Selective Inhibition of Tyrosine Kinase 2 (TYK2) with BMS-986165 Is Efficacious in IL-23-Mediated Diseases: Evidence from Preclinical IBD Models and From a Psoriasis Study
Notice bibliographique
Résumé
Introduction: BMS-986165, a potent, highly selective oral TYK2 inhibitor, blocks signaling pathways of interleukin (IL)-23, IL-12 and type I interferons (IFN) involved in the pathology of many immunemediated diseases. We report efficacy of BMS-986165 in IL-23-mediated conditions: two inflammatory bowel disease (IBD) models in mice and plaque psoriasis (PsO) in a Phase (Ph) 2 clinical trial, providing evidence that TYK2 inhibition is an attractive therapeutic target for a range of autoimmune diseases. Methods: BMS-986165 was evaluated biochemically and in cellular assays of IL-23-, IL-12- and type I IFN-driven signaling and response, and in two models of colitis: anti-CD40 agonistic antibody-induced colitis and adoptive transfer of CD4+CD45RBhigh T cells, both in SCID mice. It was evaluated in a doubleblind placebo (pbo)-controlled Ph 2 study in adults with moderate-to-severe plaque PsO at 5 doses (3 mg QOD, 3 mg QD, 3 mg BID, 6 mg BID, 12 mg QD) vs pbo. Primary endpoint was PASI 75 at Week 12. Results: BMS-986165 blocked receptor-stimulated TYK2 activation in vitro with high selectivity and potency, and blocked signaling and functional responses in human TH17, TH1, B and myeloid cells integral to autoimmunity. BMS-986165 (5-50 mpk PO BID) inhibited wasting and protected mice from anti-CD40 agonistic antibody-induced colitis. BMS-986165 (10-50 mpk BID) protected mice from CD4+CD45RBhigh T cell-induced colitis (Figure). Protection was at least as effective as anti-IL-12/23 p40 antibody treatment. In the PsO study, baseline disease and patient (pt) characteristics of 267 pts were balanced among groups. At Week 12, significantly more pts achieved PASI 75, PASI 90 and sPGA 0/1 at doses ≥3 mg QD vs pbo (p<0.05; Table). AEs (generally mild to moderate) were reported in 51% (pbo), 59% (3 mg QOD), 55% (3 mg QD), 64% (3 mg BID), 80% (6 mg BID) and 77% (12 mg QD) of pts. Overall safety was acceptable with no abnormalities associated with inhibition of other tyrosine kinases, such as JAKs 1-3. Conclusion: The potent suppression of IL-23-, IL-12- and type I IFN-driven pathobiology by BMS-986165 resulted in robust activity in two preclinical models of IBD. These data, combined with encouraging results in the Ph 2 PsO study, warrant further evaluation of BMS-986165 as a therapeutic option for IL-23-mediated diseases, including Crohn's disease (CD) and ulcerative colitis. A Ph 2 study in CD is underway to explore this further.627_A Figure 1. Figure. Treatment With BMS-986165 Protects From Wasting and Colitis in Mice. Treatment with BMS-986165 (PO BID) protects from wasting and colitis induced in SCID mice by adoptive transfer of CD4+CD45RBhigh T cells. A blocking anti-p40 antibody was included as a comparator. (A) Mean body weight (n=9 mice per group) was assessed throughout the course of the disease, and (B) histological evaluation of colons at the end of the study. The results represent the mean +/- SEM. * p<0.05, **p<0.01 versus vehicle control group. BID=twice daily; mpk=milligrams per kilogram; PO=oral; SCID=severe combined immune deficiency; SEM=standard error of the mean627_B Figure 2. Table. Response Rates at Week 12
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 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 | 0,001 |
| 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) | 0,000 | 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 tête enseignante, 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 ».