Randomised clinical trial: a phase 1b study of GB004, an oral HIF-1α stabiliser, for treatment of ulcerative colitis

Abstract

Background: Epithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut-targeted stabiliser of hypoxia-inducible factor-1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut.

Aims: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC.

Methods: This double-blind, placebo-controlled study randomised patients 2:1 to receive an oral solution of GB004 120 mg or placebo once daily for 28 days. Eligible patients had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score 3-12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool, despite treatment with 5-aminosalicylates, corticosteroids or immunosuppressants.

Results: Thirty-four patients were randomised. GB004 120 mg for 28 days was generally well-tolerated. Adverse events occurred in 27.3% (3/11) and 39.1% (9/23) of patients in the placebo and GB004 groups respectively. Nausea and dysgeusia were most commonly reported in the GB004 group (0% for placebo and 21.7% [5/23] and 13.0% [3/23] respectively for GB004). There were no treatment-related serious adverse events or deaths. GB004 exhibited minimal accumulation, with higher colonic concentrations relative to plasma. Exploratory pharmacodynamic and efficacy analyses demonstrated GB004 target engagement and numerically higher proportions of patients achieving improvement in multiple measures of disease activity, respectively, at day 28 for GB004 compared to placebo.

Conclusion: Results from this phase 1b trial support evaluation of the full therapeutic potential of GB004 for the treatment of UC. A phase 2 study (NCT04556383) is ongoing. Clinicaltrials.gov NCT03860896.

Keywords: HIF-1α; epithelial barrier dysfunction; histologic remission; mucosal healing.

© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Patient disposition

FIGURE 2

Changes from baseline to day 28 in pharmacodynamic measures of GB004 target engagement and biomarkers. (A) proportion of HIF‐1α‐positive cells; (B) faecal calprotectin; (C) proportion of MPO‐positive cells; (D) faecal secretory immunoglobulin A. Analyses were based on observed data. Treatment effect estimates (95% CIs) are shown as differences between GB004 and placebo. Abbreviations: HIF, hypoxia inducible factor; MPO, myeloperoxidase

FIGURE 3

Exploratory efficacy endpoints at day 28. (A) clinical response, rectal bleeding resolution, and clinical remission; (B) improvement in endoscopic appearance; histologic remission; and mucosal healing; (C) composite endpoints requiring concurrent achievement of: rectal bleeding resolution and histologic remission; rectal bleeding resolution, clinical response, and histologic remission; and rectal bleeding resolution, clinical response, histologic remission, and molecular improvement; (D) composite endpoints requiring concurrent achievement of: rectal bleeding resolution and mucosal healing; rectal bleeding resolution, clinical response, and mucosal healing; and rectal bleeding resolution, clinical response, mucosal healing, and molecular improvement. Proportions are the number of patients meeting the endpoint out of the number evaluable. Evaluable patients with missing values for an endpoint were considered as not meeting the endpoint (0 patients in the placebo group, and 2 patients in the GB004 group for all endpoints in (A) and (B), with the exceptions of clinical response and clinical remission [3 patients each]). One patient in the GB004 group meeting the composite endpoint of rectal bleeding resolution and clinical response and histologic remission or mucosal healing had missing gene expression data. Treatment effect estimates (95% CIs) are shown as differences between GB004 and placebo