Px 102 / Gilead - LARVOL DELTA

Development of Cilofexor, an intestinally-biased Farnesoid X Receptor agonist, for the treatment of fatty liver disease. (PubMed, J Pharmacol Exp Ther) - "Here, we examined the preclinical and clinical effects of the first-generation FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid), to enable the selection of an analog, cilofexor, with unique properties that reduced side effects yet maintained efficacy. Cilofexor is one of few remaining FXR agonists in clinical development."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Dysfunction-Associated Steatohepatitis • Solid Tumor

Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway. (PubMed, Arch Toxicol) - "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. 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."

Journal • Hepatology

Phenex reports successful completion of Phase I Studies with FXR-Agonist Px-102 and publishes research progress in two independent papers (Earth Times) - P1, N=96; The drug candidate was safe & well tolerated at all doses indicated; 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; 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 overall hepatoprotective effects of Px-102

P1 data • Dyslipidemia

How to develop a differentiated FXR agonist: GS-9674 shows a reduced side effect profile in mice, monkeys amd human phase I studies compared to its predecessor Px-102 (EASL-ILC 2019) - "Background: FXR agonists such as Obeticholic Acid (OCA) have proven to be effective pharmacotherapies in liver diseases such as Primary Biliary Cirrhosis (PBC) or Non-alcoholic Steatohepatitis (NASH). In this translational effort the human side effects of Px-102 were recapitulated in an appropriate animal model. Using the model as a screen we identified GS-9674 as a differentiated FXR agonist with intestinally biased activity and clearly reduced side effects for further clinical development in NASH, PBC, and PSC."

Adverse events • P1 data

Lowering of Circulating FGF21 by Modulation of Bile Acid Metabolism in Healthy Males (ENDO 2019) - "...In this study we aimed to evaluate the response of circulating FGF21 to perturbations of bile acid metabolism in healthy humans.We studied samples obtained from two clinical studies characterizing bile acid metabolism: (i) Eight healthy males underwent repeated blood sampling during 32 hr in three experiments: under basal conditions, following initiation of treatment with cholestyramine (CME), and following initiation of CME when under treatment with atorvastatin (CME+STAT). (ii) 54 healthy males were randomized into 8 groups that were treated orally with a single dose of placebo or the nonsteroidal FXR agonist, Px-102 (0.15mg/kg, 0.3mg/kg, 0.6mg/kg, 1.12mg/kg, 2.25mg/kg, 3.38mg/kg, or 4.5mg/kg) and monitored for 24 hr...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*"

Clinical

Lowering of Circulating FGF21 by Modulation of Bile Acid Metabolism in Healthy Males (ENDO 2019) - "...In this study we aimed to evaluate the response of circulating FGF21 to perturbations of bile acid metabolism in healthy humans.We studied samples obtained from two clinical studies characterizing bile acid metabolism: (i) Eight healthy males underwent repeated blood sampling during 32 hr in three experiments: under basal conditions, following initiation of treatment with cholestyramine (CME), and following initiation of CME when under treatment with atorvastatin (CME+STAT). (ii) 54 healthy males were randomized into 8 groups that were treated orally with a single dose of placebo or the nonsteroidal FXR agonist, Px-102 (0.15mg/kg, 0.3mg/kg, 0.6mg/kg, 1.12mg/kg, 2.25mg/kg, 3.38mg/kg, or 4.5mg/kg) and monitored for 24 hr...The Results do not support the proposal that FXR activation is an important regulator of hepatic FGF21 secretion in humans, which has been suggested from animal experiments. Instead, we would propose that our findings reflect the response to depletion..."

Clinical