P-101 Anti-MAdCAM Antibody PF-00547659 in Crohnʼs Disease
Notice bibliographique
Résumé
The fully human anti-MAdCAM monoclonal antibody PF-00547659 is being developed to treat inflammatory bowel disease. It interrupts the a4b7 integrin-MAdCAM-1 interaction, thereby selectively inhibiting leukocyte migration from the bloodstream into the intestinal wall but not the central nervous system Patients with moderate to severe Crohn's disease (HBI >8 and hsCRP ≥5 mg/L or intestinal stoma and active disease on imaging or endoscopy) who failed prior treatment with anti-TNF and immunosuppressant (IS) agents underwent a lumbar puncture (LP) followed by 3 doses of 225 mg PF-00547659 at 4 week intervals. A 2nd LP was performed after the last dose and CSF analyzed by flow cytometry. Clinical Crohn's disease activity was measured throughout using the Harvey Bradshaw Index (HBI). The efficacy outcomes of interest were the rate of response (decrease in HBI ≥3 points) and the rate of remission (HBI <5) at week 12 in evaluable patients. All the responders in the study were eligible for enrollment into an open label extension study with up to 19 months of treatment Forty-nine patients were enrolled (28 women, 21 men) in 8 European centers; mean (SD) age = 38.1 (11.8) yr, CD duration = 12.7 (6.2) yr, hsCRP = 16.3 (19.9) mg/L (Geometric mean hsCRP = 7.0). Fourteen patients had stomas and hence were not evaluable for HBI; 29 (59%) were seropositive for antibody to the JC virus. All had failed previous treatment with thiopurines (TP) and either infliximab and/or adalimumab. Twenty-six had also failed methotrexate (MTX). Ten patients (7 evaluable) were taking IS at study entry: 7 TP and 4 MTX (1 took both TP and MTX). As observed efficacy results are shown in the Table. At week 12, the geometric mean of hsCRP declined from baseline 7.0 mg/L to 5.7 mg/L (-16%). A full induction course of the highest clinical dose of PF-00547659 did not affect CSF lymphocytes while it resulted in increased circulating b7+ lymphocytes indicating that it is pharmacologically active. Overall good safety and tolerability was observed with low rates of adverse events. All subjects have completed study treatment and 4 subjects were in follow up at the time of the targeted data extraction. Selective inhibition of white blood cell translocation to the gut with PF-00547659 in patients with moderate to severe Crohn's disease and prior treatment with anti-TNF and IS drugs is associated with high rates of disease response and remission by week 12 in the open label TOSCA study. Administration was safe, and side effects were generally those seen in this population. The results of the TOSCA study support the gut selectivity and the CNS-sparing mechanism proposed for PF-00547659.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| 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 ».