ccx282-b and Crohn-Disease

Inflammatory bowel disease (IBD) is a chronic, debilitating condition with a significant impact on quality of life. In spite of recent advances with antibody therapies, there remains a significant unmet medical need in IBD. Ongoing research and development efforts aim to identify new therapies that will increase remission rates beyond those achieved with current standard-of-care, while maintaining a high safety margin. This review will provide an overview of the small-molecule agents that are being explored in this regard.

Topics: Animals; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Protein Kinase Inhibitors; Signal Transduction

The increased understanding of the molecular mechanisms that are responsible for inflammatory bowel disease (IBD) has led to a wide range of potential therapeutic targets for this condition. Physicians treating individuals with Crohn's disease and ulcerative colitis have a growing armamentarium of options to choose from in managing these patients. This article aims to summarize the relevant literature in the area of emerging therapy in IBD.. The widespread use of antitumor necrosis factor medications brought a landmark change in the treatment of IBD. More recently, several drugs have been shown to provide benefit in IBD in phase III studies by blocking other antiinflammatory pathways. The most likely new medications that will be available include vedolizumab for ulcerative colitis and ustekinumab for Crohn's disease, which target cellular adhesion and inflammatory cell signaling, respectively. Other promising drugs focus on blockade of Janus kinase, inhibition of various chemokines, and biologic therapy such as hematopoietic stem cell transplants and mesenchymal cell infusions.. The growing understanding of the pathogenesis of IBD has led to new molecular targets for therapy. Over the next decade, the number of treatments available will grow, targeting cellular adhesion, protein regulation, inflammatory signal pathways, and immune tolerance.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Crohn Disease; Hematopoietic Stem Cell Transplantation; Humans; Molecular Targeted Therapy; Natalizumab; Signal Transduction; Sulfonamides; Treatment Outcome; Ustekinumab

CCR9 antagonism is a promising new therapeutic approach for the treatment of Crohn's disease. CCR9 is expressed on the cell surface of memory/effector CD4(+) T cells and selectively binds to the small intestinal lymphocyte chemoattractant CCL25 (TECK). Blockade of the CCR9/CCL25 interaction inhibits lymphocyte homing to the intestinal mucosa, thereby limiting inflammation and disease at this site.. This review details the current research on CCR9 antagonism and summarizes available clinical trial data for vercirnon , a selective CCR9 antagonist currently under development.. If the results of ongoing large-scale clinical trials of vercirnon are in line with preliminary reports, CCR9 antagonism may have comparable efficacy to anti-TNF therapies and a potentially superior safety profile, making it the latest addition to the growing arsenal of immunomodulatory drug therapies available to combat Crohn's disease. Moreover, since vercirnon is an oral drug, its associated costs will likely be much lower than expensive infusion-based anti-TNF therapies, providing further economic benefits.

Topics: Animals; Anti-Inflammatory Agents; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Crohn Disease; Humans; Intestinal Mucosa; Molecular Structure; Receptors, CCR; Sulfonamides; Treatment Outcome

Many patients with active Crohn's disease do not adequately respond to therapies, highlighting the need for new treatments.. To conduct a randomised, double-blind, placebo-controlled phase 3 study to assess the efficacy and safety of vercirnon, an oral inhibitor of CC chemokine receptor-9, for the treatment of patients with moderately-to-severely active Crohn's disease.. Patients with a Crohn's Disease Activity Index (CDAI) of 220-450, plus evidence of active disease (endoscopically confirmed or elevation of both C-reactive protein and faecal calprotectin), who had failed corticosteroid or immunosuppressant therapy were enrolled. Patients were equally randomised to receive placebo, vercirnon 500 mg once daily or vercirnon 500 mg twice daily. The primary endpoint was clinical response, defined as a 100-point decrease in CDAI from baseline to week 12.. Six hundred and eight patients were randomised. Patient characteristics and baseline demographics were similar among the groups. The proportions of patients achieving a clinical response were 25.1%, 27.6% and 27.2% for placebo, once daily and twice daily respectively; treatment differences were not significant (2.5%; 95% confidence interval, CI -6.1% to 11.0%, P = 0.546 for once daily vs. placebo, and 2.1%; 95% CI -6.5% to 10.7%, P = 0.648 for twice daily vs. placebo). Adverse events were reported in 69.8%, 73.3% and 78.1% with serious adverse events in 8.9%, 5.9%, and 6.0% of patients in the placebo, once-daily and twice-daily groups, respectively.. We did not demonstrate efficacy of vercirnon as an induction therapy in patients with moderately-to-severely active Crohn's disease; its effect in maintenance therapy was not addressed.

Topics: Adult; C-Reactive Protein; Crohn Disease; Double-Blind Method; Feces; Female; Humans; Leukocyte L1 Antigen Complex; Male; Middle Aged; Receptors, CCR; Sulfonamides; Young Adult

CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn's disease. Crohn's Disease Activity Index (CDAI) scores were 250-450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn's medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥ 70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn's disease.. ClinicalTrials.gov NCT00306215.

Topics: Administration, Oral; Adult; Analysis of Variance; C-Reactive Protein; Cell Movement; Crohn Disease; Endoscopy, Gastrointestinal; Endpoint Determination; Female; Humans; Intestines; Male; Middle Aged; Odds Ratio; Receptors, CCR; Sulfonamides; Treatment Outcome

Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12.

Topics: Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Discovery; Humans; Indoles; Molecular Structure; Receptors, CCR; Structure-Activity Relationship

The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC(50) of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC(50) of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC(50) values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.

Topics: Administration, Oral; Animals; Calcium; Cell Line; Chemotaxis, Leukocyte; Crohn Disease; Gastrointestinal Agents; Humans; Ileitis; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Radioligand Assay; Rats; Receptors, CCR; Sulfonamides; T-Lymphocytes; Tretinoin; Tumor Necrosis Factor-alpha