S1134 Association of Nonswitched Memory B-Cell (MBC) Levels With Ozanimod (OZA) Efficacy in Patients (Pts) With Moderately to Severely Active Crohn’s Disease (CD): Results From the Phase 2 STEPSTONE Study
Bibliographic record
Abstract
Introduction: OZA is approved for the treatment (tx) of moderately to severely active ulcerative colitis and is under investigation for CD. Clinical, endoscopic, and histologic improvements were observed after 12wk of tx with OZA in pts with moderately to severely active CD in the phase 2 STEPSTONE study. Methods: This exploratory analysis of STEPSTONE assessed the association between levels of circulating lymphocyte subsets and OZA efficacy. Pts received OZA 0.92 mg for 12wk. Lymphocyte subsets were evaluated using multicolor flow analysis on blood samples collected before tx and at Week (W) 12; differences between Day 1 and W12 were analyzed by Wilcoxon signed-rank tests. Change in disease activity from baseline (BL) to W12 was determined for Simple Endoscopic Score for Crohn’s Disease, size of ulcers, extent of ulcerated surface, extent of affected surface, presence of narrowing, Crohn’s Disease Activity Index (CDAI), Robart’s Histopathology Index (RHI), Geboes Histology Activity Score (GHAS), and stool frequency. Efficacy outcomes were evaluated at W12. Associations of lymphocyte subset levels with disease activity changes and efficacy outcomes were assessed using Spearman’s correlation and logistic regression, respectively. Results: Of 69 pts enrolled, 52 had disease activity, efficacy outcome, and flow cytometry data at BL and W12 and were included in this analysis. Most lymphocyte subsets assessed were significantly associated with 1 or 2 efficacy outcomes. Nonswitched MBCs were significantly associated with most outcomes, including endoscopic response-25, endoscopic response-50, endoscopic remission, global GHAS remission, and RHI mucosal healing (Table 1). BL levels of nonswitched MBCs were significantly correlated with change from BL to W12 in extent of affected surface (Spearman’s rho [SR] = –0.44, P< 0.05), RHI (SR = –0.34, P< 0.05), and GHAS (SR = –0.47, P< 0.05). Changes in levels of nonswitched MBCs were significantly correlated with change from BL to W12 in CDAI (SR = 0.38, P< 0.05), RHI (SR = 0.37, P< 0.05), GHAS (SR = 0.43, P< 0.05), and stool frequency (SR = 0.43, P< 0.05). Conclusion: After 12wk of OZA tx, higher levels of nonswitched MBCs at BL were associated with endoscopic and histologic improvement, and reductions in nonswitched MBCs were associated with decreases in clinical and histologic disease activity. These data implicate nonswitched MBCs, which are involved in T cell–dependent immune responses and some inflammatory diseases, as a marker associated with OZA response in CD. Table 1. - Association of BL lymphocytes with W12 efficacy Lymphocyte subset Clinical responsea Clinical remissionb Endoscopic response-25c Endoscopic response-50d Endoscopic remissione Global GHAS remissionf RHI remissiong RHI mucosal healingh CD4 EM T cell; CD8 CM T cell NS; NS NS; NS NS; NS NS; NS NS; NS 0.0350 (–0.69); 0.0233 (–0.87) NS; NS NS; NS CD8 skin-homing CCR4 EM cell NS NS NS NS NS NS 0.0155 (0.15) NS CD8 TEMRA (fully differentiated) NS NS NS NS 0.0484 (0.61) 0.0138 (0.95) NS NS Naive CD8+ T cell NS NS NS 0.0449 (0.55) NS NS NS NS CD8 EM T cell NS NS NS NS NS 0.0344 (0.79) NS NS B cell NS NS NS 0.0404 (0.68) NS NS NS NS Nonswitched MBC NS NS 0.0368 (0.52) 0.0046 (0.86) 0.0163 (0.84) 0.0036 (1.20) NS 0.0136 (0.95) IgD-CD27 MBC NS NS NS NS NS 0.0159 (0.88) NS NS MBC NS NS NS NS NS 0.0403 (0.76) NS NS All lymphocyte subsets were measured in cells/µl. The values in each cell represent the P-value with logistic regression coefficient beta in parentheses.aCDAI reduction from BL of ≥100 points.bCDAI score of < 150.cDecrease of ≥25% in SES-CD from BL.dDecrease of ≥50% in SES-CD from BL.eSES-CD ≤4 points and SES-CD decrease ≥2 points with no SES-CD subscore >1 point.fNo active inflammation in any measured segment based on the GHAS.gNo active inflammation in any measured segment based on the RHI.hEndoscopic remission plus RHI remission.CM, central memory; EM, effector memory; NS, not specified; SES-CD, Simple Endoscopic Score for Crohn’s Disease; TEMRA, terminally differentiated effector memory.
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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 | 0.001 | 0.001 |
| 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 | 0.000 |
| 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".