Molecular Profiling of Ulcerative Colitis Subjects from the TURANDOT Trial Reveals Novel Pharmacodynamic/Efficacy Biomarkers
Huanyu Zhou, Li Xi, Daniel Ziemek, Shawn O'Neil, Julie Lee, Zachary Stewart, Yutian Zhan, Shanrong Zhao, Ying Zhang, Karen Page, Austin Huang, Mateusz Maciejewski, Baohong Zhang, Kenneth J Gorelick, Lori Fitz, Vivek Pradhan, Fabio Cataldi, Michael Vincent, David Von Schack, Kenneth Hung, Mina Hassan-Zahraee, Huanyu Zhou, Li Xi, Daniel Ziemek, Shawn O'Neil, Julie Lee, Zachary Stewart, Yutian Zhan, Shanrong Zhao, Ying Zhang, Karen Page, Austin Huang, Mateusz Maciejewski, Baohong Zhang, Kenneth J Gorelick, Lori Fitz, Vivek Pradhan, Fabio Cataldi, Michael Vincent, David Von Schack, Kenneth Hung, Mina Hassan-Zahraee
Abstract
Background and aims: To define pharmacodynamic and efficacy biomarkers in ulcerative colitis [UC] patients treated with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody, in the TURANDOT study.
Methods: Transcriptome, proteome and immunohistochemistry data were generated in peripheral blood and intestinal biopsies from 357 subjects in the TURANDOT study.
Results: In peripheral blood, C-C motif chemokine receptor 9 [CCR9] gene expression demonstrated a dose-dependent increase relative to placebo, but in inflamed intestinal biopsies CCR9 gene expression decreased with increasing PF-00547659 dose. Statistical models incorporating the full RNA transcriptome in inflamed intestinal biopsies showed significant ability to assess response and remission status. Oncostatin M [OSM] gene expression in inflamed intestinal biopsies demonstrated significant associations with, and good accuracy for, efficacy, and this observation was confirmed in independent published studies in which UC patients were treated with infliximab or vedolizumab. Compared with the placebo group, intestinal T-regulatory cells demonstrated a significant increase in the intermediate 22.5-mg dose cohort, but not in the 225-mg cohort.
Conclusions: CCR9 and OSM are implicated as novel pharmacodynamic and efficacy biomarkers. These findings occur amid coordinated transcriptional changes that enable the definition of surrogate efficacy biomarkers based on inflamed biopsy or blood transcriptomics data.ClinicalTrials.gov identifierNCT01620255.
Keywords: MAdCAM-1; PF-00547659; Ulcerative colitis; biomarkers; inflammatory bowel disease.
© The Author(s) 2019. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.
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Source: PubMed