ged0301 and tofacitinib

There is an ongoing, unmet need for effective therapies for Crohn's disease. Treatments for Crohn's disease continue to evolve from the traditional biologics to novel small molecules, with targeted mechanisms directed toward pathways that are dysregulated in Crohn's disease. There are multiple emerging mechanisms of action, including Janus kinase inhibition, Smad7 inhibition, and sphingosine-1-phosphate receptor modulators, that are administered as oral medications, and small molecules represent the next generation of therapies for Crohn's disease.

Topics: B-Lymphocytes; Colitis, Ulcerative; Crohn Disease; Humans; Indans; Janus Kinase 1; Janus Kinase Inhibitors; Oligonucleotides; Oxadiazoles; Piperidines; Pyridines; Pyrimidines; Pyrroles; Receptors, Lysosphingolipid; Smad7 Protein; T-Lymphocytes; Triazoles

Insights into the pathogenesis of inflammatory bowel diseases (IBDs) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are increased in inflamed intestinal tissues of patients with IBD. Loss-of-function variants of the IL23-receptor gene (IL23R) protect against IBD, and, in animals, blocking IL23 reduces the severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for the treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms also are emerging for the treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cytokines; Humans; Inflammatory Bowel Diseases; Interleukin-23; Janus Kinases; Lysophospholipids; Molecular Targeted Therapy; Oligonucleotides; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction; Smad7 Protein; Sphingosine; Th17 Cells; Transforming Growth Factor beta; Ustekinumab

Tumor necrosis factor (TNF) antagonists are the cornerstone of therapy for moderately to severely active inflammatory bowel disease (IBD). Although our understanding of pharmacokinetics, pharmacodynamics, and treatment optimization for these agents has evolved considerably over the past decade, a substantial majority of individuals fail to respond or lose response to TNF-antagonists over time. A need therefore remains for efficacious treatment options in these patients. Alternative immunological targets have now been identified, and several novel therapeutic agents are in development for IBD. In this review article, we discuss these novel therapeutic agents, with a particular focus on those demonstrated to be efficacious in phase 2 and 3 clinical trials. We further discuss considerations to be made when integrating these agents into routine practice over the next decade.

Topics: Antibodies, Monoclonal, Humanized; Biological Products; Cell Adhesion Molecules; Gastrointestinal Agents; Humans; Immunoglobulins; Indans; Inflammatory Bowel Diseases; Mucoproteins; Oligonucleotides; Oxadiazoles; Piperidines; Pyrimidines; Pyrroles; Tumor Necrosis Factor-alpha; Ustekinumab