P0197 Comparison of pharmacodynamic and mechanistic response of guselkumab intravenous and subcutaneous induction in moderately to severely active Crohn’s disease: molecular analysis of the GRAVITI and GALAXI Phase 3 studies
Notice bibliographique
Résumé
Abstract Background Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks IL-23 and binds to CD64 demonstrated efficacy with intravenous (IV) induction in patients with moderately to severely active Crohn’s disease (CD) in the GALAXI trials.1 Subcutaneous (SC) induction with GUS evaluated in the Ph3 GRAVITI trial was also efficacious in treating patients with CD.2 Here we present a comparison of the pharmacodynamic and mechanistic response of GUS SC and GUS IV induction therapy in CD. Methods Serum proteins were evaluated from 290 GRAVITI patients randomised to PBO or GUS 400mg SC q4w, and a subset of 292 GALAXI patients randomised to PBO or GUS 200mg IV q4w at Weeks 0 and 12 using a 92-analyte inflammatory protein panel. Transcriptional profiling from each of the five anatomic segments in GRAVITI was conducted with samples from 277 patients at WK0 and WK12 using RNA sequencing. A tissue inflammation score (bMIS3) was used to assess segmental molecular inflammation which correlated with segmental histology scores defined by Global Histologic Activity Score (GHAS), endoscopic scores and subscores defined by Simple Endoscopic Score for CD (SES-CD).3 Analysis of treatment effect was performed using molecularly inflamed samples (defined as bMIS >0) from segments with SES-CD >0 at baseline. Transcriptional gene modules were evaluated for differential expression. Results In serum, protein changes observed with GUS 400mg SC q4w induction at WK12 were highly correlated with those observed with GUS 200mg IV q4w induction at WK12 (R=0.96, p<0.05), including similar reduction of IFNγ, IL-17A, CRP and fecal calprotectin (p<0.05; Figure 1). In tissue, segmental molecular inflammation assessed by bMIS correlated with segmental histological and endoscopic subscores (percent affected tissue and ulceration severity). In each anatomic segment, GUS SC induction reduced key cellular and inflammatory transcriptional modules at WK12 including plasma cell, inflammatory epithelial, neutrophil, and IL-23/Th17 biology consistent with molecular analysis from GUS IV induction in GALAXI Ph2b.4 The decrease in molecular inflammation in 5 anatomic segments corresponded to the segmental endoscopic improvement observed in isolated ileal, ileocolonic and colonic patient subgroups. Conclusion Following SC induction, the protein changes observed in serum at WK12 in GRAVITI were highly correlated with those seen with GUS IV induction from GALAXI Ph3. These data demonstrate similar molecular effects of GUS SC and IV induction doses and are aligned with previously reported similar efficacy results, supporting the flexible choice for patients and healthcare professionals between GUS SC and IV to treat patients with CD. References 1.Panaccione R, Danese S, Feagan BE, et al. Efficacy and safety of guselkumab therapy in patients with moderately to severely active Crohn’s disease: results of the GALAXI 2 & 3 phase 3 studies. Gastroenterology. 2024; 5 (Supplement): p1057b. 2.Panaccione R, Hart A, Steinwurz F et al. Efficacy and Safety of Subcutaneous Guselkumab Induction Therapy in Patients with Moderately to Severely Active Crohn’s Disease: Results Through Week 48 From the Phase 3 GRAVITI Study. ACG 2024. 3.C Argmann, et al. Biopsy and blood-based molecular biomarker of inflammation in IBD. Gut. 2022; 0:1-17. 4.Richards D, Venkat S, Ruane D, et al. Guselkumab Decreases Key Cellular Inflammatory Processes Across Ileum and Colon Tissue in Crohn’s Disease. P0950 ACG 2024.
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 | 0,001 |
| 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 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».