Emerging Safety Profile of Vedolizumab: A novel, selective Integrin Inhibitor for the treatment of IBD
Bibliographic record
Abstract
Vedolizumab, a humanized version of Act-11 (previously known as MLN0002, MLN02, LDP-02), is a monoclonal antibody to α4β7 integrin. Vedolizumab inhibits lymphocyte trafficking to gastrointestinal tissue by blocking α4β7 adhesion to MAdCAM-1 (mucosal vascular addressin cell adhesion molecule). Humanized Act-1 has demonstrated therapeutic activity in both ulcerative colitis (UC) and Crohn's disease (CD) trials2,3. Because of its unique specificity for α4β7 vedolizumab is not expected to lead to systemic opportunistic infections (OIs) such as progressive multifocal leukoencephalopathy (PML), observed in patients treated with a non-specific antagonist to α4. We report safety findings from phase 1 and 2 clinical trials of vedolizumab and its precursor (LDP-02). An integrated safety analysis was performed on data from 9 clinical trials (8 placebo controlled) in 579 healthy subjects and patients with IBD. 415 subjects received vedolizumab or its precursor at single or multiple doses up to 10 mg/kg intravenously for up to 4 doses. Overall, 348 (84%) of subjects who received drug/treatment reported at least one adverse event (AE) compared to 143 (87%) placebo subjects. The most common AEs among treated subjects were headache, nausea, exacerbation of ulcerative colitis, abdominal pain, fatigue and nasopharyngitis. Rates of serious adverse events were similar among treatment groups: 12% (50 subjects) in the drug treated group vs. 14% (23 subjects) in the placebo group. 135 (33%) treated subjects experienced at least 1 infection vs. 37 (23%) placebo subjects. The upper respiratory tract was the most common site of infection. Herpes labialis was reported by 11 (2.3%) treated subjects vs. 1 (0.6%) in placebo, and mucosal candidiasis by 5 (1.2%) treated subjects vs. none in placebo. Rates of GI infections (≤1% overall) and serious infections (1.4% drug treated vs. 1.8% placebo) were similar between treatment groups. Similarly, there was no increase in rates of systemic infections (eg pneumonia, pyelonephritis) in drug treated subjects. To date, no systemic OIs have been reported during any clinical trial (including in an ongoing open-label study in which 53 subjects have received’ 7 doses of vedolizumab [>1 year exposure]). One patient with UC who received one dose of drug developed a primary cytomegalovirus infection 21 days later that resolved without antiviral therapy. Vedolizumab was not associated with lymphocytosis or increases in other WBC subsets. Rates of LFT abnormalities were similar to placebo. In these multiple dose studies, 2 (<1%) subjects who received drug developed an infusion related hypersensitivity reaction. There were no cases of PML or JC viremia in vedolizumab subjects. Vedolizumab has been well-tolerated to date with no increase in systemic infections and a possible trend in increased upper respiratory and mucosal infections. These data and the absence of lymphocytosis are consistent with the target specificity of vedolizumab and the distribution of MAdCAM-1 in mucosal tissue. The selectivity of vedolizumab for α4β7 and the GI-specific function of α4β7, provide regional immunomodulation of the GI tract with less potential for systemic immunosuppression. This promising profile will be further defined in ongoing Phase 3 trials in UC and CD.
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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 | 0.004 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".