A Double-blind, Randomised, Placebo-controlled, Dose-escalation Study of the Safety, Tolerability and Pharmacokinetics of Increasing Multiple Oral Doses of Px-102 to Healthy Subjects

The purpose of this study is to assess the safety and tolerability of the FXR agonist Px-102 in healthy subjects after 7 days multiple oral dosing.

开始日期2012-02-01

申办/合作机构

Phenex Pharmaceuticals AG

NCT01998659 / Completed临床1期

A Double-blind, Randomized, Placebo-controlled, Dose-escalation Study of the Safety, Tolerability and Pharmacokinetics of Increasing Single Oral Doses of Px-102 to Healthy Subjects

The purpose of this study is to assess the safety and tolerability of the FXR agonist Px-102 in healthy subjects after single oral dosing.

开始日期2011-09-01

申办/合作机构

Phenex Pharmaceuticals AG

100 项与 Px-102 相关的临床结果

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100 项与 Px-102 相关的转化医学

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100 项与 Px-102 相关的专利（医药）

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项与 Px-102 相关的文献（医药）

2022-06-01·Archives of Toxicology2区 · 医学

Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway

2区 · 医学

Article

作者: Wu, Zhitao ; Pan, Guoyu ; Feng, Shanshan ; Deng, Qiangqiang ; Zhang, Tianwei ; Li, Jiahuan ; Li, Jing ; Yang, Wei

Farnesoid X receptor (FXR) plays an indispensable role in liver homeostasis and has been a promising drug target for hepatic diseases. However, the concerns of undesired biological actions limit the clinical applications of FXR agonists. To reveal the intrinsic mechanism of FXR agonist-induce hepatotoxicity, two typical FXR agonists with different structures (obeticholic acid (OCA) and Px-102) were investigated in the present study. By detecting MMP, ROS, and ATP and analyzing the fate of cells, we found that both OCA and Px-102 reduced the mitochondrial function of hepatocytes and promoted cell apoptosis. Gene ablation or inhibition of FXR or SHP ameliorated the cytotoxicities of OCA and Px-102, which indicated the adverse actions of FXR/SHP activation including down-regulation of phosphorylation of PI3K/AKT and functional hepatic genes. The dose-related injurious effects of OCA (10 mg/kg and 30 mg/kg) and Px-102 (5 mg/kg and 15 mg/kg) on the liver were confirmed on a high-fat diet mouse model. The decrease of hepatocyte-specific genes and augmenter of liver regeneration in the liver caused by OCA or Px-102 suggested an imbalance of liver regeneration and a disruption of hepatic functions. Exploration of intestinally biased FXR agonists or combination of FXR agonist with apoptosis inhibitor may be more beneficial strategies for liver diseases.

2018-10-01·Gastroenterology1区 · 医学

An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers

1区 · 医学

Article

作者: Al-Khaifi, Amani ; Rudling, Mats ; Angelin, Bo

Bile acid (BA) synthesis is regulated through suppression of hepatic cholesterol 7α-hydroxylase via farnesoid X receptor (FXR) activation in hepatocytes and/or enterocytes; in enterocytes, this process requires FGF19 signaling. To study these pathways, we quantified markers of BA synthesis (7α-hydroxy-4-cholesten-3-one [C4]) and cholesterol production (lathosterol), fibroblast growth factor (FGF)19, and BAs in serum from healthy male volunteers given 1 oral dose of the nonsteroidal FXR agonist Px-102 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.12 mg/kg, 2.25 mg/kg, 3.38 mg/kg, or 4.5 mg/kg). After 8 hours, serum levels of C4 decreased by 80% in volunteers given 0.15 mg/kg, whereas serum levels of FGF19 were unchanged. Serum levels of FGF19 increased significantly, in a dose-dependent manner, in volunteers given >0.3 mg/kg Px-102, up to as much as 1600%, whereas C4 levels remained significantly reduced (by >80%). For all doses, FGF19 levels returned to normal 24 hours after administration of Px-102. Serum levels of C4 decreased before levels of FGF19 levels increased, and were still reduced by 95% 24 hours after the highest dose (4.5 mg/kg) of Px-102, even though levels of FGF19 had returned to baseline. Our findings indicate that activation of hepatic FXR is able to suppress BA synthesis, independent of FGF19.

2017-04-01·Journal of Hepatology1区 · 医学

Steroidal or non-steroidal FXR agonists – Is that the question?

1区 · 医学

Communications

作者: Nevens, Frederik ; Laleman, Wim ; Verbeke, Len

A review.The author discusses about the detection of therapeutic potential of non-steroidal FXR agonist such as PX20606 and steroidal FXR agonist such as obeticholic acid in human and rat models with cirrhotic portal hypertension, hepatic fibrosis and bacterial translocation.

