P225 Mucosal transcriptomic profiles associated with clinical response in patients with Ulcerative Colitis receiving filgotinib
Bibliographic record
Abstract
Abstract Background Filgotinib (FIL) is an oral, once-daily, JAK1 preferential inhibitor approved for the treatment of Ulcerative Colitis (UC). In the phase 2b/3 SELECTION trial (NCT02914522), FIL had a high level of efficacy in inducing and maintaining histological remission and endoscopic response, relative to placebo (PBO). Here, we described the changes in the mucosal transcriptomic profiles associated with histologic and endoscopic responses following FIL or PBO treatment. Methods Patients with moderately to severely active UC were enrolled into one of two cohorts (biologic-naive or biologic-experienced) and randomized 2:2:1 to receive FIL 200 mg (FIL200), FIL 100 mg (FIL100) or PBO from baseline to week 10. RNA was extracted from colon biopsies collected at baseline and week 10, and RNA sequencing (RNA-seq) was performed according to standard protocols. Clinical responses of interest included histological remission (assessed by categorical Geboes score) and endoscopic response (both defined in Figure legend) at week 10. To assess transcriptional variability, RNA-Seq data were analyzed by a spectral map separately for baseline and week 10. Differentially expressed gene (DEG) analysis was used to explore differences in transcriptional expression for multiple comparators: from baseline to week 10 between patients with or without clinical response, separately, by treatment arm and cohort. Results RNA-Seq data were available for 1086 patients across treatment arms at baseline and/or week 10. Spectral map analysis showed no visual association between baseline transcriptional variability (principal component [PC]1: 26%) and achieving either histological remission or endoscopic response at week 10, nor with the treatment arm. At week 10, the main source of transcriptional variability (PC1: 32%) was visually associated with achieving histological remission or endoscopic response, but not with the treatment arm. From the DEG analysis, more significant genes were associated with histological remission in the FIL200 arm compared with either the FIL100 or PBO arms, especially for biologic-naive compared with biologic-experienced patients (Figure A). Furthermore, more significant genes were associated with endoscopic response in the FIL arms compared with PBO (Figure B). Conclusion The overall transcriptional response associated with histological remission or endoscopic response was greater in FIL treatment arms than the PBO arm. This transcriptional response differed between biologic-naive and experienced patients, suggesting that transcriptional changes associated with clinical response were influenced by both FIL treatment and previous biologic use. Preliminary data suggests these transcriptional changes occur in pathways related to UC pathogenesis.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".