oxadiazoles and Crohn-Disease

Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials.. We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents.. Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug-drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms.

Topics: Acetates; Animals; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Indans; Indoles; Janus Kinase Inhibitors; Oxadiazoles; Piperidines; Pyridines; Pyrimidines; Quinolones; Sphingosine-1-Phosphate Receptors; Triazoles

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

Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the safety and efficacy of ozanimod in patients with moderately to severely active CD.. The YELLOWSTONE program consists of phase 3, randomized, double-blind, placebo-controlled induction (NCT03440372 and NCT03440385) and maintenance (NCT03464097) trials and an open-label extension (OLE) study (NCT03467958). Patients with inadequate response or intolerance to ≥1 CD treatment are randomized to receive daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo for 12 weeks during induction. Those who respond to ozanimod are rerandomized to continue ozanimod or placebo maintenance therapy for 52 weeks. Patients who do not meet criteria for maintenance, experience relapse during maintenance, or complete maintenance or ≥ 1 year of STEPSTONE are eligible for open-label treatment for up to 234 weeks. Efficacy endpoints include clinical, endoscopic, and histologic outcomes.. Expected 2023 (induction studies), 2024 (maintenance study), and 2026 (OLE).. YELLOWSTONE will provide pivotal phase 3 data on the safety and efficacy of ozanimod in patients with moderately to severely active CD using state-of-the-art methods, including centrally read endoscopic and histologic measurements, along with subjective assessments of symptom control based on the Crohn's Disease Activity Index. These studies could enable approval of ozanimod as a new CD therapy.. NCT03440372, NCT03440385, NCT03464097, NCT03467958.

Topics: Crohn Disease; Humans; Immunologic Factors; Indans; Oxadiazoles

Although treatment of Crohn's disease has improved with development of tumour necrosis factor antagonists, fewer than 50% of patients have sustained benefit. Durable maintenance therapy with orally administered alternative treatments remains an unmet need. We aimed to evaluate the effects of ozanimod, an oral agent selectively targeting sphingosine-1-phosphate receptor subtypes 1 and 5, on endoscopic disease activity in Crohn's disease.. STEPSTONE was a phase 2, uncontrolled, multicentre trial in adults with moderately to severely active Crohn's disease recruited at 28 hospital and community research centres in Canada, the USA, Hungary, Poland, and Ukraine. All patients began treatment with a 7-day dose escalation (4 days on ozanimod 0·25 mg daily followed by 3 days at 0·5 mg daily). Patients then received ozanimod 1·0 mg oral capsule daily for a further 11 weeks, for a 12-week induction period, followed by a 100-week extension. The primary endpoint was change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline to week 12, as determined by a blinded central reader. Data are reported for the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02531113 and EudraCT, number 2015-002025-19, and is completed.. 69 patients were enrolled between Nov 17, 2015, and Aug 18, 2016. At week 12, the mean change from baseline in SES-CD was -2·2 (SD 6·0); 16 (23·2%, 95% CI 13·9-34·9) patients experienced endoscopic response. A reduction from baseline in Crohn's Disease Activity Index (CDAI) score also was observed (mean change -130·4 [SD 103·9]). Clinical remission (CDAI <150 points) was shown in 27 (39·1%, 95% CI 27·6-51·6) patients and response (CDAI decrease from baseline ≥100) in 39 (56·5%, 95% CI 44·0-68·4) of patients. The mean change from baseline in two-item patient-reported outcome (PRO2, stool frequency, abdominal pain scores) score was -66·1 (SD 65·4). Mean change from baseline in Geboes Histology Activity Score (GHAS) was -5·9 (SD 11·0) and in Robart's Histopathology Index (RHI) -10·6 (25·1). Adverse events were most frequently those attributed to Crohn's disease, most commonly Crohn's disease (flare) in 18 (26%) patients. The most commonly reported serious treatment-related adverse events were Crohn's disease (six [9%]) and abdominal abscess (two [3%]).. Endoscopic, histological, and clinical improvements were seen within 12 weeks of initiating ozanimod therapy in patients with moderately to severely active Crohn's disease. Phase 3 placebo-controlled trials have been initiated.. Celgene Corporation.

