Impact of mirikizumab therapy on histologic measures of intestinal inflammation in a Phase 2 study of patients with moderately to severely active Crohn’s disease
Bibliographic record
Abstract
Introduction Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial (NCT02891226) in patients with Crohn’s disease (CD). Methods Patients were randomized 2:1:1:2 across 4 treatment arms (PBO, 200, 600, 1000mg miri) administered intravenously (IV) Q4W at Weeks0, 4, and 8. Patients receiving miri and achieving ≥1 point improvement from baseline (BL) at W12 in SES-CD were re-randomized 1:1 into double-blind maintenance to continue their IV dose assignment Q4W (IV/IV) or to 300mg miri SC Q4W (IV/SC); maintenance IV arms were pooled for analysis. W12 non-improvers and all induction PBO patients received 1000mg miri Q4W from W12 through W52. Biopsies from terminal ileum and 4 colonic segments were obtained during endoscopy at W0, 12 and 52 and scored blind to treatment and response status. Endpoints were defined post-hoc but prior to performing analyses and only included patients with active histologic disease at BL (see [ Table 1 ]). Histologic response was defined as: a) absence of neutrophils in epithelium, and absence of epithelial damage, erosions and ulceration or b) decrease of either RHI or modified GHAS ≥50% from BL. Histologic remission was defined as absence of mucosal neutrophils, epithelial damage, erosions, and ulceration. Table 1 Week 12 histologic outcomes. Active histologic disease - Ileum(N=96) Active histologic disease – Colon (4 colonic segments)(N=113) Active histologic disease – Total Intestine (all 5 segments) (N=152) Placebo N=34 Miri200mg N=15 Miri600mg N=16 Miri1000mg N=31 Placebo N=36 Miri200mg N=22 Miri600mg N=21 Miri1000mg N=34 Placebo N=48 Miri 200mg N=28 Miri 600mg N=26 Miri 1000mg N=50 Response, n (%) 11 (32.4) 6 (40.0) 5 (31.3) 22 (71.0)*** 13 (36.1) 13 (59.1) 12 (57.1) 23 (67.6)** 14 (29.2) 15 (53.6)* 13 (50.0)** 33 (66.0)*** Remission, n (%) 6 (17.6) 5 (33.3) 4 (25.0) 15 (48.4)** 3 (8.3) 7 (31.8)** 6 (28.6)** 11 (32.4)** 3 (6.3) 3 (10.7) 4 (15.4) 13 (26.0)*** Pre-defined two-sided alpha of 0.1 considered significant; *P<0.1, **p<0.05, ***p<0.01 vs. placebo; P values were determined using logistic regression analysis with treatment, geographic region, and prior biologic CD therapy as factors, using non-responder imputation.Active histologic disease at BL: modified Global Histologic Disease Activity Score >0 [GHAS; Q1, 3, 4, 5, 6] or sum of Robarts Histopathology Index [RHI] questions 2-4>0.Histologic response: absence of neutrophils in lamina epithelia, absence of epithelial damage, erosions and ulceration or decrease of either RHI or active GHAS (sum Q1, 4, 5, 6 >0) of ≥50%.Histologic remission: GHAS Q1=Normal, GHAS Q4=Normal, GHAS Q5=Absent, and GHAS Q6=No or sum of RHI Q2-4 = 0 when total RHI≤3. Results At W12, histologic response and remission were significantly higher in all segments of the 1000mg group versus PBO (response: ileum p<0.01, total intestine p<0.01, colon p<0.05; remission: ileum p<0.05, colon p<0.05, total intestine p<0.01). Among the W12 improvers, both histologic response and remission at W52 were similar in ileum and colon in the IV/IV group, but lower in ileum than colon in the IV/SC group. All but 2 patients with remission at W52 were in deep histologic remission ([ Table 2 ]). Table 2 Week 52 histologic outcomes. Active histologic disease - Ileum(N=87) Active histologic disease – Colon (4 colonic segments)(N=104) Active histologic disease – Total Intestine (all 5 segments) (N=139) IV/IVN =25 IV/SCN =15 NI/1000mgN =16 PBO/1000mgN =31 IV/IVN =29 IV/SCN =25 NI/1000mgN =16 PBO/ 1000mgN =34 IV/IVN =39 IV/SCN =31 NI/ 1000mgN =24 PBO/1000mgN=45 Response, n (%) 17 (68.0) 4 (26.7) 5 (31.3) 11 (35.5) 22 (75.9) 17 (68.0) 6 (37.5) 18 (52.9) 27 (69.2) 14 (45.2) 10 (41.7) 21 (46.7) Remission, n (%) 13 (52.0) 2 (13.3) 4 (25.0) 10 (32.3) 13 (44.8) 8 (32.0) 2 (12.5) 11 (32.4) 13 (33.3) 4 (12.9) 4 (16.7) 10 (22.2) Deep Remission, n (%) 13 (52.0) 2 (13.3) 4 (25.0) 10 (32.3) 13 (44.8) 7 (28.0) 2 (12.5) 11 (32.4) 13 (33.3) 3 (9.7) 4 (16.7) 10 (22.2) Active histologic disease at BL: modified Global Histologic Disease Activity Score >0 [GHAS; Q1, 4, 5, 6] or sum of Robarts Histopathology Index [RHI] questions 2-4>0.Histologic response: absence of neutrophils in lamina epithelia, absence of epithelial damage, erosions and ulceration or decrease of either RHI or active GHAS ≥50%.Histologic remission: GHAS Q1=Normal, GHAS Q4=Normal, GHAS Q5=Absent, and GHAS Q6=No or sum of RHI Q2-4 = 0 when total RHI≤3.Deep histologic remission: Modified GHAS=0 or RHI=0 Conclusion Miri-treated patients achieved and sustained histologic response and remission over 52weeks of treatment. Publication History Article published online: 24 May 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".