Inflammatory Bowel Diseases | August 24, 2021

Hassan-Zahraee M, Ye Z, Xi L, Baniecki ML, Li X, Hyde CL, Zhang J, Raha N, Karlsson F, Quan J, Ziemek D, Neelakantan S, Lepsy C, Allegretti JR, Romatowski J, Scherl EJ, Klopocka M, Danese S, Chandra DE, Schoenbeck U, Vincent MS, Longman R and Hung KE

Inflamm Bowel Dis. 2021

https://doi.org/10.1093/ibd/izab193

This study was performed using Simoa Homebrew assay(s).

Abstract

Background

The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known.

Methods

Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis.

Results

Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy.

Conclusions

The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.