scholarly journals P259 Safety, tolerability and pharmacokinetics of BT051, an oral inhibitor of neutrophil migration and activation in clinical development for Inflammatory Bowel Disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S294-S294
Author(s):  
C Murphy ◽  
C Stevens ◽  
E Hershberger ◽  
M Quintas ◽  
B Miller ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Healthy Subjects ◽  
Human Study ◽  
Neutrophil Migration ◽  
Systemic Exposure ◽  
Clinical Development ◽  
Blood Concentrations ◽  
Systemic Immunosuppression ◽  
Inflammatory Bowel

Abstract Background BT051 is an oral, locally acting inhibitor of neutrophil trafficking and activation in clinical development for the treatment of patients with Inflammatory Bowel Disease (IBD). Herein we report the results of this first-in-human study of BT051 in healthy subjects. Methods This was a phase 1, randomised, double-blind, placebo-controlled, single-centre, single ascending dose (SAD) study. Healthy subjects (n=50) were randomised into 5 SAD cohorts to receive BT051 (100, 300, 700, 1500 or 3500 mg) or placebo (8 active:2 placebo in each cohort). A safety review committee evaluated any dose-limiting adverse events (AEs) through Day 3 before proceeding to the next cohort. Samples for pharmacokinetic (PK) analysis were collected from blood, stool and urine predose and up to 48 hours postdose; stool samples for PK analysis were also collected on Day 7. An exploratory endpoint of systemic immunosuppression was performed by assessing cytokine secretion induced from T-cells in subjects’ peripheral blood mononuclear cells (PBMC) at 4 and 24 hours postdose. Results Fifty healthy subjects were dosed with BT051 (n=40) or placebo (n=10). No dose-limiting toxicities, serious AEs or study discontinuations due to AEs were observed. Nine (22.5%) BT051 subjects and 2 (20%) placebo subjects experienced at least 1 mild or moderate AE with only vessel puncture site pain and constipation reported in more than 1 subject (n=2). Mean % of dose excreted in stool from partial collection ranged between 11.3–26.3%. At all doses tested, concentrations of BT051 in the large intestine were estimated to exceed >20x the threshold for inhibition of neutrophil transmigration and activation in vitro (1 μM) and continued to be detected out to 7 days postdose. Generally, blood concentrations of BT051 were undetectable except in two subjects at one time point each: one subject at 24 hours postdose who received 700 mg BT051 (70 ng/mL) and another subject at 12 hours postdose who received 1500 mg BT051 (8 ng/mL). Mean % of dose excreted in urine through 48 hours postdose ranged between 0.01–0.03%. No evidence of systemic T-cell immunosuppression was observed at any dose level. Conclusion Single ascending doses up to 3500 mg of BT051 were safe and well-tolerated in healthy subjects. Stool concentrations out to 7 days postdose that exceed the expected efficacious threshold, minimal to no systemic exposure and the lack of systemic immunosuppression support the continued development of BT051 as a gut-targeted therapy for patients with IBD.

scholarly journals P306 MORF-057, an oral selective α4β7 integrin inhibitor for Inflammatory Bowel Disease, leads to specific target engagement in a single and multiple ascending dose study in healthy subjects

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S333-S335
Author(s):  
A Ray ◽  
D Cui ◽  
D Lee ◽  
M M Mangada ◽  
J Jones ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Systemic Exposure ◽  
Drug Discontinuation ◽  
Target Engagement ◽  
Evening Dose ◽  
Limit Of Quantitation ◽  
Inflammatory Bowel

