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Background Ulcerative colitis (UC) is characterized by the loss of epithelial barrier function and chronic mucosal inflammation. GB004 is an oral, gut-targeted, small molecule stabilizer of hypoxia inducible factor (HIF-1α) that promotes epithelial repair and function. A phase 1b study was conducted in patients with active UC where trends in clinical efficacy favoring GB004 were observed. Here we report the target engagement (TE) and pharmacodynamic (PD) biomarker analysis of colon biopsies and stool samples from the phase 1b study. Methods Subjects with active UC despite 5-ASA treatment were randomized 2:1 to GB004 120 mg solution or placebo (PBO) once daily for 28 days. Colon biopsies (sigmoid and rectum) and stool samples were collected at baseline and Day 28. HIF-1a and myeloperoxidase (MPO) immunohistochemistry was performed on formalin-fixed paraffin-embedded colon biopsies. Gene expression profiling (Affymetrix HTA 2.0) was performed on mRNA extracted from colon biopsies. Fecal calprotectin (FC) and secretory IgA (sIgA) were measured from stool samples. Results presented are overall means for baseline characteristics and differences in mean (HIF-1a, MPO) and median (FC, sIgA) percent change from baseline to Day 28 for GB004 vs PBO. Results Thirty-four subjects (age 45.4 years, Mayo score 7.5, sigmoid colon Mayo endoscopic subscore 2.2, sigmoid colon Robarts Histopathology Index 14.1) were randomized to a GB004 120 mg solution (n=23) or PBO (n=11) group. GB004 demonstrated evidence of TE, with an increase in the percent of HIF-1α positive cells (+11.4%) in sigmoid colon segment sections. Tissue and stool-based PD biomarkers of intestinal inflammation associated with lamina propria neutrophil infiltration and cytotoxicity measured by the MPO+ cell count per mm2 (-7.3%) and FC (-30.4%) levels decreased. Lastly, GB004 resulted in an increase in sIgA levels (+87.16%) and transcriptional changes consistent with enhanced epithelial integrity, such as increases in ITGA6 and TJP1. Conclusion In this phase 1b study, GB004, an oral gut-targeted HIF-1α stabilizer, demonstrated TE in the sigmoid colon and histologic, fecal biomarker, and transcriptional PD effects consistent with a reduction in inflammation and mucosal healing. These observations are consistent with the role of HIF-1α stabilization in improving barrier function in UC patients and support the trends in clinical effects observed, including histologic endpoints. A Phase 2 study of GB004 in patients with mild-to-moderate UC (SHIFT-UC, NCT04556383) is currently ongoing. Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.

journal of crohn's and colitis

DOP05 Target engagement and pharmacodynamic biomarker analysis following treatment with the oral gut-targeted HIF-1α stabilizer GB004 in a Phase 1b trial in Active Ulcerative Colitis