Date: 2012-10-31
Type of information: Initiation of preclinical development
phase: 1
Announcement: completion of the studies
Company: Phenex Pharmaceuticals (Germany)
Product: Px-102
Action
mechanism: 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.
Disease: NASH (non-alcoholic steatohepatitis)
Therapeutic area: Metabolic diseases - Liver diseases
Country:
Trial details:
Latest
news: Phenex Pharmaceuticals has announced the successful completion of its Phase I studies with Px-102, the company´s proprietary FXR agonist. Px-102 was tested in a single and in a multiple ascending dose Phase I study in 54 and 42 healthy volunteers, respectively. The drug candidate was safe and well tolerated at all doses indicated. Additional detailed data on the beneficial effects of Px-102 in animal models of lipid lowering and in preventing tumor growth in a liver cancer model were published by Phenex senior authors in the Journal of Experimental Therapeutics and Pharmacology (Hambruch et al, JPET, epub Aug 23, 2012) and in PLOSone (Deuschle et al. PLOSone 7(10) e43044, 2012).
The published data underscore that the massive cholesterol lowering effects of Px-102 observed in various animal models including primates, results in the prevention of atherosclerosis in a standard mouse model (JPET paper). The accumulation of free cholesterol in the liver is believed to be a main driving force for NASH thus cholesterol lowering will contribute to the overallhepatoprotective effects of Px-102. Given that Px-102 will be developed as a novel treatment for NAFLD and NASH, it was also important to investigate if the lipid lowering and other hepatoprotective effects observed so far might also be useful in the prevention of liver cancer. In the PLOSone paper the Phenex authors show that multiple weeks of treatment with Px-102 inhibit tumor growth in a xenograft
liver cancer model, probably via activation of a tumor suppressor gene, NDRG-2, which was identified as a novel target gene of FXR. The fact that Px-102 also effectively inhibits growth of liver tumors is relevant in a clinical setting where currently up to 5% of all NASH patients develop liver cancer over time so that the prevention of liver cancer is a main clinical goal in the treatment of NASH.
The outcome of the Phase I human studies combined with the published data from animal models provide encouraging evidence that the FXR agonist Px-102 will show beneficial effects in patients with NASH, a metabolically induced chronic inflammatory and fibrotic disease of the liver.
These data together with the progress in Phenex´ second R&D program which targets RORgamma-T prompted Phenex existing investors to invest another 5 M Euro into Phenex.
