obeticholic-acid and Cholangitis

Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.

Topics: Autoimmune Diseases; Biomarkers; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Fatigue; Humans; Pruritus; Risk Factors; Ursodeoxycholic Acid

Primary biliary cholangitis is a chronic liver disorder characterized by progressive cholestasis that may evolve to liver cirrhosis. While ursodeoxycholic acid is the treatment of choice, around 30% of patients do not respond to this therapy. These patients have a poorer prognosis, hence should be identified early in order to be offered therapy options. Along these lines, improved understanding of the condition's pathophysiology has allowed the development of newer drugs, including obeticholic acid and fibrates. This review offers a perspective on risk stratification and treatment for these patients, from ursodeoxycholic acid to second-line treatments.

Topics: Adult; Age Factors; Alkaline Phosphatase; Biomarkers; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Cholestasis; Disease Progression; Fibric Acids; Glucocorticoids; Humans; Liver Cirrhosis; Liver Transplantation; Middle Aged; Risk Assessment; Risk Factors; Sex Factors; Treatment Failure; Ursodeoxycholic Acid

The name of chronic liver disease: primary biliary cirrhosis, has been changed to: primary biliary cholangitis, primarily because of the stigma associated with the word "cirrhosis", as only a minority of the patients develop cirrhosis. In this review we present data on epidemiology and discuss the current treatments with focus on ursodeoxycholic acid and the newly described effects of the farnesoid receptor agonist obeticholic acid.

Topics: Anti-Inflammatory Agents; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Fibric Acids; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

Primary biliary cholangitis (previously primary biliary cirrhosis) is a chronic liver disease caused by the destruction of small intra-hepatic bile ducts resulting in stasis of bile (cholestasis), liver fibrosis, and liver cirrhosis. The optimal pharmacological treatment of primary biliary cholangitis remains uncertain.. To assess the comparative benefits and harms of different pharmacological interventions in the treatment of primary biliary cholangitis through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to February 2017 to identify randomised clinical trials on pharmacological interventions for primary biliary cholangitis.. We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with primary biliary cholangitis. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention.. We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.. We identified 74 trials including 5902 participants that met the inclusion criteria of this review. A total of 46 trials (4274 participants) provided information for one or more outcomes. All the trials were at high risk of bias in one or more domains. Overall, all the evidence was low or very low quality. The proportion of participants with symptoms varied from 19.9% to 100% in the trials that reported this information. The proportion of participants who were antimitochondrial antibody (AMA) positive ranged from 80.8% to 100% in the trials that reported this information. It appeared that most trials included participants who had not received previous treatments or included participants regardless of the previous treatments received. The follow-up in the trials ranged from 1 to 96 months.The proportion of people with mortality (maximal follow-up) was higher in the methotrexate group versus the no intervention group (OR 8.83, 95% CI 1.01 to 76.96; 60 participants; 1 trial; low quality evidence). The proportion of people with mortality (maximal follow-up) was lower in the azathioprine group versus the no intervention group (OR 0.56, 95% CI 0.32 to 0.98; 224 participants; 2 trials; I. nine trials had no special funding or were funded by hospital or charities; 31 trials were funded by pharmaceutical companies; and 34 trials provided no information on source of funding.. 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.

Topics: Azathioprine; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Chronic Disease; Colchicine; Cyclosporine; Humans; Immunosuppressive Agents; Methotrexate; Mitochondria; Network Meta-Analysis; Penicillamine; Quality of Life; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by chronic cholestasis. Treatment with the accepted primary therapy ursodeoxycholic acid (UDCA) has been shown to be associated with delayed disease progression probably through reduced impact of cholestatic injury on the target biliary epithelial cells. Patients with inadequate response to UDCA (which can be identified through validated biochemical criteria) are at increased risk of disease progression, need for liver transplantation, and death. Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second-line therapy in PBC and has been recently licensed by the Food and Drug Administration and European Medicines Agency for use in patients showing an inadequate response to UDCA or who are unable to tolerate it. Although evidence for biochemical improvement by OCA is compelling, there is, as yet, no evidence that OCA improves hard clinical outcomes or quality of life. In addition, OCA may not be suitable for PBC patients with pruritus as it can worsen the symptom. Other novel agents currently in clinical development may have better side-effect profile. Fibrates have the potential but currently lack high quality evidence to support their routine clinical use in PBC. Symptom management of PBC is challenging and ASBT inhibitors and rituximab are being evaluated for pruritus and fatigue, respectively.

