Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid

Hirschfield, Gideon M.; Mason, Andrew L.; Luketic, Velimir A.; Lindor, Keith D.; Gordon, Stuart C.; Mayo, Marlyn J.; Kowdley, Kris V.; Vincent, Catherine; Bodhenheimer, Henry C.; Parés, Albert; Trauner, Michael; Marschall, Hanns‐Ulrich; Adorini, Luciano; Sciacca, Cathi; Beecher-Jones, T.; Castelloe, Erin; Böhm, O.; Shapiro, D. A.

doi:10.1053/j.gastro.2014.12.005

Cited by 499 publications

(428 citation statements)

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“…An analysis of the primary end point was performed in the phase 2 trial, in which obeticholic acid was added to ursodiol therapy 16 : 9% of the patients in the placebo group and 40% of those who were assigned to receive 10 mg of obeticholic acid had a positive response. We then calculated the sample size using more conservative numbers.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15] In two 12-week phase 2 studies, daily doses of up to 50 mg of obeticholic acid resulted in reductions from baseline in levels of alkaline phosphatase and bilirubin that were significantly greater than those with placebo. 16 However, dose-related increases in the incidence and severity of pruritus were evident, particularly at doses of more than 10 mg. The aim of our phase 3 trial was to assess the longer-term efficacy, safety, and adverse-event profile of obeticholic acid in patients with primary biliary cholangitis who were receiving daily doses of 5 mg or 10 mg.…”

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confidence: 98%

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A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

et al. 2016

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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

et al. 2016

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“…This is especially pertinent in PBC, with second-line agents currently in development. (20) However, it should also be useful to identify patients at low risk of developing ESLD within a relevant time frame, who could potentially be monitored in primary care.…”

Section: Discussionmentioning

confidence: 99%

The UK‐PBC risk scores: Derivation and validation of a scoring system for long‐term prediction of end‐stage liver disease in primary biliary cholangitis

et al. 2015

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; and the members of the UK-PBC Consortium*The biochemical response to ursodeoxycholic acid (UDCA)-so-called "treatment response"-strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). Conclusions: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care. (HEPATOLOGY 2016;63:930-950) SEE EDITORIAL ON PAGE 697 P rimary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the intrahepatic bile ducts results in cholestasis and progressive fibrosis.(1) Biliary injury may eventually lead to cirrhosis and liver failure-but the rate of disease progression is variable.(2) Across the spectrum, some patients with PBC progress to end-stage liver disease (ESLD) within a few years of diagnosis; some develop cirrhosis that remains well compensated; others (perhaps the majority) do not even develop cirrhosis. In PBC, as in other conditions, accurate prognostication enables management of the disease to be tailored to the patient. This is the basis of precision medicine-and it has clear benefits: patients at higherAbbreviations: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALP12, alkaline phosphatase after 12 months of UDCA; AMA, anti-mitochondrial antibody; ANA, anti-nuclear antibodies; ALT, alanine aminotransferase; ALT12, ALT after 12 months of UDCA; AST, aspartate transaminase; AST12, AST after 12 months of UDCA; AUC, area under receiver operating characteristic curve; BIL, bilirubin; BIL12, bilirubin after 12 months of UDCA; CI, confidence interval; CRFs, case record forms; EASL, European Association for the Study of Liver; ESLD, end-stag...

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“…An FXR agonist has been shown to be beneficial in several preclinical models of NASH/NAFLD; this has been attributed to its metabolic actions using natural ligands, semisynthetic modified BAs, or synthetic nonsteroidal molecules 76, 77. Human studies are ongoing with the BA‐derivative agonist obeticholic acid (OCA), which improves insulin resistance and decreases liver fibrosis markers 78. OCA has also been approved for treatment of primary biliary cholangitis79 and is in late clinical studies for NASH.…”

Section: Nuclear Receptors As Therapeutic Targetsmentioning

confidence: 99%

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

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Liu

Huang

et al. 2018

Hepatology Communications

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The nuclear receptor superfamily contains important transcriptional regulators that play pleiotropic roles in cell differentiation, development, proliferation, and metabolic processes to govern liver physiology and pathology. Many nuclear receptors are ligand‐activated transcription factors that regulate the expression of their target genes by modulating transcriptional activities and epigenetic changes. Additionally, the protein complex associated with nuclear receptors consists of a multitude of coregulators, corepressors, and noncoding RNAs. Therefore, acquiring new information on nuclear receptors may provide invaluable insight into novel therapies and shed light on new interventions to reduce the burden and incidence of liver diseases. (Hepatology Communications 2018;2:765‐777)

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Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid

Cited by 499 publications

References 44 publications

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

The UK‐PBC risk scores: Derivation and validation of a scoring system for long‐term prediction of end‐stage liver disease in primary biliary cholangitis

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

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