in the model and partitions the likelihood function into two components: F-statistic function for variances, and t-statistic function for the ratio of two means. By incorporating unspecified variances, the proposed method can help identify a numeric range of variances where equivalence is more likely to be achieved, which cannot be accomplished by current analysis methods. By partitioning the likelihood function into two components, the proposed method provides more inference information than a method that relies solely on one component. Using a published set of real example data, we show that the proposed method produces the same results as the likelihood-ratio test and is comparable to Bayesian analysis in the general case. In a special case where the ratio of two variances is directly proportional to the ratio of two means, the proposed method yields better results in inference about equivalence than either the likelihood-ratio test or the Bayesian method. Using a published set of real example data, the proposed likelihood method is shown to be a better alternative than current analysis methods for equivalence inference.