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: Massa, Carmen ; Ricci, Patrizia ; Monti, Maria Chiara ; Bucci, Mariarosaria ; Biagioli, Michele ; Morretta, Elva ; 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 ; Rapacciuolo, Pasquale ; Urbani, Ginevra ; Lupia, Antonio ; Morretta, Elva ; Di Giorgio, Cristina ; Moraca, Federica ; 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.

02 Nov 2022·Expert Opinion on Therapeutic Targets

Kidney and lipids: novel potential therapeutic targets for dyslipidemia in kidney disease?

Article

Author: Małyszko, Jacek ; Małyszko, Jolanta ; Zuzda, Konrad ; Grycuk, Wiktoria

INTRODUCTIONAltered lipid distribution and metabolism may lead to the development and/or progression of chronic kidney disease (CKD). Dyslipidemia is a major risk factor for CKD and increases the risk of cardiovascular events and mortality. Therefore, lipid-lowering treatments may decrease cardiovascular risk and prevent death.AREAS COVEREDKey players involved in regulating lipid accumulation in the kidney; contribution of lipids to CKD progression, lipotoxicity, and mitochondrial dysfunction in kidney disease; recent therapeutic approaches for dyslipidemia.EXPERT OPINIONThe precise mechanisms for regulating lipid metabolism, particularly in kidney disease, are poorly understood. Guidelines for lipid-lowering therapy for CKD are controversial. Several hypolipemic therapies are available, but compared to others, statin therapy is the most common. No clinical trial has evaluated the efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in preventing cardiovascular events or improving kidney function among patients with CKD or kidney transplant recipients. Attractive alternatives, such as PCSK9-small interfering RNA (siRNA) molecules or evinacumab are available. Additionally, several promising agents, such as cyclodextrins and the FXR/TGR5 dual agonist, INT-767, can improve renal lipid metabolism disorders and delay CKD progression. Drugs targeting mitochondrial dysfunction could be an option for the treatment of dyslipidemia and lipotoxicity, particularly in renal diseases.

100 Deals associated with BAR-502

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Metabolic dysfunction-associated steatotic liver disease	Phase 3	PT	BAR Pharmaceuticals s.r.l.	25 Nov 2022
Nonalcoholic Steatohepatitis	Phase 1	CH	BAR Pharmaceuticals s.r.l.	04 Dec 2024

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