Investigative drug for ulcerative colitis passes muster in early trial

The orally administered, small molecule, gut-targeted stabiliser of hypoxia-inducible factor-1α (HIF-1α) GB004 appears to improve disease activity in patients with ulcerative colitis, with the drug being well-tolerated, according to the results of a phase Ib trial.

In the trial, 34 patients (mean age 45 years, 67.6 percent male) were randomized to receive an oral solution of GB004 120 mg (n=23) or placebo (n=11) once-daily for 28 days. These patients were on 5-aminosalicylates, corticosteroids, or immunosuppressants. However, they still had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score of 3–12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool.

Daily oral doses of GB004 120 mg over the course of 28 days were generally well-tolerated. Adverse events were documented in three patients (27.3 percent) on placebo and nine (39.1 percent) on GB004. Nausea and dysgeusia were most frequently reported in the latter group. None of the patients developed treatment-related serious adverse events or died.

GB004 demonstrated minimal accumulation, with drug concentrations being higher in the colon than in plasma.

Exploratory pharmacodynamic and efficacy analyses showed that GB004 was able to achieve what it was designed to do, increasing HIF-1α-positive cell proportions in the sigmoid colon. There was also a noticeable rise in the levels of faecal secretory immunoglobulin A in response, suggesting improvements in local gut epithelial immune defence.

Finally, more patients on GB004 vs placebo achieved improvements in multiple measures of disease activity at day 28.

In patients with ulcerative colitis, epithelial barrier dysfunction contributes to a dysregulated intestinal immune response. The present data indicate that GB004, which directly affects the restoration of the intestinal barrier, is a novel and promising approach for the treatment of this population.