Fxr Agonism by Gs-9674 Decreases Steatosis and Fibrosis in a Murine Model of Nash

Liles, John T.; Karnik, Satyajit K.; Hambruch, Eva; Kremoser, Claus; Birkel, M.; Watkins, William J.; Tumas, Daniel B.; Breckenridge, David G.; French, Dorothy

doi:10.1016/s0168-8278(16)01682-2

Cited by 21 publications

(13 citation statements)

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“…In addition to OCA, other FXR agonists are emerging as potential therapies for cholestatic liver diseases. In mouse models, 2 non‐steroidal FXR agonists have shown promising results with reduction in liver biochemistries, improvement of inflammatory infiltrates and improvement in fibrosis (Figure ) . These FXR agonists, GS‐9674 by Gilead Sciences and Tropifexor (otherwise known as LJN‐452) by Novartis, are currently undergoing phase II trials for PBC.…”

Section: Novel Therapiesmentioning

confidence: 99%

Novel and emerging therapies for cholestatic liver diseases

Goldstein

Levy

2018

Liver International

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While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

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Section: Novel Therapiesmentioning

confidence: 99%

Novel and emerging therapies for cholestatic liver diseases

Goldstein

Levy

2018

Liver International

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“…To the best of our knowledge, there is currently no publication on the effects of GS-9674 (previously called Px-102) in animal models for cholestatic liver diseases available. Rather, in a mouse model of diet-induced obesity, GS-9674 was shown to reduce hepatic steatosis and fibrosis, as well as serum levels of cholesterol, ALT, and AST [28]. Furthermore, dose-dependent antifibrotic effects and lowered portal pressure were observed in portal hypertensive rats [29].…”

Section: Gs-9674mentioning

confidence: 97%

Future Medical Treatment of PSC

Krones

Marschall

Fickert

2019

Curr Hepatology Rep

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Purpose of Review Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterized by inflammation of intrahepatic and/or extrahepatic bile ducts leading to stricturing, biliary fibrosis, cirrhosis, and liver failure. PSC is highly associated with inflammatory bowel diseases (IBD) and bears significant risk for cholangiocellular and colorectal cancer. To date, no medical treatment has been proven in randomized controlled trials to improve transplant-free and overall patient survival. However, numerous innovative therapeutic concepts are currently tested in phase 2 to phase 3 clinical trials. Based on currently suggested pathogenetic mechanisms of PSC, such drugs target its immunopathogenesis and nuclear and membrane receptors regulating bile acid transport and metabolism, gut microbiota, and liver fibrosis. The purpose of this review is to discuss recent advances in targeted medical treatment options for PSC. Recent Findings While a large carefully designed phase 2b trial targeting fibrosis development in PSC failed (simtuzumab), another compound was promoted from phase 2a to phase 3 trial based on significant improvements of alkaline phosphatase (AP) and excellent safety profile (norursodeoxycholic acid, norUDCA). Summary Ongoing trials evaluate numerous different targets considered to be involved in PSC pathogenesis, with so far, no clear advantage of either compound. This must be attributed to the still unknown cause of PSC. It may turn out that only combination therapy may reach a breakthrough. The fact that numerous studies isochronally test the same drug or therapeutic concept like in the case of vancomycin or faecal microbiota transplantation (FMT) demands improved and coordinated international strategies for study design to develop more effective drug pipelines, which is one major target of the International PSC Study Group (IPSCSG).

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“…FXR is a hormone receptor expressed in the liver that functions in the regulation of bile acid [ 14 ]. Furthermore, FXR plays a key role as a mediator of inflammatory responses, in the regulation of lipid-related pathways, and in glucose metabolism.…”

Section: Potential Drug Targets For the Treatment Of Nafldmentioning

confidence: 99%

“…More recently, a phase 3 clinical trial (REVERSE; NCT03439254) studying OCA in compensated cirrhosis was initiated [ 22 ]. Unlike OCA, an FXR agonist, GS-9674, is still in the preliminary phases of clinical evaluation [ 14 ]. GS-9674 produces FGF19, a protective hormone with reduction in its levels in patients with NASH, insulin resistance, and metabolic syndrome; and reversal to normal levels following bariatric surgery [ 14 ].…”

Section: Potential Drug Targets For the Treatment Of Nafldmentioning

confidence: 99%

Emerging Therapeutic Targets and Experimental Drugs for the Treatment of NAFLD

Dibba

Perumpail

et al. 2018

Diseases

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The two main subsets of nonalcoholic fatty liver disease (NAFLD) include: (1) nonalcoholic fatty liver (NAFL), the more common and non-progressive subtype; and (2) nonalcoholic steatohepatitis (NASH), the less common subtype, which has the potential to progress to advanced liver damage. Current treatment strategies have focused on lifestyle management of modifiable risk factors, namely weight, and on the optimization of the management of individual components of metabolic syndrome. Various hypothetical pathogenic mechanisms have been proposed, leading to the development of novel drugs with the potential to effectively treat patients with NASH. Numerous clinical trials are ongoing, utilizing these experimental drugs and molecules targeting specific mechanistic pathway(s) to effectively treat NASH. Some of these mechanistic pathways targeted by experimental pharmacologic agents include chemokine receptor 2 and 5 antagonism, inhibition of galectin-3 protein, antagonism of toll-like receptor 4, variation of fibroblast growth factor 19, agonism of selective thyroid hormone receptor-beta, inhibition of apoptosis signal-regulating kinase 1, inhibition of acetyl-coenzyme A carboxylase, agonism of farnesoid X receptor, antibodies against lysl oxidase-like-2, and inhibition of inflammasomes. Emerging data are promising and further updates from ongoing clinical trials are eagerly awaited.

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Fxr Agonism by Gs-9674 Decreases Steatosis and Fibrosis in a Murine Model of Nash

Cited by 21 publications

References 0 publications

Novel and emerging therapies for cholestatic liver diseases

Novel and emerging therapies for cholestatic liver diseases

Future Medical Treatment of PSC

Emerging Therapeutic Targets and Experimental Drugs for the Treatment of NAFLD

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