Abstract Background MORF-057 is an orally administered small molecule designed to inhibit the α 4β 7 receptor, addressing an unmet medical need in inflammatory bowel disease (IBD) patients, and avoiding the need for periodic therapeutic infusions and the risk for infusion-related reactions. This study evaluated single (SAD) and multiple ascending doses (MAD) of MORF-057 in healthy volunteers. Methods This was a randomized, double-blind, placebo-controlled, single and multiple doses, phase 1 study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MORF-057 conducted in a Phase I Unit in the USA. Subjects were randomized 3:1 to MORF-057 or placebo capsules once daily in the SAD cohorts: 25, 50, 100, 150, and 400 mg; or twice daily (BID) in the MAD cohorts: 100 and 200 mg total daily doses (dosed as 50 and 100 mg BID, respectively). In the MAD cohorts, trough PK samples were obtained premorning or pre-evening dose following administration of 50 or 100 mg BID, respectively. Blood samples to assess receptor occupancy (RO) of α 4β 7 and α 4β 1 integrins were obtained prior to the first dose and 12 hours after treatment. Results To date, 51 healthy subjects were dosed; 1 subject withdrew consent on Day 2 for personal reasons. Eleven non-serious adverse events (AEs) were reported; AEs were mild and did not result in discontinuation. Two reversible mild AEs in the 200 mg MAD cohort were possibly related to MORF-057 (macular / maculopapular rash). No safety signals were identified to date. Following dosing, MORF-057 was rapidly absorbed and systemic exposure increased approximately dose-proportionally (Fig.1). Mean α 4β 7 RO was found to be greater than 95% after each of the three highest single doses (Fig.2). In multiple dosing, mean α 4β 7 RO was greater than 90% at the lower dose, while the highest dose tested resulted in α 4β 7 RO saturation at steady state. α 4β 1 RO was below the limit of quantitation with mean trough values estimated to be <10% at any of the dose levels. Conclusion Current results demonstrated that single and multiple ascending doses of MORF-057 were well tolerated, with only mild, non-serious AEs reported that did not result in study drug discontinuation. MORF-057 demonstrated a favorable PK profile where target engagement was confirmed and resulted in α4β7 receptor saturation in many subjects receiving higher doses. These results support further investigation of MORF-057 and provide a basis for dose selection phase 2 studies in patients with IBD. (NCT04580745)

scholarly journals P540 GB004, a novel prolyl hydroxylase inhibitor for inflammatory bowel disease, leads to gut-targeted HIF-1α pathway engagement in a multiple-dose study in healthy subjects

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S461-S462
Author(s):  
B Levesque ◽  
K Taylor Meadows ◽  
A Buch ◽  
M Flynn ◽  
K Peters ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Healthy Subjects ◽  
Multiple Dose ◽  
Prolyl Hydroxylase ◽  
Colonic Tissue ◽  
Dose Study ◽  
Inflammatory Bowel ◽  
Hif Pathway ◽  
Dose Levels

Abstract Background GB004 is a small-molecule prolyl hydroxylase inhibitor that stabilises hypoxia-inducible factors (HIF-1α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-1α stabilisation. GB004 is in clinical development for the treatment of inflammatory bowel disease and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple daily doses of GB004 in plasma and colon biopsies. Methods This was a randomised, double-blind, placebo-controlled, multiple-dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 or placebo formulated as a solution were administered orally once a day for 8 days; safety and PK were evaluated. Colon biopsies were obtained one day prior to the first dose and on Day 8. Colonic tissue concentrations of GB004 and HIF pathway target genes were determined. Results Forty-two subjects (20 male and 22 female) were dosed. No serious adverse events or deaths were recorded. The most commonly observed adverse event in GB004-treated subjects was dizziness (31%,10/32); all events were mild and did not result in study drug discontinuation. There were no identified risks of GB004. Following oral dosing, GB004 was rapidly absorbed and eliminated from the systemic circulation, with a median time to maximum concentration of 0.5 h for all dose levels. Concentrations of GB004 measured in colon biopsies were greater than in plasma at the time of the biopsy. Dose-related HIF pathway target gene engagement and PD were confirmed. Conclusion This study demonstrated that multiple daily doses of GB004 solution were safe and tolerable. The PK profile was consistent with its intended preferential exposure in the gut. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, tolerability, PK and PD both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed.

scholarly journals The Possible Role of the Novel Cytokines IL-35 and IL-37 in Inflammatory Bowel Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Yanmei Li ◽  
Yanan Wang ◽  
Ying Liu ◽  
Yatian Wang ◽  
Xiuli Zuo ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Healthy Subjects ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Intestinal Epithelial ◽  
Gene Expressions ◽  
Expression Studies ◽  
Novel Biomarkers ◽  
Inflammatory Bowel