Topics: Chenodeoxycholic Acid; Cholangitis; Disease Progression; Humans; Liver Cirrhosis, Biliary; Quality of Life; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic cholestatic liver disease characterized by an immune mediated destruction of intrahepatic bile ducts. Ursodeoxycholic acid (UDCA) has been the primary medication for the treatment of PBC, resulting in improved liver tests, resolution of symptoms and increased transplant free survival. However, not all patients respond to UDCA. The aim of this systematic review is to provide an evidence based assessment of the medications that have been studied in patients who are refractory to UDCA.. We performed a systematic literature search on MEDLINE and the Cochrane Database of Systematic Reviews of the published literature. A total of 23 articles fulfilling our inclusion criteria were found.. Several studies have shown an improvement in liver biochemistries with the use of obeticholic acid in conjunction with UDCA. Fibrates, including fenofibrate and bezafibrate, have evidence supporting benefit in this population but need more robust studies to confirm these observational results. Neither obeticholic acid nor fibrates have shown to increase transplant free survival. While there may be some benefit with methotrexate, colchicine, budesonide, mycophenolate mofetil and azathioprine, these findings were not consistent and the benefits were marginal. Further investigation is needed.. In patients with PBC refractory to UDCA, obeticholic acid or a fibrate is a reasonable choice as an adjunctive treatment to UDCA. Further investigation with randomized controlled trials is needed to provide high quality evidence to formulate standardized therapies in this difficult to treat population.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Colchicine; Fibric Acids; Humans; Immunosuppressive Agents; Silymarin; Treatment Failure; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that may lead to biliary fibrosis, and eventually cirrhosis. The primary treatment for PBC is ursodeoxycholic acid (UDCA), which has favorably altered its natural history. However, up to 40% of patients have an inadequate response to UDCA, and are therefore at high risk of liver-related complications. Obeticholic acid has recently been approved for use in patients with PBC with inadequate response or who are intolerant to UDCA, but improvement in long-term outcomes has not yet been demonstrated. Alternative therapeutic options for PBC are needed. Areas covered: Recent advances in research including epidemiological, genetic and pre-clinical studies in animal models of PBC have yielded numerous agents currently at different stages of development for treatment of patients with PBC; in this review, we cover novel therapies that were recently or are recently being investigated in phase II clinical trials. Expert opinion: Despite the evolving landscape in PBC, the main challenges facing development of novel therapies remain the rarity of the disease and the limitations to design and conduct of controlled clinical trials in PBC, which are needed to determine the long-term effects of novel therapies on the clinical outcomes of PBC.

Topics: Animals; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Disease Progression; Drug Design; Drugs, Investigational; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by chronic inflammation of the intrahepatic bile ducts, causing progressive ductopenia, cholestasis and fibrosis, and leading to liver failure. Ursodeoxycholic acid (UDCA) is the first-line therapy for the treatment of PBC patients. This is effective in majority of patients; however, up to 20 percent of patients have an incomplete response to UDCA therapy and have a reduced prognosis as compared to healthy individuals. Obeticholic acid (OCA) has been recently registered as second-line therapy for patients with incomplete response to UDCA, with plans to demonstrate the long-term clinical efficacy. Areas covered: Recent evolution in our understanding of disease mechanisms is leading to the advent of new and re-purposed therapeutic agents targeting key processes in the etiopathogenesis. Several therapeutic targets have been proposed which can be categorized into three compartments: immune, biliary and fibrosis. In this review we describe the main biological mechanisms underpinning disease development and progression in PBC and the new targeted therapies on the horizon. Expert commentary: Testing new drugs towards hard clinical endpoints is challenging in PBC due to its low prevalence and the slow progression of the disease. Novel promising biomarkers are under study and should be evaluated as surrogate endpoints in clinical trials.

