P540 GB004, a novel prolyl hydroxylase inhibitor for inflammatory bowel disease, leads to gut-targeted HIF-1α pathway engagement in a multiple-dose study in healthy subjects
Bibliographic record
Abstract
Abstract Background GB004 is a small-molecule prolyl hydroxylase inhibitor that stabilises hypoxia-inducible factors (HIF-1α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-1α stabilisation. GB004 is in clinical development for the treatment of inflammatory bowel disease and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple daily doses of GB004 in plasma and colon biopsies. Methods This was a randomised, double-blind, placebo-controlled, multiple-dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 or placebo formulated as a solution were administered orally once a day for 8 days; safety and PK were evaluated. Colon biopsies were obtained one day prior to the first dose and on Day 8. Colonic tissue concentrations of GB004 and HIF pathway target genes were determined. Results Forty-two subjects (20 male and 22 female) were dosed. No serious adverse events or deaths were recorded. The most commonly observed adverse event in GB004-treated subjects was dizziness (31%,10/32); all events were mild and did not result in study drug discontinuation. There were no identified risks of GB004. Following oral dosing, GB004 was rapidly absorbed and eliminated from the systemic circulation, with a median time to maximum concentration of 0.5 h for all dose levels. Concentrations of GB004 measured in colon biopsies were greater than in plasma at the time of the biopsy. Dose-related HIF pathway target gene engagement and PD were confirmed. Conclusion This study demonstrated that multiple daily doses of GB004 solution were safe and tolerable. The PK profile was consistent with its intended preferential exposure in the gut. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, tolerability, PK and PD both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".