GS-02-Efficacy of GKT831 in patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid: Interim efficacy results of a phase 2 clinical trial

Dalekos, George Ν.; Invernizzi, Pietro; Nevens, Frederik; Hans, Van Vlierberghe; Zigmond, Ehud; Andrade, Raúl J.; Ari, Ziv Ben; Heneghan, Michael A.; Huang, Jonathan; Harrison, Stephen A.; Minuk, Gerald; JörnPD, Schattenberg; Moreno, Christophe; Vierling, John M.; Vincent, Catherine; Bowlus, Christopher L.; Lurie, Yoav; Muratori, Luigi; Niro, G.A.; Hirschfield, Gideon; Post, Anthony B.; Zeuzem, Stefan; Welzel, Tania M.; Ch’ng, Chin Lye; Levy, Cynthia; Miller, Michael D.; Albillos, Agustı́n; Collier, Jane; Corless, Lynsey; Dieterich, Douglas T.; Kremer, Andreas E.; Papatheodoridis, George V.; Romeo, David P.; Silveira, Marina Nogueira; Bernstein, David; Cohen‐Naftaly, Michal; Floreani, Annarosa; Borg, Brian B.; Carey, Elizabeth J.; Hollywood, Coral; Maliakkal, Benedict; Marzioni, Marco; Rabinovitz, Mordechai; Rupp, Christian; Sheridan, David; Stanca, Carmen; Swain, Mark G.; Veitsman, Ella; Dourakis, P Spyridon; Wiese, Philippe

doi:10.1016/s0618-8278(19)30002-7

Cited by 18 publications

(14 citation statements)

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“…A greater GGT reduction was reached in patients with more advanced disease (GGT ≥ 2.5 X ULN at baseline). Changes in ALP were statistically significant in the 400 mg BID versus placebo [38].…”

Section: Antifibrotic Agentmentioning

confidence: 87%

The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

Mazzetti

Marconi

Mancinelli

et al. 2021

JCM

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Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two chronic cholestatic liver diseases affecting bile ducts that may progress to biliary cirrhosis. In the past few years, the increasing knowledge in the pathogenesis of both diseases led to a growing number of clinical trials and possible new targets for therapy. In this review, we provide an update on the treatments in clinical use and summarize the new drugs in trials for PBC and PSC patients. Farnesoid X Receptor (FXR) agonists and Pan-Peroxisome Proliferator-Activated Receptor (PPAR) agonists are the most promising agents and have shown promising results in both PBC and PSC. Fibroblast Growth Factor 19 (FGF19) analogues also showed good results, especially in PBC, while, although PBC and PSC are autoimmune diseases, immunosuppressive drugs had disappointing effects. Since the gut microbiome could have a potential role in the pathogenesis of PSC, recent research focused on molecules that could change the microbiome, with good results. The near future of the medical management of these diseases may include new treatments or a combination of multiple drugs targeting different signaling pathways at different stages of the diseases.

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Section: Antifibrotic Agentmentioning

confidence: 87%

The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

Mazzetti

Marconi

Mancinelli

et al. 2021

JCM

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“…In a Phase 2 study of 111 participants with PBC, there was a trend toward reduced liver stiffness compared to placebo as well as modest biochemical improvements, but the effect size was not great enough to be pursued further. [ 59 ]…”

Section: Fibrosismentioning

confidence: 99%

Mechanisms and molecules: What are the treatment targets for primary biliary cholangitis?

Mayo

2022

Hepatology

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Treatment of primary biliary cholangitis (PBC) with ursodeoxycholic acid (UDCA) is not always sufficient to prevent progression to hepatic decompensation and/or need for liver transplant. Adjuvant therapy with obeticholic acid may provide additional biochemical improvements in some patients, but it is not well-tolerated by patients with significant itch or advanced cirrhosis. Thus, new and creative approaches to treating patients with PBC are important to identify. This review discusses major potential therapeutic targets in PBC and provides examples of some specific agents currently in development for the treatment of PBC. Targets are broadly classified into those which strive to modify bile, inflammation, cell survival, or fibrosis. In bile, shrinking the size of the bile acid pool or modifying the quality of the bile by making it more hydrophilic or enriched in phosphatidylcholine may ameliorate cholestatic injury.Biliary epithelial cell survival may be extended by fortifying the bicarbonate umbrella or improving cell membrane integrity. Autoimmunity and cholangitis have the potential to be improved via regulation of the immune system.Targeting cytokines, immune checkpoints, and anti-mitochondrial antibodies are examples of a more focused immunosuppression approach. Stem cell therapy and lymphocyte trafficking inhibition are more novel methods of broad immune regulation. Anti-fibrotic therapies are also potentially useful for preventing progression of PBC. The nuclear hormone receptors, farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) regulate many of these pathways: cholestasis, inflammation, and fibrosis, which is why they are being enthusiastically pursued as potential therapeutic targets in PBC.

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“…A multicentre, randomized, double-blind, placebo-controlled, phase 2 study evaluating safety and efficacy of GKT137831 in patients with PBC and incomplete response has recently terminated the recruitment phase. A six-week ad-interim analysis has shown a rapid, dose-dependent reduction in the levels of GGT and ALP, without significant concomitant side effects [64] (ClinicalTrials.gov Identifier: NCT03226067).…”

Section: Antifibrotic Therapiesmentioning

confidence: 99%

Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies

Gerussi

D’Amato

Cristoferi

et al. 2020

Annals of Hepatology

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Primary biliary cholangitis and primary sclerosing cholangitis are rare diseases affecting the bile ducts and the liver. The limited knowledge of their pathogenesis leads to limited therapeutic options. Nevertheless, the landscape of novel therapies for these cholangiopathies is now rapidly changing, providing new treatment opportunities for patients and clinicians involved in their care. The aim of this review is to summarize the evidence of novel molecules under investigation for primary biliary cholangitis and primary sclerosing cholangitis and to discuss how they can potentially change current treatment paradigms.

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GS-02-Efficacy of GKT831 in patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid: Interim efficacy results of a phase 2 clinical trial

Cited by 18 publications

References 0 publications

The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

Mechanisms and molecules: What are the treatment targets for primary biliary cholangitis?

Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies

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