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 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.

P066 GB004, A NOVEL GUT-TARGETED PROLYL HYDROXYLASE INHIBITOR FOR INFLAMMATORY BOWEL DISEASE: FIRST-IN-HUMAN, MUTLIPLE-DOSE STUDY IN HEALTHY SUBJECTS WITH GUT BIOPSIES

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S9-S10
Author(s):  
Barrett Levesque ◽  
Kristen Taylor Meadows ◽  
Akshay Buch ◽  
Michael Flynn ◽  
Kevin Peters ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Healthy Subjects ◽  
Target Genes ◽  
Prolyl Hydroxylase ◽  
Drug Discontinuation ◽  
Dependent Manner ◽  
Dose Study ◽  
Inflammatory Bowel ◽  
Prolyl Hydroxylase Inhibitor

Abstract Background GB004 is a small molecule prolyl hydroxylase inhibitor (PHDi) that stabilizes hypoxia inducible factors (HIF1-α), 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 HIF1-α stabilization. Consistent with this, orally administered GB004 in a healthy non-human primate model engaged HIF-related genes in the gut, and, in animal models of colitis, demonstrated a significant reduction in disease activity, improvements in histologic measures, and greater exposure in GI tissue relative to plasma. GB004 is in clinical development for treatment of inflammatory bowel disease (IBD) and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, and pharmacokinetics (PK) of multiple daily doses of GB004 in plasma and colon biopsies. Methods This was a randomized, double-blind, placebo-controlled, multiple dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 formulated as a solution or placebo solution were administered orally once a day for 8 days; safety and PK were evaluated. Plasma levels of HIF target genes EPO and VEGF were determined by immunoassays from samples collected at pre-dose, 4, 8, and 12 hours post dose on Day 1 and Day 7. Colon biopsies were obtained one day prior to first dose and at Day 8. Results 42 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%;10/22); 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 hour for all doses. Both Cmax and AUC of GB004 increased in a dose-dependent manner on Day 1 and 7. Concentrations of GB004 measured in colon biopsies were greater than concentrations in the plasma at the time of biopsy. Changes in plasma EPO or VEGF levels were similar for GB004 and placebo with no dose-related effects observed. Conclusions 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. In support of the gut-targeted exposure, HIF target genes EPO and VEGF were not modulated in plasma. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, PK, and pharmacodynamics both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed.

Codesign and implementation of an equity-promoting national health literacy programme for people living with inflammatory bowel disease (IBD): a protocol for the application of the Optimising Health Literacy and Access (Ophelia) process

BMJ Open ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. e045059
Author(s):  
Melanie Hawkins ◽  
Wayne Massuger ◽  
Christina Cheng ◽  
Roy Batterham ◽  
Gregory T Moore ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Health Literacy ◽  
Bowel Disease ◽  
Phase 1 ◽  
Qualitative Interviews ◽  
Local Health ◽  
Literacy Programme ◽  
Sustainable Solutions ◽  
University Of Technology ◽  
Inflammatory Bowel

IntroductionNon-government organisations (NGOs) often represent people who are underserved or experiencing vulnerability. Crohn’s & Colitis Australia (CCA) is aware that many Australians with inflammatory bowel disease (IBD) are not reached by current communication and engagement activities. The aim of the CCA IBD project is to implement the Optimising Health Literacy and Access (Ophelia) process over 3 years to collaboratively codesign ways to improve delivery of information, services and resources for people with IBD and their carers.Methods and analysisHealth literacy and other data for phase 1 will be collected using the Health Literacy Questionnaire, eHealth Literacy Questionnaire, IBD-related questions and qualitative interviews with people with IBD and their carers to ascertain their lived experience. Quantitative data will be analysed using descriptive statistics and cluster analysis. Identified clusters will be combined with qualitative data to develop vignettes (narratives of people’s experiences of living with IBD) for stakeholder workshops to generate ideas for useful, accessible and sustainable solutions for identified health literacy needs. Selection and testing of health literacy actions happens in phase 2 and implementation and evaluation in phase 3 (2021–2023). Outcomes of this project include giving voice to people living with IBD, their carers and frontline healthcare practitioners. Genuine codesign informs the development and implementation of what is needed and wanted to improve access to and availability and quality of information and resources that support people to manage their health. There is potential for other NGOs to use the CCA Ophelia model in other health contexts to improve engagement with and understanding of the needs of the people they serve and to reduce health inequalities and improve health outcomes.Ethics and disseminationEthics approval for Ophelia phase 1 has been obtained from the Human Research Ethics Committee of Swinburne University of Technology (Ref: 20202968–4652) and by the South West Sydney Local Health District Research and Ethics Office for the purposes of questionnaire recruitment at Liverpool Hospital (Ref: 20202968–4652). Dissemination of the study findings will be the national codesign process and ownership development across the CCA community and through the genuine engagement of clinicians and relevant managers across Australia. The model and process will be directly distributed to international IBD associations and to other NGOs. It will also be disseminated through publication in a peer-reviewed journal, conference presentations and public reports on the CCA and Swinburne University of Technology website.

