Delving into the Latest Updates on PX-104 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

FXR

Mechanism

FXR agonists(Bile acid receptor FXR agonists)

Therapeutic Areas

Digestive System Disorders

Active Indication-

Inactive Indication

Metabolic dysfunction-associated steatotic liver diseaseNonalcoholic Steatohepatitis

Originator Organization

Gilead Sciences, Inc.

Active Organization-

Inactive Organization

Gilead Sciences, Inc.

Phenex Pharmaceuticals AG

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC29H22Cl3NO4

InChIKeyXBUXXJUEBFDQHD-VSVVGSIZSA-N

CAS Registry1268244-88-7

SummaryBackgroundThe PX-104 is an oral non-steroidal agonist for the farnesoid X receptor (FXR), a key regulator of bile acid (BA), glucose and lipid homeostasis.Aims and methodsThis single center, proof of concept study evaluated the efficacy, safety and tolerability of PX-104 in non-diabetic NAFLD patients. 12 individuals were treated daily with 5 mg of PX-104 orally for 4 weeks. Serum liver enzymes, insulin sensitivity by clamp like index (CLIX) and hepatic fat by proton 1H‑MRS, MRI-PDFF and CAP were assessed. Hepatic energy metabolism and Kupffer cell function were evaluated by phosphorus 31P‑MRS and superparamagnetic iron oxide MRI (SPIO-MRI). Other readouts included serum lipids and markers of BA metabolism/signaling besides fecal microbiome and BA analysis.ResultsA significant decrease in ALT (p = 0.027; 1‑tailed) and GGT (p = 0.019) was observed, without changes in serum alkaline phosphatase or serum lipids. Insulin sensitivity improved in 92% of patients (p = 0.02). However, hepatic steatosis measured by PDFF-MRI, 1H‑MRS and CAP besides extended serum lipoprotein and BA profiles did not change. NADPH/γATP ratios at 31P‑MRS significantly decreased (p = 0.022) possibly reflecting reduced hepatic inflammatory stress, but SPIO-MRI remained unchanged. Reduced preponderance of Coriobacteriaceae (p = 0.036) correlated with a relative reduction of total fecal BAs. There were no serious adverse events but short intervals of cardiac arrhythmia recorded in 2 patients led to termination of the study.ConclusionThe non-steroidal FXR agonist PX-104 improved insulin sensitivity and liver enzymes after 4 weeks of treatment in non-diabetic NAFLD patients. Changes in fecal BAs and gut microbiota deserve more extensive investigations.

02 Jun 2020·Expert Opinion on Investigational DrugsQ2 · MEDICINE

Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH)

Q2 · MEDICINE

Review

Author: Biagioli, Michele ; Zampella, Angela ; Sepe, Valentina ; Distrutti, Eleonora ; Fiorucci, Stefano

INTRODUCTIONNonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) for which therapy is suboptimal. The farnesoid-X-receptor (FXR) and the G protein bile acid receptor (GPBAR)1 are two bile acid-activated receptors that exert regulatory effects on lipid, glucose, energy, and immune homeostasis. GPBAR1 and FXR ligands have shown efficacy in reversing steatohepatitis and fibrosis in preclinical models of NASH.AREA COVEREDThis article evaluates the efficacy and pitfalls of GPBAR1 and FXR-based therapies in the treatment of NASH. While there are no GPBAR1 agonist in clinical development, several FXR ligands have completed phase 2 and phase 3 trials in NASH. EDP305, tropifexor, cilofexor, nidufexor, TERN.101, Px-104, EYP001, MET409. Individual FXR agonists have shown variable efficacy in reversing liver steatohepatitis and fibrosis. Class-related, dose-dependent side effects: pruritus, increased plasma levels of cholesterol and LDLc, and reduction of HDL have been reported.EXPERT OPINIONEfficacy of FXR agonists as stand-alone therapy is limited by dose-related side effects. Efficacy of combining an FXR agonist with statins, CCR2, and ACC inhibitors is currently investigated. Identification of patient subsets would allow development of patients tailored therapy using a combination of drugs acting on different molecular mechanisms.

24 Nov 2014·Current Topics in Medicinal ChemistryQ4 · MEDICINE

Knocking on FXR's Door:The "Hammerhead"-Structure Series of FXRs Agonists - Amphiphilic Isoxazoles with Potent In Vitro and In Vivo Activities

Q4 · MEDICINE

Review

Author: Steeneck, Christoph ; Kinzel, Olaf ; Kremoser, Claus ; Schulz, Andreas ; Gege, Christian

The Farnesoid X Receptor (FXR) was recently validated in clinical studies using the bile acid analogue Obeticholic Acid (OCA) as an attractive drug target for liver diseases such as Primary Biliary Cirrhosis (PBC) or Non-alcoholic Steatohepatitis (NASH). OCA, however, turned out to induce cholesterol- related side effects upon prolonged treatment and it shows bile acid like pharmacokinetics. The quest for synthetic non-steroidal FXR agonists with general drug likeliness and improved pharmacokinetic and - dynamic properties has started more than a decade ago: The first non-steroidal and selective FXR agonist with decent submicromolar potency, GW4064, was patented in 1998 and published in 2000. Since then, many pharmaceutical companies have taken GW4064 as a structural template for their efforts in identifying novel patentable FXR agonists with the GW-derived trisubstituted isoxazole general structure. However, so far only one compound out of these different series has made it into the early stages of clinical development: The Px-102/Px-104 from Phenex is currently tested in a phase IIa study in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). In this review we try to summarize from the patent and scientific literature the attempts to improve the GW4064 structure into different directions. Furthermore, we suggest directions for further improvements of this special class of synthetic FXR agonists which all display the typical "hammerhead"-conformation in the FXR ligand binding pocket that provides the basis for their impressive in vitro and in vivo potencies.

100 Deals associated with PX-104

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metabolic dysfunction-associated steatotic liver disease	Phase 2	AT	Phenex Pharmaceuticals AG	01 Oct 2013
Nonalcoholic Steatohepatitis	Phase 2	-	Gilead Sciences, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01999101 (Pubmed \| Wien Klin Wochenschr) Manual	Phase 2	Metabolic dysfunction-associated steatotic liver disease	12	PX-104	(wtzrmemivm) = There were no serious adverse events but short intervals of cardiac arrhythmia recorded in 2 patients led to termination of the study. jtzbntuokf (yajnabnuhi )	Positive	01 May 2021