Interleukin- (IL-) 35 and IL-37 are newly discovered immune-suppressing cytokines. They have been described in inflammatory diseases such as collagen-induced arthritis and asthma. However, their expressions in inflammatory bowel disease (IBD) patients have not been yet explored. Our aim was to evaluate serum and inflamed mucosal levels in IBD patients. In 20 ulcerative colitis (UC) patients, 7 Crohn’s disease (CD) patients, and 15 healthy subjects, cytokine levels in serum were determined using ELISA and mucosal expression studies were performed by immunohistochemistry, quantitative real-time PCR, and Western blot. The results showed that serums IL-35 and IL-37 levels were significantly decreased in UC and CD patients compared with healthy subjects. The cytokines levels correlated inversely with UC activity. IL-35 was expressed in infiltrating immune cells while IL-37 in intestinal epithelial cells as well as inflammatory cells. IBD patients had significantly higherEbi3,p35(two subunits of IL-35), andIL-37bgene expressions; IL-35 and IL-37 protein expressions were higher in IBD patients compared with controls. The study showed that serums IL-35 and IL-37 might be potentially novel biomarkers for IBD. Intestinal IL-35 and IL-37 proteins are upregulated, suggesting that regulating the expression of the two cytokines may provide a new possible target for the treatment of IBD.

scholarly journals High Prevalence of Ultrasound Verified Enthesitis in Patients With Inflammatory Bowel Disease With or Without Spondylarthritis

2021 ◽  
Vol 8 ◽  
Author(s):  
Rusmir Husic ◽  
Angelika Lackner ◽  
Patrizia Katharina Kump ◽  
Christoph Högenauer ◽  
Winfried Graninger ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Irritable Bowel Syndrome ◽  
Bowel Disease ◽  
Healthy Subjects ◽  
Ultrasound Examination ◽  
Clinical Signs ◽  
Extraintestinal Manifestation ◽  
High Prevalence ◽  
Inflammatory Bowel ◽  
Irritable Bowel

Background: Inflammatory bowel disease (IBD) is closely associated with spondylarthritis (SpA) and enthesitis, as an important feature of SpA, is a common extraintestinal manifestation of IBD. Enthesitis may be clinically silent in a high proportion of patients with IBD without clinical signs or a diagnosis of SpA.Objectives: The aim of this study was to compare the prevalence of ultrasound (US) verified enthesitis in IBD patients with and without SpA, with patients with irritable bowel syndrome (IBS) and healthy subjects (HC) serving as controls.Methods: IBD patients with or without SpA, patients with IBS and HC were prospectively recruited and clinically assessed. Ultrasound examination was performed at 14 entheses. The ultrasound abnormalities were scored according to the Madrid Ankylosing Spondylitis Enthesitis Index (MASEI).Results: We included 33 IBD patients without SpA, 14 IBD patients with SpA, 26 IBS patients and 18 HC. Higher MASEI scores were found in patients with IBD without SpA [median 21.0 range (8.0–53.0)] and IBD associated SpA [33.0 (8–50)] than in IBS patients [10.5 (0–42.0)-p < 0.001 for both comparison] and HC [12.0 (2.0–38.0)-p < 0.01]. PD, enthesophytes and erosions were more common in patients with IBD with or without SpA as compared to IBS patients and HC. IBD patients with SpA compared to IBD without SpA demonstrated significant higher prevalence of erosion and structural irregularity and consequently significant higher MASEI (p < 0.05 for all comparison).Conclusions: Ultrasound verified enthesitis is more common in patients with IBD with or without SpA as compared to patients with IBS or HC.

scholarly journals How could nanobiotechnology improve treatment outcomes of anti-TNF-α therapy in inflammatory bowel disease? Current knowledge, future directions

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Piotr Eder ◽  
Aleksandra Zielińska ◽  
Jacek Karczewski ◽  
Agnieszka Dobrowolska ◽  
Ryszard Słomski ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Treatment Outcomes ◽  
Bowel Disease ◽  
Current Knowledge ◽  
Systemic Exposure ◽  
Serious Adverse Events ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Long Term Treatment ◽  
Inflammatory Bowel

