OP033 Reduction of tissue pSTAT3 in Crohn's disease patients treated with filgotinib (GLPG0634, GS-6034), a JAK1-selective inhibitor
Bibliographic record
Abstract
Background: Janus kinases (JAK) are a family of tyrosine kinases that play a key role in the signalling of more than 60 cytokines and growth factors. Many of these cytokines display pro-inflammatory activity in Crohn's Disease (CD). The selective JAK1 inhibitor filgotinib blocks cytokine signalling through the inhibition of STAT phosphorylation and has shown clinical efficacy in a double-blind, placebo-controlled Phase 2 study in CD (FITZROY). In order to understand the mechanism of action of filgotinib in CD patients, we measured the level of pSTAT3 in gut biopsies from this study. Methods: CD patients were randomized 3:1 to receive 200mg filgotinib or placebo QD for the first 10 weeks. Two biopsies, one each from the most and least affected mucosa, were collected during screening and at Wk 10 from each of the 6 predefined segments of the lower gastrointestinal tract. Samples from 60 patients with complete set of paired biopsies were selected. pSTAT3 was evaluated by IHC using an antibody specific to phosphorylated Y705. H-Score was quantified using Definiens Tissue Studio software. The mixed effect ANOVA method was used for evaluating the treatment effect and difference between patients achieving clinical remission (defined as CDAI <150) and those who did not. Results: Basal pSTAT3 level was comparable for the filgotinib and placebo groups. Following filgotinib treatment, pSTAT3 level was significantly reduced in the most affected mucosa from all segments combined: −36% (95% CI: −51%, −17%), whereas reduction in the placebo arm was not significant (although with less subjects): −24% (95% CI: −49%, +14%). In patients with clinical remission at Wk 10, pSTAT3 levels showed a significant reduction from baseline in each group: −62% (95% CI: −83%, −16%) with placebo, and −42% (95% CI: −57%,-21%) with filgotinib. In patients not achieving clinical remission, pSTAT3 from the placebo arm showed an average numerical increase of +12% (95% CI: −21%, +94%) whereas pSTAT3 was on average reduced with filgotinib: −28% (95% CI: −51%, +7%). Similar observations were made in the least affected mucosa of different segments. Table 1. Percent reduction of pSTAT3 at Week 10 from most affected area in all segments in CD patients Conclusions: Significant reduction of pSTAT3 by filgotinib on inflamed gut of CD patients provides direct evidence of its anti-inflammatory effect. Clinical remission status is associated with a decrease in pSTAT3. In non-remitters, the observed pSTAT3 reduction with filgotinib illustrates its pharmacodynamic effect through JAK1 inhibition. A large phase 3 program in CD and UC is ongoing.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".