Emerging Safety Profile of Vedolizumab: A novel, selective Integrin Inhibitor for the treatment of IBD
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,004 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».