项与 Px-102 相关的新闻（医药）

2011-09-15

·BioSpace

Phenex Pharmaceuticals AG Begins Phase I First-In-Man Study With its Clinical Development Candidate Px-102

Ludwigshafen, September 15th, 2011 -- Phenex Pharmaceuticals AG announced today the start of a first-in-man Phase I study with its clinical drug candidate Px-102, a synthetic non-steroidal FXR agonist. The volunteers of the first dose level received the drug and showed no signs of discomfort or other adverse effects. This Phase I first-in-man study will be escalated from the initial dose over seven dose levels to obtain information about the tolerance and pharmacokinetics of Px-102 in healthy volunteers. Following this first Phase I study Phenex plans to run a multiple ascending dose Phase I study where the same parameters will be observed during several days of multiple administrations. The Phase I studies for Px-102 will be finished by early 2012. If all requirements are met, Phenex then plans to test Px-102 in a Phase II study in patients with Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease (NAFLD) to confirm if the potent therapeutic effects such as lipid lowering, improvement of insulin sensitivity and reduction of markers for liver damage which were observed in several animal studies can be reproduced in human patients Px-102 is a potent, fully-synthetic and non-steroidal FXR agonist. The Farnesoid X Receptor (FXR) is a bile acid receptor which when activated by Px-102 has a profound positive impact on cholesterol, triglyceride and glucose metabolism in liver and intestine. As was already demonstrated in several publications and Phenex-proprietary animal studies the FXR agonist Px-102 potently reduces intestinal uptake of neutral lipids and cholesterol and at the same time enhances the excretion of these lipid species. In addition, Px-102 improves hepatic insulin sensitivity and shows massive hepatoprotective effects in animal models of liver cirrhosis or fibrosis. It is this combination of potent metabolic and liver protective effects that makes Px-102 an ideal candidate for the treatment of Non-Alcoholic Steatohepatitis (NASH). Inflammation and beginning fibrosis are the hallmarks in people with NASH-livers which affects a subset of individuals who have developed a fatty liver due to an unhealthy lifestyle and overweight. The prevalence of NASH is estimated to approach 5% of the total population in industrialized countries. NASH markedly increases the likelihood to develop liver cancer or end stage liver cirrhosis. Currently there is no approved therapy for NASH. We aim at filling exactly this gap in medical treatment of liver diseases,“ says Dr. Claus Kremoser, CEO of Phenex. “NASH and associated liver and metabolic diseases are on the rise and there is no pharmacotherapy approved. Potent synthetic FXR-agonists such as Px-102 have the potential to improve the overall metabolic state as well as the inflammatory and fibrotic changes in livers of NASH patients. Next to the therapy of NASH itself, Px-102 may be well suited to treat related diseases such as liver cirrhosis and fibrosis, Primary Biliary Cirrhosis (PBC) or Portal Hypertension.” About Phenex Pharmaceuticals AG: Phenex is a privately held drug discovery and development company headquartered in Ludwigshafen with a research site in Heidelberg. The company focuses on novel attractive nuclear receptor targets to develop innovative small molecule therapeutics in the fields of metabolic syndrome / NASH and in autoimmune diseases. Phenex´ most advanced program is Px-102, now at Phase I clinical stage, and it targets the nuclear bile acid receptor FXR. This FXR agonist has unique properties in that it shows beneficial effects in lipid lowering, in improving insulin sensitivity, in reducing body weight and in ameliorating the liver inflammation and fibrosis that are hallmarks of Non-Alcoholic Steatohepatitis (NASH). NASH is a metabolically induced liver disease with a worldwide prevalence of at least 25 million affected individuals. If untreated, the disease can progress towards liver cirrhosis and liver failure or to Hepatocellular Carcinoma (HCC). There is no approved treatment for NASH. Px-102 addresses this medical need and represents a significant commercial opportunity. Phenex´ second R&D program targets the nuclear receptor ROR?t. ROR?t inhibitors hold the promise to become a new therapeutic approach in different autoimmune diseases with substantially reduced side effects. This project is at lead optimisation status. The company intends to develop its R&D programs up to a proof-of-concept study in humans in the case of FXR and up to late preclinical stage in the case of ROR?t. At these stages the company will seek partners from the pharmaceutical industry to license these molecules for further development. Phenex is financed through three consecutive rounds of funding bringing the total equity raised to 17,2 million Euros. The circle of investors encompasses EVP Capital Partners/VRP, LBBW Venture, Creathor Venture, KfW as well as private individuals and key persons from the pharmaceutical and high-tech industry. Visit our homepage at:

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100 项与 Px-102 相关的药物交易

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