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 Proactive Infliximab Monitoring Following Reactive Testing is Associated With Better Clinical Outcomes Than Reactive Testing Alone in Patients With Inflammatory Bowel Disease

2018 ◽  
Vol 12 (7) ◽  
pp. 804-810 ◽  
Author(s):  
Konstantinos Papamichael ◽  
Ravy K Vajravelu ◽  
Byron P Vaughn ◽  
Mark T Osterman ◽  
Adam S Cheifetz
Keyword(s):  
Inflammatory Bowel Disease ◽  
Treatment Failure ◽  
Bowel Disease ◽  
Cox Regression ◽  
Drug Discontinuation ◽  
Cox Regression Analysis ◽  
Loss Of Response ◽  
Group A ◽  
Inflammatory Bowel ◽  
Group B

Abstract Background and Aims Reactive testing has emerged as the new standard of care for managing loss of response to infliximab in inflammatory bowel disease [IBD]. Recent data suggest that proactive infliximab monitoring is associated with better therapeutic outcomes in IBD. Nevertheless, there are no data regarding the clinical utility of proactive infliximab monitoring after first reactive testing. We aimed to evaluate long-term outcomes of proactive infliximab monitoring following reactive testing compared with reactive testing alone in patients with IBD. Methods This was a retrospective multicenter cohort study of consecutive IBD patients on infliximab maintenance therapy receiving a first reactive testing between September 2006 and January 2015. Patients were divided into two groups; Group A [proactive infliximab monitoring after reactive testing] and Group B [reactive testing alone]. Patients were followed through December 2015. Time-to-event analysis for treatment failure and IBD-related surgery and hospitalization was performed. Treatment failure was defined as drug discontinuation due to either loss of response or serious adverse event. Results The study population consisted of 102 [n = 70, 69% with CD] patients [Group A, n = 33 and Group B, n = 69] who were followed for (median, interquartile range [IQR]) 2.7 [1.4–3.8] years. Multiple Cox regression analysis identified proactive following reactive TDM as independently associated with less treatment failure (hazard ratio [HR] 0.15; 95% confidence interval [CI] 0.05–0.51; p = 0.002) and fewer IBD-related hospitalizations [HR: 0.18; 95% CI 0.05–0.99; p = 0.007]. Conclusions This study showed that proactive infliximab monitoring following reactive testing was associated with greater drug persistence and fewer IBD-related hospitalizations than reactive testing alone.

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 Efficacy of Anti-TNF Therapy for the Treatment of Patients with Moderate-to-Severe Inflammatory Bowel Disease; a First Iranian Report

2019 ◽  
Vol 12 (1) ◽  
pp. 12-18
Author(s):  
Samaneh Mohagheghi Darehranj ◽  
Sudabeh Alatab ◽  
Homayoon Vahedi ◽  
Anahita Sadeghi ◽  
Alireza Sima ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Adverse Events ◽  
Bowel Disease ◽  
National Level ◽  
Complete Response ◽  
Drug Discontinuation ◽  
Serious Adverse Events ◽  
Inflammatory Bowel ◽  
One Year ◽  
First Time

BACKGROUND The anti-TNF drugs are shown to be highly effective in treatment of patients with moderate-tosevere inflammatory bowel disease (IBD). Here, we aimed to assess the efficacy and safety of antiTNF therapy at the national level. METHODS IBD patients aged 15 > years who received Infliximab and/or CinnoRA® between 2013 to July 2018 were identified. The data extracted from medical dossier and telephonic interview. The efficacy of therapy was defined as time to drug discontinuation or need for IBD-related surgery. The safety was assessed based on patient’s reported adverse events. RESULTS We included 315 patients. The mean age of patients was 37.2 years and 62.2% of them developed the disease before age 30 years. Involvement of masculoskeletal system was reported in 7.3% of patients. Partial and complete response to Anti-TNF therapy was seen in 67% of patients. About 16% of patients did not respond to induction therapy and 16.9% of patients lost their response to Anti-TNF during one year. No serious adverse events, serious opportunistic infection, tuberculosis and malignancies reported by patients. Two patients reported pneumonia. CONCLUSION This study for the first time in our country, provides the evidences for efficacy of anti-TNF therapy in moderate to severe IBD patients.

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