A Phase I, Two Parts Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of BAR502 in Healthy Subjects

First-in-human, single centre, two parts, dose-escalation, parallel-group, safety, tolerability, pharmacokinetic and pharmacodynamic Phase I study. Part A: randomised, double-blind, placebo-controlled, single ascending dose study.
Part B: open label, multiple ascending dose study.

Start Date04 Dec 2024

Sponsor / Collaborator

BAR Pharmaceuticals s.r.l.

NCT05203367

/ WithdrawnPhase 1

Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses of BAR 502 in Healthy Subjects

This is a prospective, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 study to evaluate the safety and tolerability of single-ascending doses of BAR 502 in healthy male and female subjects.

Start Date25 Nov 2022

Sponsor / Collaborator

BAR Pharmaceuticals s.r.l.

100 Clinical Results associated with BAR-502

100 Translational Medicine associated with BAR-502

100 Patents (Medical) associated with BAR-502

Literatures (Medical) associated with BAR-502

05 Dec 2023·Journal of the American Heart Association

Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G‐Protein Bile Acid Receptor 1/Farnesoid X Receptor Agonism and Statins in the Treatment of Nonalcoholic Fatty Liver Disease

Article

Author: Ricci, Patrizia ; Monti, Maria Chiara ; Massa, Carmen ; Morretta, Elva ; Biagioli, Michele ; Bucci, Mariarosaria ; Urbani, Ginevra ; Cari, Luigi ; Brancaleone, Vincenzo ; Cirino, Giuseppe ; Fiorucci, Stefano ; Bordoni, Martina ; Di Giorgio, Cristina ; Roselli, Rosalinda ; Bellini, Rachele ; Zampella, Angela ; Distrutti, Eleonora ; Giordano, Antonino ; Marchianò, Silvia ; Cieri, Enrico ; Vellecco, Valentina

BackgroundPatients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid–activated receptors exploited in the treatment of nonalcoholic fatty liver disease: whether dual GPBAR1/FXR agonists synergize with statins in the treatment of the liver and cardiovascular components of nonalcoholic fatty liver disease is unknown.Methods and Results Investigations of human aortic samples obtained from patients who underwent surgery for aortic aneurysms and Gpbar1−/− , Fxr−/− , and dual Gpbar1−/‐Fxr−/− mice demonstrated that GPBAR1 and FXR are expressed in the aortic wall and regulate endothelial cell/macrophage interactions. The expression of GPBAR1 in the human endothelium correlated with the expression of inflammatory biomarkers. Mice lacking Fxr and Gpbar1−/− / Fxr−/− display hypotension and aortic inflammation, along with altered intestinal permeability that deteriorates with age, and severe dysbiosis, along with dysregulated bile acid synthesis. Vasomotor activities of aortic rings were altered by Gpbar1 and Fxr gene ablation. In apolipoprotein E −/− and wild‐type mice, BAR502, a dual GPBAR1/FXR agonist, alone or in combination with atorvastatin, reduced cholesterol and low‐density lipoprotein plasma levels, mitigated the development of liver steatosis and aortic plaque formation, and shifted the polarization of circulating leukocytes toward an anti‐inflammatory phenotype. BAR502/atorvastatin reversed intestinal dysbiosis and dysregulated bile acid synthesis, promoting a shift of bile acid pool composition toward FXR antagonists and GPBAR1 agonists. ConclusionsFXR and GPBAR1 maintain intestinal, liver, and cardiovascular homeostasis, and their therapeutic targeting with a dual GPBAR1/FXR ligand and atorvastatin holds potential in the treatment of liver and cardiovascular components of nonalcoholic fatty liver disease.

01 Jan 2023·Frontiers in oncology

Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma.

Article

Author: Ricci, Patrizia ; Fiorucci, Stefano ; Zampella, Angela ; Massa, Carmen ; Distrutti, Eleonora ; Rosselli, Rosalinda ; Bellini, Rachele ; Urbani, Ginevra ; Rapacciuolo, Pasquale ; Lupia, Antonio ; Morretta, Elva ; Moraca, Federica ; Di Giorgio, Cristina ; Marchianò, Silvia ; Biagioli, Michele ; Sepe, Valentina ; Monti, Maria Chiara ; Bordoni, Martina ; Catalanotti, Bruno

IntroductionThe leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).MethodsHerein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues.ResultsThe transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC₅₀ of 3.8 µM.DiscussionBAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.

01 Oct 2011·HepatologyQ1 · MEDICINE

Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2 −/− ( Abcb4 −/−) mouse cholangiopathy model by promoting biliary HCO Symbol output

Q1 · MEDICINE

Article

Author: Gumhold, Judith ; Vecchiotti, Stefania ; Strazzabosco, Mario ; Gonzalez, Frank J. ; Schoonjans, Kristina ; Roda, Aldo ; Fickert, Peter ; Silbert, Dagmar ; Trauner, Michael ; Adorini, Luciano ; Claudel, Thierry ; Baghdasaryan, Anna

Chronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. The nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled receptor, TGR5, regulate bile acid (BA) homeostasis and inflammation. Therefore, we hypothesized that activation of FXR and/or TGR5 could ameliorate liver injury in Mdr2 −/− ( Abcb4 −/−) mice, a model of chronic cholangiopathy. Hepatic inflammation, fibrosis, as well as bile secretion and key genes of BA homeostasis were addressed in Mdr2 −/− mice fed either a chow diet or a diet supplemented with the FXR agonist, INT-747, the TGR5 agonist, INT-777, or the dual FXR/TGR5 agonist, INT-767 (0.03% w/w). Only the dual FXR/TGR5 agonist, INT-767, significantly improved serum liver enzymes, hepatic inflammation, and biliary fibrosis in Mdr2 −/− mice, whereas INT-747 and INT-777 had no hepatoprotective effects. In line with this, INT-767 significantly induced bile flow and biliary HCO Symbol output, as well as gene expression of carbonic anhydrase 14, an important enzyme able to enhance HCO Symbol transport, in an Fxr-dependent manner. In addition, INT-767 dramatically reduced bile acid synthesis via the induction of ileal Fgf15 and hepatic Shp gene expression, thus resulting in significantly reduced biliary bile acid output in Mdr2 −/− mice. Conclusion: This study shows that FXR activation improves liver injury in a mouse model of chronic cholangiopathy by reduction of biliary BA output and promotion of HCO Symbol -rich bile secretion. (Hepatology 2011;54:1303–1312)

100 Deals associated with BAR-502

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Indication	Highest Phase	Country/Location	Organization	Date
Metabolic dysfunction-associated steatotic liver disease	Phase 2	Portugal	BAR Pharmaceuticals s.r.l.	25 Nov 2022
Nonalcoholic Steatohepatitis	Phase 1	Switzerland	BAR Pharmaceuticals s.r.l.	04 Dec 2024

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