O168 the First Primary Biliary Cirrhosis (Pbc) Phase 3 Trial in Two Decades – An International Study of the FXR Agonist Obeticholic Acid in PBC Patients

Nevens, Frederik; Andreone, Pietro; Mazzella, Giuseppe; Strasser, Stephan; Bowlus, Christopher L.; Invernizzi, Pietro; Drenth, Joost P.H.; Pockros, P.; Reguła, Jarosław; Hansen, Bruno; Hooshmand‐Rad, Roya; Sheeron, S.; Shapiro, D. A.

doi:10.1016/s0168-8278(14)61463-x

Cited by 34 publications

(33 citation statements)

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“…The fact that UDCA seems to be effective and have a major anticholestatic effect suggests that cholestasis has a central role in disease progression. Current second-line therapy evaluation in the areas of cholestasis and fibrosis is largely around two therapy types, farnesoid X receptor (FXR) agonists (in particular obeticholic acid, which has shown efficacy in both phase II and III evaluation) 24,25 and peroxisome proliferator-activated receptor-α (PPARα) agonists (bezafibrate and fenofibrate), which have shown efficacy in case reports and series, and which are currently undergoing phase III evaluation (NCT01654731 26 ). 27,28 The fibroblast growth factor-19 (FGF-19) analogue NGM282 is also undergoing evaluation (NCT02026401 29 ) and is relevant given the evidence suggesting that FXR agonists act in part through FGF-19 upregulation.…”

Section: Current Status Of Second-line Therapymentioning

confidence: 99%

Novel therapeutic targets in primary biliary cirrhosis

Dyson

Hirschfield

Adams

et al. 2015

Nat Rev Gastroenterol Hepatol

113

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Primary biliary cirrhosis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis. It results in characteristic symptoms with marked effects on life quality. The advent of large patient cohorts has challenged the view of PBC as a benign condition treated effectively by the single licensed therapy-ursodeoxycholic acid (UDCA). UDCA nonresponse or under-response has a major bearing on outcome, substantially increasing the likelihood that liver transplantation will be required or that patients will die of the disease. In patients with high-risk, treatment-unresponsive or highly symptomatic disease the need for new treatment approaches is clear. Evolution in our understanding of disease mechanisms is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. Notable opportunities are offered by targeting what could be considered as the 'upstream' immune response, 'midstream' biliary injury and 'downstream' fibrotic processes. Combination therapy targeting several pathways or the development of novel agents addressing multiple components of the disease pathway might be required. Ultimately, PBC therapeutics will require a stratified approach to be adopted in practice. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.

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Section: Current Status Of Second-line Therapymentioning

confidence: 99%

Novel therapeutic targets in primary biliary cirrhosis

Dyson

Hirschfield

Adams

et al. 2015

Nat Rev Gastroenterol Hepatol

113

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“…32 The POISE trial is an international, multicenter, placebo-controlled, randomized clinical trial designed to study the safety and efficacy of once-daily OCA in PBC patients with an incomplete response to or unable to tolerate UDCA. The primary end point of the 12-month double-blind portion of the trial was a composite of an ALP level <1.67× ULN with a ≥15% reduction from baseline and a normal bilirubin level compared to placebo.…”

Section: Obeticholic Acidmentioning

confidence: 99%

Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection

Bowlus¹

2016

HMER

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Primary biliary cholangitis (PBC), previously known as primary biliary “cirrhosis”, is a rare autoimmune liver disease characterized by the hallmark autoantibodies to mitochondrial antigens and immune-mediated destruction of small bile duct epithelial cells leading to cholestasis and cirrhosis. Surprisingly, while immune modulators have not been effective in the treatment of PBC, supplementation with the hydrophilic bile acid (BA) ursodeoxycholic acid (UDCA) has been demonstrated to slow the disease progression. However, a significant minority of PBC patients do not have a complete response to UDCA and remain at risk of continued disease progression. Although the mechanisms of action are not well understood, UDCA provided proof of concept for BA therapy in PBC. Obeticholic acid (OCA), a novel derivative of the human BA chenodeoxycholic acid, is a potent agonist of the nuclear hormone receptor farnesoid X receptor, which regulates BA synthesis and transport. A series of clinical trials of OCA in PBC, primarily in combination with UDCA, have established that OCA leads to significant reductions in serum alkaline phosphatase that are predicted to lead to improved clinical outcomes, while dose-dependent pruritus has been the most common adverse effect. On the basis of these studies, OCA was given conditional approval by the US Food and Drug Administration with plans to establish the long-term clinical efficacy of OCA in patients with advanced PBC.

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“…Importantly, all 3 mentioned classes of drugs act as nuclear receptor ligands. Recent phase 2 and 3 studies showed improvement of biochemical cholestasis in patients with PBC and suboptimal response to UDCA therapy by OCA treatment [27,28]. Reported side effects were pruritus and lipid changes (increase in low density lipoprotein (LDL)-cholesterol and reduction in high density lipoprotein (HDL)-cholesterol).…”

Section: Fxr (And Other Future Therapies) In Treatment Of Cholestaticmentioning

confidence: 99%

Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease

Halilbasic

Fuchs

Traussnigg

et al. 2016

Dig Dis

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The intracellular nuclear receptor farnesoid X receptor (FXR) and the transmembrane G protein-coupled receptor 5 (TGR5) respond to bile acids (BAs) by activating transcriptional networks and/or signaling cascades. These cascades affect the expression of a great number of target genes relevant for BA, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. FXR activation in the liver tissue and beyond, such as the gut-liver axis, kidney and adipose tissue, plays a role in metabolic diseases. These BA receptors activators hold promise to become a new class of drugs to be used in the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This review discusses the relevant BA receptors, the new drugs that target BA transport and signaling and their possible applications.

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O168 the First Primary Biliary Cirrhosis (Pbc) Phase 3 Trial in Two Decades – An International Study of the FXR Agonist Obeticholic Acid in PBC Patients

Cited by 34 publications

References 0 publications

Novel therapeutic targets in primary biliary cirrhosis

Novel therapeutic targets in primary biliary cirrhosis

Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection

Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease

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