Topics: Abdominal Abscess; Administration, Oral; Adult; Aged; Canada; Crohn Disease; Endoscopy; Female; Humans; Hungary; Indans; Induction Chemotherapy; Intention to Treat Analysis; Male; Middle Aged; Oxadiazoles; Patient Reported Outcome Measures; Poland; Prospective Studies; Remission Induction; Sphingosine 1 Phosphate Receptor Modulators; Ukraine; United States

Topics: Crohn Disease; Humans; Indans; Oxadiazoles; Prospective Studies

Topics: Administration, Oral; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Humans; Immunologic Factors; Indans; Inflammatory Bowel Diseases; Oxadiazoles; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinolones; Randomized Controlled Trials as Topic; Treatment Outcome; Tumor Necrosis Factor-alpha

Loss of intestinal epithelial barrier function including typical tight junction changes and epithelial cell apoptosis plays an important role in Crohn's disease. SEW2871, a selective sphingosine-1-phosphate type-1 receptor agonist, has been proven to be efficient in protecting against colitis in IL-10(-/-) mice in our previous study. Here we performed additional studies to investigate whether treatment with SEW2871 was associated with an improved epithelial barrier function in IL-10(-/-) mice. SEW2871 was administered by gavage at a dose of 20 mg/kg/day for 2 weeks to IL-10(-/-) mice. Severity of colitis, CD4+ T cells in colon lamina propria and proinflammatory cytokine productions were evaluated. Furthermore, intestinal permeability, tight junction (occludin and ZO-1) expressions and distributions, as well as epithelial cell apoptosis, were also assessed. SEW2871 treatment attenuated established colitis associated with decreased CD4+ T cells in colon lamina propria and reduced TNF-α and IFN-γ levels. Moreover, enhanced barrier function, which resulted from ameliorated tight junction (occludin and ZO-1) expressions and suppressed epithelial cell apoptosis, was found to contribute to the therapeutic effects. SEW2871 treatment protects from colitis in IL-10(-/-) mice through reduced epithelial cell apoptosis and improved barrier function. Thus, targeting sphingosine-1-phosphate may represent a new therapeutic approach in Crohn's disease.

Topics: Animals; Apoptosis; CD4-Positive T-Lymphocytes; Colitis; Colon; Crohn Disease; Cytokines; Epithelial Cells; Humans; Immunosuppressive Agents; Interleukin-10; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Oxadiazoles; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Thiophenes; Tight Junctions

SEW2871, a selective sphingosine-1-phosphate type 1 receptor (S1P1) agonist, has been shown to be effective in protecting kidneys against ischaemia-reperfusion injury by reducing CD4(+) T cell infiltration in mice. However, the effects of SEW2871 on colitis remain unclear. The aim of this study was to investigate the effects of SEW2871 on established colitis in interleukin (IL)-10 gene-deficient (IL-10(-/-)) mice, a murine model of Crohn's disease (CD). SEW2871 was administered by gavage at a dose of 20 mg/kg/day for 2 weeks to IL-10(-/-) mice. Severity of colitis, serum amyloid A, tissue myeloperoxidase (MPO), T cells in blood and colon lamina propria (LP) and proinflammatory cytokine productions were evaluated. Furthermore, the phospho-signal transducer and activator of transcription (STAT)-3 (p-STAT-3) expression in lymphocytes isolated from colon LP was also assessed. The 2-week administration of SEW2871 ameliorated established colitis in IL-10(-/-) mice, associated with a reduction of serum amyloid A concentration, a decreased colon MPO concentration, a depletion of the peripheral CD4(+) CD45(+) T cells and a reduction of the homing of T cells into colon LP. Moreover, typical cytokines of T helper type 1 (Th1) and Th17 cells and p-STAT-3 expression were also suppressed by SEW2871 treatment. SEW2871 treatment ameliorates established experimental colitis in IL-10(-/-) mice, which may provide a new therapeutic approach for human CD therapy.

Topics: Administration, Oral; Animals; Cell Movement; Colon; Crohn Disease; Cytokines; Disease Progression; Humans; Interleukin-10; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Oxadiazoles; Peroxidase; Receptors, Lysosphingolipid; Serum Amyloid A Protein; STAT3 Transcription Factor; Th1 Cells; Th17 Cells; Thiophenes