OP010. AlphaE integrin expression as a predictive biomarker for induction of clinical remission by etrolizumab: Analysis of a phase II trial in moderate-to-severely active ulcerative colitis
M. Keir1, G.W. Tew1, D. Luca1, J. Eastham-Anderson1, L. Diehl1, J.G. Egen1, S. Vermeire2, J.C. Mansfield3, C.A. Lamb3, J. Panes4, D.C. Baumgart5, S. Schreiber6, I. Dotan7, W.J. Sandborn8, G. De Hertogh2, J.A. Kirby3, G. Van Assche2, P. Rutgeerts2, S. O'Byrne1, 1Genentech, Research and Early Development, South San Francisco, United States, 2KU Leuven, Division of Gastroenterology, Leuven, Belgium, 3Royal Victoria Infirmary, Gastroenterology, Newcastle upon Tyne, United Kingdom, 4Hospital Clínic Barcelona, Gastroenterology, Barcelona, Spain, 5Humboldt-University of Berlin, Charite Medical School, Berlin, Germany, 6Christian Albrechts University, Institute of Clinical Molecular Biology, Kiel, Germany, 7Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel, 8University of California, San Diego, Gastroenterology, San Diego, United States
Etrolizumab is a humanized monoclonal antibody to the beta7 integrin subunit that blocks alpha4beta7:MAdCAM-1 and alphaEbeta7:E-cadherin interactions and has been shown to be effective at inducing remission in patients with moderate to severely active ulcerative colitis (UC).
Patients enrolled in the Phase 2 study of etrolizumab in UC were assessed for baseline biopsy gene expression of MAdCAM1, alphaE and alpha4 integrin by qPCR (n = 106) as well as baseline alphaE+ cells per total cells in biopsies from the inflamed colon by immunohistochemistry (n = 76). Enrichment of baseline measures was evaluated using the primary outcome measure of the study, remission at week 10, defined as a total MCS of ≤2 with no individual subscore >1.
AlphaE gene expression and alphaE+ cells were log-normally distributed in baseline biopsies from UC patients. No difference in baseline characteristics was observed between alphaE high and alphaE low groups. Enrichment in response to treatment with 100 mg/dose etrolizumab as measured by remission was observed in patients with higher than median levels of alphaE gene expression at screening (38% alphaE high vs. 13% alphaE low). No enrichment was observed in alpha4 high patients (27% alpha4 high vs. 24% alpha4 low) or MAdCAM1 high patients (27% MAdCAM1 high vs. 24% MAdCAM1 low). Enrichment in response to treatment as measured by remission was observed in TNF antagonist naïve patients with high levels of alphaE gene expression at screening (67% alphaE high vs. 17% alphaE low). Similarly, enrichment of remission in response to treatment was observed in patients with higher than median levels of alphaE+ cells per total cells (50% alphaE high vs. 7% alphaE low). TNF antagonist naïve patients with high levels of alphaE+ cells per total cells at screening had enriched response to treatment with etrolizumab as measured by remission (67% alphaE high vs. 25% alphaE low).
These results suggest that higher than median levels of alphaE gene expression and/or alphaE+ cells per total cells in the inflamed colon are associated with increased clinical benefit of etrolizumab treatment in patients. Thus alphaE gene expression or alphaE+ cells in colonic biopsies may be predictive biomarkers to identify UC patients most likely to benefit from etrolizumab treatment.