OP034 Efficacy and safety of abrilumab in subjects with moderate to severe ulcerative colitis: results of a phase 2b, randomised, double-blind, multiple-dose, placebo-controlled study
Bibliographic record
Abstract
Background: α4β7 integrin is a validated target in IBD. We studied abrilumab (AMG181/MEDI7183), a fully human monoclonal antibody against α4β7 integrin, in subjects with ulcerative colitis (UC) and inadequate or loss of response to anti-tumor necrosis factors (TNFs) or immunomodulators. Methods: This phase 2b, multicentre, randomised, double-blind, placebo (PBO)-controlled, parallel-group, multi-dose study enrolled subjects with moderate to severe UC (total Mayo Score 6–12, rectosigmoidoscopy score ≥2). Subjects received PBO or abrilumab (7, 21, or 70 mg) subcutaneously (SC) on day 1, weeks 2 and 4, and every 4 weeks or abrilumab 210 mg SC on day 1, stratified by prior anti-TNF exposure and participation in a pharmacokinetic (PK) substudy. The primary endpoint was remission at week 8 (table); key secondary endpoints were response and mucosal healing at week 8. Endoscopy was centrally read. CD4+ T cell subsets were enumerated and α4β7 receptor occupancy was measured in a subset of subjects. Results: This study enrolled 354 subjects. The final allocation of 116, 21, 40, 98, and 79 in the PBO, 7, 21, 70, and 210 mg groups, respectively, was due to a systematic misalignment in investigational product; study blind and randomisation were intact. Remission rates were 4.4, 1.6, 2.9, 13.5, and 13.4% in the PBO, 7, 21, 70, and 210 mg groups, respectively; response and mucosal healing rates are listed in the table. Table 1. Rates of remission, response, and mucosal healing at week 8 in subjects who received abrilumab. Higher rates of remission, response, and mucosal healing in the prior anti-TNF failure subgroup 210-mg arm were observed: 13.9, 51.9, and 40.6%, respectively. Maximal reduction of free α4β7 on naïve CD4+ T cells in the peripheral blood was sustained through week 8, except for the 7-mg group. Abrilumab induced a significant post-dose increase in α4β7-high central memory CD4+ T cell (Tcm) counts from baseline to week 8. Exposure-response (E-R) modeling of PK data demonstrated that subjects in decile groups with mean trough levels >10 μg/mL showed maximal remission rates. Adverse events were balanced among groups through week 24, with no PML or deaths. No subject developed neutralising antibodies to abrilumab. Conclusions: Abrilumab demonstrated a favorable safety, immunogenicity, PK, pharmacodynamic, and efficacy profile, suitable for further testing in subjects with UC. Efficacy did not appear to correlate with peripheral target coverage or changes in α4β7-high Tcm. E-R modeling suggests that higher abrilumab exposure may result in higher remission and response rates. Disclosure: Amgen and AstraZeneca/MedImmune sponsored this study.
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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 | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".