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

Nevens, Frederik; Andreone, Pietro; Mazzella, Giuseppe; Strasser, Simone I.; Bowlus, Christopher L.; Invernizzi, Pietro; Drenth, Joost P.H.; Pockros, Paul J.; Reguła, Jarosław; Beuers, Ulrich; Trauner, Michael; Jones, David; Floreani, Annarosa; Hohenester, Simon; Luketic, Velimir A.; Shiffman, Mitchell L.; Erpecum, Karel J. van; Vargas, Vı́ctor; Vincent, Catherine; Hirschfield, Gideon M.; Shah, Hemant; Hansen, Bettina E.; Lindor, Keith D.; Marschall, Hanns‐Ulrich; Kowdley, Kris V.; Hooshmand‐Rad, Roya; Marmon, Tonya; Sheeron, S.; Pencek, Richard; MacConell, Leigh; Pruzanski, Mark; Shapiro, D. A.

doi:10.1056/nejmoa1509840

Cited by 815 publications

(755 citation statements)

References 32 publications

(35 reference statements)

Supporting

Mentioning

722

Contrasting

Unclassified

Order By: Relevance

“…An interesting example of this strategy is the use of a farnesoid X receptor ( FXR , formally NR1H4 ) agonist (obeticolic acid) for the treatment of both primary biliary cholangitis38 and NASH 39…”

Section: Discussionmentioning

confidence: 99%

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

Sookoian

Flichman

Garaycoechea

et al. 2018

Hepatology Communications

View full text Add to dashboard Cite

Long noncoding RNAs (lncRNAs) are functional molecules that orchestrate gene expression. To identify lncRNAs involved in nonalcoholic fatty liver disease (NAFLD) severity, we performed a multiscale study that included: (a) systems biology modeling that indicated metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) as a candidate lncRNA for exploring disease‐related associations, (b) translational exploration in the clinical setting, and (c) mechanistic modeling. MALAT1 liver profiling was performed in three consecutive phases, including an exploratory stage (liver samples from patients with NAFLD who were morbidly obese [n = 47] and from 13 individuals with normal liver histology); a replication stage (patients with NAFLD and metabolic syndrome [n =49]); and a hypothesis‐driven stage (patients with chronic hepatitis C and autoimmune liver diseases, [n = 65]). Liver abundance of MALAT1 was associated with NAFLD severity (P = 1 × 10–6); MALAT1 expression levels were up‐regulated 1.75‐fold (P = 0.029) and 3.6‐fold (P = 0.012) in patients with nonalcoholic steatohepatitis compared to those diagnosed with simple steatosis (discovery and replication set, respectively; analysis of covariance adjusted by age, homeostasis model assessment, and body mass index). Quantification of liver vascular endothelial growth factor A messenger RNA, a target of MALAT1, revealed a significant correlation between the two RNAs (R, 0.58; P = 5 × 10–8). Increased levels of MALAT1 were also associated with autoimmune liver diseases. Interactome assessment uncovered significant biological pathways, including Janus kinase‐signal transducers and activators of transcription and response to interferon‐γ. Conclusion: Deregulated expression of MALAT1 stratifies patients into the histologic phenotypes associated with NAFLD severity. MALAT1 up‐regulation seems to be a common molecular mechanism in immune‐mediated chronic inflammatory liver damage. This suggests that convergent pathophenotypes (inflammation and fibrosis) share similar molecular mediators. (Hepatology Communications 2018;2:654‐665)

show abstract

Section: Discussionmentioning

confidence: 99%

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

Sookoian

Flichman

Garaycoechea

et al. 2018

Hepatology Communications

View full text Add to dashboard Cite

show abstract

“…The demographic characteristics of the POISE trial cohort are reported in the original publication 12. In summary, average (± SD) age was 56 ± 10 years, 91% of patients were female, and 94% Caucasian.…”

Section: Resultsmentioning

confidence: 99%

“…The patient demographics and study design of the POISE trial were reported by Nevens and colleagues12 (Table 1). Briefly, POISE was a phase 3, randomized, double‐blind, placebo‐controlled trial.…”

