Clinical relevance of intestinal barrier dysfunction in common gastrointestinal diseases.

The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall. In this review, we focus on the intestinal barrier's relationship with the host's immune system interaction and the external environment, specifically the microbiome. The bowel allows the host to obtain nutrients vital to survival while protecting itself from harmful pathogens, luminal antigens, or other pro-inflammatory factors. Control over barrier function and the luminal milieu is maintained at the biochemical, cellular, and immunological level. However, disruption to this highly regulated environment can cause disease. Recent advances to the field have progressed the mechanistic understanding of compromised intestinal barrier function in the context of gastrointestinal pathology. There are numerous examples where bowel barrier dysfunction and the resulting interaction between the microbiome and the immune system has disease-triggering consequences. The purpose of this review is to summarize the clinical relevance of intestinal barrier dysfunction in common gastrointestinal and related diseases. This may help highlight the importance of restoring barrier function as a therapeutic mechanism of action in gastrointestinal pathology.

Safety, Tolerability and Pharmacokinetics of Vidofludimus calcium (IMU-838) After Single and Multiple Ascending Oral Doses in Healthy Male Subjects.

BACKGROUND AND OBJECTIVE: Vidofludimus is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The clinical efficacy and safety profile of vidofludimus has been analyzed in patients suffering from rheumatoid arthritis and Crohn's disease and ulcerative colitis. In previous sudies, hematuria at higher doses occurred in close temporal relationship to vidofludimus administration and appeared to be dose related. The present report describes the results from two phase 1 studies conducted in healthy male subjects to investigate the safety, tolerability and pharmacokinetics after single and multiple ascending (SAD and MAD) oral doses of IMU-838 (vidofludimus calcium, tablets containing a specific polymorph). The effect of food on the pharmacokinetics of IMU-838 was also assessed in the SAD study. METHODS: In the SAD study, 12 subjects received single doses of IMU-838 under fasting (10-40 mg) or fed (10 mg) condition in an open-label, partial parallel group design. In the MAD study, 52 subjects received multiple doses of IMU-838 (30-50 mg) in a double-blind, placebo-controlled, parallel group design. RESULTS: IMU-838 showed dose-proportional pharmacokinetics after single and multiple oral dosing in both SAD and MAD studies. IMU-838 was well absorbed after single daily doses. Food did not impact the pharmacokinetics of IMU-838. The accumulation factor for multiple daily dosing was approximately 2. Steady-state concentrations were reached within about 6-8 days for 30-50 mg groups. The geometric mean plasma half-life of IMU-838 at steady state was approximately 30 h, which supports its use for once-daily dosing regimen. Single and multiple oral doses of IMU-838 were safe and well tolerated. CONCLUSION: Overall, oral IMU-838 was generally well tolerated in SAD and MAD studies in healthy subjects over a wide dose range of 10-50 mg. IMU-838 was well absorbed after single daily doses. IMU-838 showed dose proportional pharmacokinetics after single and multiple oral dosing.

The Selective Oral Immunomodulator Vidofludimus in Patients with Active Rheumatoid Arthritis: Safety Results from the COMPONENT Study.

INTRODUCTION: The dihydroorotate dehydrogenase (DHODH) inhibitors leflunomide and teriflunomide are immunomodulatory agents approved to treat rheumatoid arthritis (RA) and multiple sclerosis, respectively, and are actively being investigated as therapeutic agents for other immune-related diseases; however, both structurally related compounds have a number of potentially serious adverse effects. Vidofludimus, a new selective second-generation DHODH inhibitor, is chemically distinct from leflunomide/teriflunomide and appears to exhibit a distinct safety profile. OBJECTIVE: The aim of the COMPONENT study was to assess the efficacy, safety, and pharmacokinetics of vidofludimus in the treatment of patients with active RA on a background therapy of methotrexate. This report focuses solely on the safety results of the COMPONENT trial. METHODS: Patients received once-daily oral vidofludimus (N = 122) or placebo (N = 119) along with their standard of care methotrexate treatment for 13 weeks. Efficacy endpoints were assessed. Safety parameters were monitored throughout treatment and at follow-up. Plasma concentrations of vidofludimus were measured. RESULTS: The primary efficacy endpoint, American College of Rheumatology 20 (ACR20) responder rate at 13 weeks, demonstrated numerical superiority in the treatment group compared with placebo; however, it did not reach statistical significance. Nonetheless, the COMPONENT study yielded important safety and pharmacokinetic data that could provide important information regarding the use of vidofludimus in other clinical trials, not only for RA but also for other autoimmune diseases. A safety profile for vidofludimus similar to placebo was obtained in this RA patient population. This includes similar rates of the adverse events of diarrhea, alopecia, neutropenia, and elevated liver enzymes, all of which are known drug-related adverse events reported for leflunomide and teriflunomide. A potential pharmacokinetic interaction between vidofludimus and methotrexate was observed. CONCLUSIONS: Vidofludimus demonstrated a positive safety profile, making it a promising candidate for the treatment of a variety of immune-related diseases. TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT01010581.

4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease.

BACKGROUND: Dihydroorotate dehydrogenase (DHODH) is a key enzyme involved in pyrimidine biosynthesis. DHODH is a known target for the treatment of autoimmune diseases. 4SC-101 is a novel immunosuppressive drug that inhibits DHODH. A goal of our study was to examine the in vitro effects of 4SC-101 on IL-17 production by mononuclear cells. In addition, we evaluated the efficacy of 4SC-101 against acute TNBS (2,4,6-tritrobenzene sulfonic acid) and chronic dextran sodium sulfate (DSS)-induced colitis in mice. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy human donors were used to evaluate cellular proliferation and cytokine (IL-17, TNF-α) production. The oral effects of 4SC-101 (100 or 200 mg/kg) were examined following induction of chronic colitis by the administration of 3% DSS (4 cycles) to Balb/c mice. Morphometric and histological indices of colitis were evaluated as indicators of drug efficacy. 4SC-101 was also administered for 6 days after the intracolonic administration of TNBS (20 mg in 50% ethanol) to female Balb/c mice. The colons were analyzed for overall macroscopic damage, ulceration, total length, distal segment weight, MPO activity, and histological pathology as indicators for the effectiveness of 4SC-101. RESULTS: In vitro, 4SC-101 is a potent inhibitor of human DHODH, inhibits lymphocyte proliferation, and uniquely blocks phytohemagglutinin-stimulated IL-17 production by lymphocytes. In vivo, oral administration of 4SC-101 effectively improved both chronic DSS and acute TNBS colitis in mice. In these colitis models the overall efficacy profile of 4SC-101 was similar to that of dexamethasone. CONCLUSIONS: 4SC-101 is a novel immunosuppressive drug with excellent potential for the treatment of intestinal inflammation.