Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study

Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti–IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23–driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes.

Section: The Role Of the Il-23 Pathway In Immune-mediated Inflammator...mentioning

confidence: 99%

IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy

Krueger,

Eyerich,

Kuchroo

et al. 2024

“…Guselkumab, an interleukin-23p19 subunit antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis ( 38 ). Two phase 2 trials indicated that guselkumab induced greater clinical and endoscopic improvements in patients with CD or UC with inadequate response or intolerance to conventional or biologic therapy, with a favorable safety profile ( 38 , 39 ). Moreover, phase 3 studies evaluating the efficacy and safety of guselkumab for the treatment of patients with IBD are currently in progress ( 38 ) (clinicaltrials.gov).…”

Section: Anti-il-23/12 Agentsmentioning

confidence: 99%

Anti-IL23/12 agents and JAK inhibitors for inflammatory bowel disease

Tian,

Zhao,

Teng

2024

IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

“…For example, the monoclonal antibody ustekinumab, which specifically targets IL-12/23p40, demonstrated a significant reduction in endoscopic range of motion among patients with IBD, thereby exhibiting its capacity to facilitate the restoration of mucosal integrity (60). Risankizumab, guselkumab, and mirikizumab are inhibitors of IL-23p19 that have demonstrated efficacy in clinical trials for symptom improvement, endoscopic findings enhancement, and histological remission (61)(62)(63). Additionally, the specific target of vedolizumab is the a4b7 integrin, which interacts with cell adhesion molecule 1 (MAdCAM-1).…”

Section: The Progress and Dilemma Of Traditional Therapiesmentioning

confidence: 99%

Emerging strategy towards mucosal healing in inflammatory bowel disease: what the future holds?

Wang,

Shi,

et al. 2023

For decades, the therapeutic goal of conventional treatment among inflammatory bowel disease (IBD) patients is alleviating exacerbations in acute phase, maintaining remission, reducing recurrence, preventing complications, and increasing quality of life. However, the persistent mucosal/submucosal inflammation tends to cause irreversible changes in the intestinal structure, which can barely be redressed by conventional treatment. In the late 1990s, monoclonal biologics, mainly anti-TNF (tumor necrosis factor) drugs, were proven significantly helpful in inhibiting mucosal inflammation and improving prognosis in clinical trials. Meanwhile, mucosal healing (MH), as a key endoscopic and histological measurement closely associated with the severity of symptoms, has been proposed as primary outcome measures. With deeper comprehension of the mucosal microenvironment, stem cell niche, and underlying mucosal repair mechanisms, diverse potential strategies apart from monoclonal antibodies have been arising or undergoing clinical trials. Herein, we elucidate key steps or targets during the course of MH and review some promising treatment strategies capable of promoting MH in IBD.