Section: Methodsmentioning

confidence: 99%

“…All patients were over 18 years old, met the study entry criteria of ALP ≥1.67 × ULN and/or total bilirubin >ULN but <2 × ULN, and had either been taking UDCA for at least 12 months or were unable to tolerate UDCA. A total of 216 patients were randomized and dosed (once daily) 1:1:1 to placebo, OCA 5‐10 mg (patients were started on 5 mg of OCA and titrated up to 10 mg depending on tolerability/response to treatment),12 or OCA 10 mg. The primary endpoint of the trial was defined as achieving a composite of ALP below 1.67 × ULN with at least a 15% reduction in ALP and total bilirubin at or below ULN after 12 months of OCA therapy (POISE trial criteria).…”

Section: Methodsmentioning

confidence: 99%

“…Several definitions of the UDCA response have been proposed 7, 8, 9, 10, 11. One of these definitions was the Toronto criteria, and a composite of Toronto along with other criteria were used to define treatment response criteria for POISE, a phase 3 trial of treatment with obeticholic acid (OCA) reported by Nevens et al12 By these criteria, response was defined as alkaline phosphatase (ALP) <1.67 × the upper limit of normal (ULN), ≥15% reduction in ALP, and total bilirubin ≤ULN.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Clinical application of the GLOBE and United Kingdom‐primary biliary cholangitis risk scores in a trial cohort of patients with primary biliary cholangitis

Carbone

Harms

Lammers

et al. 2018

Hepatology Communications

Self Cite

View full text Add to dashboard Cite

The GLOBAL Primary Biliary Cholangitis (PBC) Study Group and United Kingdom‐PBC (UK‐PBC) Consortium have demonstrated that dichotomous response criteria are not as accurate as continuous equations at predicting mortality or liver transplantation in PBC. The aim of this analysis was to assess the clinical utility of the GLOBE and UK‐PBC risk scores using data from POISE, a phase 3 trial investigating obeticholic acid (OCA) in patients with PBC. Data (N = 216) at baseline and month 12 were used to calculate the GLOBE and UK‐PBC risk scores to assess the projected change in risk with OCA versus placebo. Additionally, the benefit of OCA was assessed in patients not meeting the POISE primary endpoint. Both the GLOBE and UK‐PBC risk scores predicted a significant reduction in long‐term risk of death and liver transplantation after OCA treatment (P < 0.0001). The differences in the relative risk reduction from baseline in the 10‐year event risk after 1 year for OCA 10 mg versus placebo was 26% (GLOBE) and 37% (UK‐PBC). The scores also predicted a significantly decreased risk in patients treated with OCA who did not meet POISE response criteria after 1 year of treatment compared to an increased risk with placebo (P < 0.0001). Conclusion: This analysis demonstrates the use of the GLOBE and UK‐PBC risk scores to assess risk reduction of a cohort treated with OCA. While validation of this risk reduction in studies with clinical outcomes is needed, this study highlights the potential use of these scores in individualizing risk prediction in PBC both in clinical practice and therapeutic trials. (Hepatology Communications 2018;2:683‐692)

show abstract

Pharmacological interventions for primary biliary cholangitis

Saffioti

Gurusamy

Eusebi

et al. 2017

Cochrane Database of Systematic Reviews

View full text Add to dashboard Cite

Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis. However, the follow-up periods in the trials were short and there is significant uncertainty in this issue. Further well-designed randomised clinical trials are necessary. Future randomised clinical trials ought to be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid post-randomisation dropouts or planned cross-overs; should have sufficient follow-up period (e.g. five or 10 years or more); and use clinically important outcomes such as mortality, health-related quality of life, cirrhosis, decompensated cirrhosis, and liver transplantation. Alternatively, very large groups of participants should be randomised to facilitate shorter trial duration.

show abstract

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

Cited by 815 publications

References 32 publications

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

Clinical application of the GLOBE and United Kingdom‐primary biliary cholangitis risk scores in a trial cohort of patients with primary biliary cholangitis

Pharmacological interventions for primary biliary cholangitis

Contact Info

Product

Resources

About