P721 The biological and clinical relevance of anti-metalloproteinase-9 antibody (GS-5745) in treatment of ulcerative colitis patients
B. R. Bhandari1, S. Lee2, X. Zhao*3, E. Huntzicker3, X. Guo3, Z. Jiang3, D. Ge3, D. French3, M. Subramanian3, J.G. McHutchison3, B. Kanwar3, B. Levesque4, W. Sandborn4, 5
1Delta Research Partners, LLC, Monroe, Louisiana, United States, 2University of Washington, Seattle, Washington, United States, 3Gilead Sciences, Inc., Foster City, California, United States, 4University of Western Ontario, Robarts Clinical Trials, London, Ontario, Canada, 5University of California, San Diego, California, United States
GS-5745 is a humanised monoclonal antibody specific to the protein MMP9, a matrix metalloproteinase thought to promote pathological effects of ulcerative colitis (UC) through destructive remodelling of basement membranes at sites of colonic mucosal inflammation. We studied the expression status of MMP9 and genes co-regulated in UC patients treated with GS-5745 to explore the biology of its potential efficacy.
Paired colon biopsy tissue samples were collected at baseline (before treatment) and at day 36 (post-treatment) from 32 patients (treatment arm n = 26; placebo arm n = 6) with moderately to severely active UC enrolled in a Phase 1 clinical study (GS-US-326–0101). MMP9 protein expression was evaluated by immunohistochemistry (IHC) to determine a histology score (H-score) that quantified intensity and percent surface area staining. Tissue samples were subjected to RNA-sequencing to measure mRNA expression across the entire transcriptome. Genes differentially expressed after treatment were identified by Generalised Linear Models.
In the treatment group, MMP9 H-score was significantly decreased at day 36 compared with baseline (p = 0.016 vs p = 0.688 for placebo; Wilcoxon; Figure 1A). This reduction was significantly more pronounced in the remission group compared with non-remission group (p = 0.03; Mann–Whitney U). We observed greater reduction in MMP9 mRNA expression at day 36 in the treatment group than placebo (Figure 1B). At baseline, TNFRSF6B mRNA expression had the strongest correlation with MMP9 H-score (r = 0.58, p = 0.0006; Spearman; Figure 1C) across the transcriptome. The baseline expression of HLA-G had the strongest correlation with MMP9 H-score reduction after treatment (r = 0.52, p = 0.002; Spearman; Figure 1D). The top differentially expressed genes per treatment were enriched for IBD pathogenesis-related genes.
Treatment with GS-5745 leads to reduction of MMP9 expression at both mRNA and protein level in UC patients, which is associated with clinical remission. The strong positive correlation between TNFRSF6B and MMP9 protein expression at baseline suggests that a potential crosstalk between MMP9 and TNF signalling underlies the pathophysiology of UC. The strong positive correlation between baseline HLA-G expression with reduction in MMP9 protein further supports that GS-5745 modulates the microenvironment of UC patients through immune regulation. Treatment also leads to perturbations in the transcriptome that underpins IBD pathogenesis. The data support the therapeutic potential and biologic relevance of MMP9 inhibition for treatment of UC.
- Posted in: Poster presentations: Genetics (2016)