AbstractDespite significant advances in therapeutic possibilities for the treatment of inflammatory bowel disease (IBD) in recent years, there is still a big room for improvement. In particular, biological treatment can induce not only clinical remission but also mucosal healing of the gastrointestinal tract. Among these therapeutic molecules, anti-tumor necrosis factor-alpha (anti-TNF-α) antibodies were the first to revolutionize treatment algorithms in IBD. However, due to the parenteral route of administration and systemic mode of action, TNF-α blockers are characterised by high rates of immunogenicity-related loss of response and serious adverse events. Moreover, intravenous or subcutaneous therapy is not considered patient-friendly and requires occasional, direct contact with healthcare centres. To overcome these limitations, several attempts have been made to design oral pharmaceutical formulations of these molecules. It is hypothesized that oral anti-TNF-α antibodies therapy can directly provide a targeted and potent anti-inflammatory effect in the inflamed gastrointestinal tissues without significant systemic exposure, improving long-term treatment outcomes and safety. In this review, we discuss the current knowledge and future perspectives regarding different approaches made towards entering a new era of oral anti-TNF-α therapy, namely, the tailoring of biocompatible nanoparticles with anti-TNF-α antibodies for site-specific targeting to IBD. In particular, we discuss the latest concepts applying the achievements of nanotechnology-based drug design in this area. Graphical Abstract

P459 Expression of SerpinE1, a potential new disease activity marker, reflects therapeutic response in Inflammatory Bowel Disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S453-S453
Author(s):  
B Jójrt ◽  
T Molnár ◽  
V Szabó ◽  
Á Varga ◽  
T Resál ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Disease Activity ◽  
Bowel Disease ◽  
Healthy Subjects ◽  
Expression Patterns ◽  
Invasive Disease ◽  
Gene Expressions ◽  
Inflammatory Bowel ◽  
Active Disease ◽  
Control Samples

Abstract Background Inflammatory Bowel Disease (IBD) occurs as a consequence of abnormal immune response generating unbalance between pro- and anti-inflammatory signalling. Analysis of cytokine profiles in view of different cytokine targeting or immunosuppressive therapy may open up new therapeutic targets and may reveal biological profiles that distinguish responders from non-responders before initiating therapy. The aim of present study was to determine cytokine profile of IBD patients and identify cytokines with predictive potential. Methods IBD patients with clinically active disease were enrolled in study. Blood and biopsy samples were obtained from 22 IBD patients and 5 healthy controls. Biopsies were taken from inflamed and non-inflamed part of colon of IBD patients. Total protein and mRNA were isolated from biopsy samples. Cytokine Array was used to analyse cytokine expression patterns. Serum and mucosal SerpinE1 levels were measured by ELISA and qRT-PCR. Results In samples from IBD patients, remarkable discrimination between inflamed, or non-inflamed areas was observed, whereas no pro-inflammatory cytokines were detected in control samples. SerpinE1 was presented in every inflamed biopsy samples, which was analyzed in more details. Mucosal expression of SerpinE1 differed significantly in healthy subjects compared to IBD patients with active disease (0 vs 24.06 pg/mg, p=0.02). After therapy induction a remarkable decrease was observed in the mucosal SerpinE1 concentration in responders (45.5 vs 9.7 pg/mg, p=0.02) versus non-responders (45 vs 61.2 pg/mg, p=0.3). Moreover, mean value of mucosal SerpinE1 did not differ significantly in healthy subjects compared to responders (5.7 vs. 0 pg/mg, p=0.12). In non-responders the fold changes of SerpinE1 gene expressions were significantly (p=0.001) higher than in responders. Lowest expression of SerpinE1 gene was measured in control samples, whereas the highest in untreated, inflamed biopsy samples. Serum and mucosal SerpinE1 concentrations were significantly higher in patients with active disease compared to inactive (tissue: 5 vs 47.4 pg/mg, p=0.00003; serum: 22.4 vs 25.94 mg/ml, p=0.022). Correlation analysis revealed that serum SerpinE1 correlates with disease activity (p<0,01, cut-off value: 22 mg/ml, sensitivity=80%, specificity=60%, accuracy=74%), whereas no correlation was observed between the mucosal SerpineE1 concentration and the disease activity (p>0.1, sensitivity=72%, specificity=77.8%, accuracy=73.5%). Conclusion These results suggest that serum and mucosal SeprinE1 expression reflects endoscopic activity of IBD. Correlation of SerpinE1expression between the blood and the bowel mucosa would open up new possibilities in non-invasive disease monitoring of IBD.

Su1291 A Selective Breath Metabolome Signature Accurately Differentiates Inflammatory Bowel Disease Patients From Healthy Subjects

2014 ◽  
Vol 146 (5) ◽  
pp. S-427-S-428
Author(s):  
Satya V. Kurada ◽  
David Grove ◽  
Frank Cikach ◽  
Nishaben Patel ◽  
Naim Alkhouri ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Healthy Subjects ◽  
Inflammatory Bowel
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