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.

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.

Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-κB target gene expression

2007 ◽  
Vol 292 (4) ◽  
pp. G1114-G1122 ◽  
Author(s):  
Yatrik M. Shah ◽  
Xiaochao Ma ◽  
Keiichirou Morimura ◽  
Insook Kim ◽  
Frank J. Gonzalez
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Target Genes ◽  
Clinical Symptoms ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Cytokine Analysis ◽  
Inflammatory Bowel

Pregnane X receptor (PXR) expression was shown to be protective in inflammatory bowel disease (IBD). However, the mechanism by which PXR provides protection remains unclear. Wild-type and Pxr-null mice were treated with the PXR agonist pregnenolone-16α-carbonitrile or vehicle and administered 2.5% dextran sulfate sodium (DSS) in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis. In vivo intestinal permeability assays and proinflammatory cytokine analysis were performed. PXR agonist-treated mice were protected from DSS-induced colitis compared with vehicle-treated mice, as defined by body weight loss, diarrhea, rectal bleeding, colon length, and histology. Pregnenolone-16α-carbonitrile did not decrease the severity of IBD in Pxr-null mice. PXR agonist treatment did not increase epithelial barrier function but did decrease mRNA expression of several NF-κB target genes in a PXR-dependent manner. The present study clearly demonstrates a protective role for PXR agonist in DSS-induced IBD. The data suggest that PXR-mediated repression of NF-κB target genes in the colon is a critical mechanism by which PXR activation decreases the susceptibility of mice to DSS-induced 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 Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents

2021 ◽  
Vol 12 ◽  
Author(s):  
Vu Q. Nguyen ◽  
Kristin Eden ◽  
Holly A. Morrison ◽  
Megan B. Sammons ◽  
Kristin K. Knight ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Signaling Pathway ◽  
Bowel Disease ◽  
Target Genes ◽  
Preliminary Evidence ◽  
Lymphocyte Migration ◽  
Clinical Criteria ◽  
Number Of Patients ◽  
Effective Therapeutic Strategy ◽  
Inflammatory Bowel

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn’s disease (CD) and ulcerative colitis (UC) patients.Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD.Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3.Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

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 Evaluations and Mechanistic Interrogation of Natural Products Isolated From Paeonia suffruticosa for the Treatment of Inflammatory Bowel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Kun-Chang Wu ◽  
Der-Yen Lee ◽  
Jeh-Ting Hsu ◽  
Chi-Fang Cheng ◽  
Joung-Liang Lan ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Therapeutic Potential ◽  
Ethyl Acetate Fraction ◽  
Root Bark ◽  
Dependent Manner ◽  
Paeonia Suffruticosa ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
The Impact

Mu Dan Pi (MDP), a traditional Chinese medicine derived from the root bark of Paeonia suffruticosa Andrews, is used to treat autoimmune diseases due to its anti-inflammatory properties. However, the impact of MDP on inflammatory bowel disease (IBD) and its principal active compounds that contribute to the anti-inflammatory properties are uncertain. Thus, this study systemically evaluated the anti-inflammatory effects of fractionated MDP, which has therapeutic potential for IBD. MDP fractions were prepared by multistep fractionation, among which the ethyl acetate-fraction MDP5 exhibited the highest potency, with anti-inflammatory activity screened by the Toll-like receptor (TLR)-2 agonist, Pam3CSK4, in a cell-based model. MDP5 (at 50 μg/ml, p < 0.001) significantly inhibited nuclear factor kappa-B (NF-κB) reporters triggered by Pam3CSK4, without significant cell toxicity. Moreover, MDP5 (at 10 μg/ml) alleviated proinflammatory signaling triggered by Pam3CSK4 in a dose-dependent manner and reduced downstream IL-6 and TNF-α production (p < 0.001) in primary macrophages. MDP5 also mitigated weight loss, clinical inflammation, colonic infiltration of immune cells and cytokine production in a murine colitis model. Index compounds including paeoniflorin derivatives (ranging from 0.1 to 3.4%), gallic acid (1.8%), and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (1.1%) in MDP5 fractions were identified by LC-MS/MS and could be used as anti-inflammatory markers for MDP preparation. Collectively, these data suggest that MDP5 is a promising treatment for IBD patients.

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