Topics: Autoimmunity; Bile Ducts, Intrahepatic; Chenodeoxycholic Acid; Cholangitis; Fibrosis; Humans; Immunotherapy; Liver; Liver Cirrhosis, Biliary; Molecular Targeted Therapy; Ursodeoxycholic Acid; Ustekinumab

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and potentially liver cirrhosis. Patients develop a well-orchestrated immune reaction, both innate and adaptive, against mitochondrial antigens that specifically targets intrahepatic biliary cells. A puzzling feature of PBC is that the immune attack is predominantly organ specific, although the mitochondrial autoantigens are found in all nucleated cells. The disease results from a combination of genetic and environmental risk factors; however, the exact pathogenesis remains unclear. Serologically, PBC is characterized by presence of antimitochondrial antibodies, which are present in 90-95 % of patients and are often detectable years before clinical signs appear. Like other complex disorders, PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. A significant number of patients develop end-stage liver disease and eventually require liver transplantation. Recent studies from large international cohorts have better identified prognostic factors, suggesting a change in patient management based on risk stratification. Therapeutic options are changing. In this review we discuss data on the autoimmune responses and treatment of the disease.

Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Biopsy; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Fibric Acids; Humans; Immunosuppressive Agents; Liver; Prognosis; Ursodeoxycholic Acid

Despite the presumed immunological pathogenesis of primary biliary cholangitis, no clear or even harmful consequences have resulted from treatments designed to modify the immunological condition. Ursodeoxycholic acid (13-16 mg/kg/d) has, however, clear favorable effects that not only improve biochemical cholestasis, but also delay histological progression. Long-term treatment with ursodeoxycholic acid is associated with excellent transplant-free survival in cases showing a biochemical response at 1 year. Data on the effects of obeticholic acid and fibrates are encouraging. Moreover, recent pilot studies evaluating several biological agents targeting immunity such as different monoclonal antibodies and other drugs that modulate cholestasis are under investigation, although with limited results at present.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Disease Progression; Fibric Acids; Gastrointestinal Agents; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Autoimmune liver diseases are a group of abnormal autoimmune-mediated inflammatory hepatobiliary injuries, mainly including autoimmune hepatitis(AIH), primary biliary cholangitis(PBC), and primary sclerosing cholangitis (PSC). The diagnosis and treatment of autoimmune liver diseases, an important type of non-viral liver disease, have become a prominent issue in hepatology. In 2016, many new advances have been achieved in the clinical and basic research on autoimmune liver diseases, including the phase 3 clinical trial of obeticholic acid, the proposal of UK-PBC risk score, and the research on gut microbiota associated with PSC. This article reviews the research advances in the diagnosis and treatment of autoimmune liver diseases in 2016.. 自身免疫性肝病是一组由异常自身免疫介导的肝胆炎症性损伤，主要包括自身免疫性肝炎、原发性胆汁性胆管炎及原发性硬化性胆管炎等。作为非病毒性肝病的重要成员，自身免疫性肝病的诊断与治疗日益成为肝病领域的突出问题之一。2016年，自身免疫性肝病在临床和基础研究方面又有了许多新进展，包括奥贝胆酸的临床III期试验，UK-PBC危险评分的提出，以及原发性硬化性胆管炎相关的肠道微生态研究等。现就自身免疫性肝病2016年的诊疗与研究进展进行介绍。.

Topics: Autoimmune Diseases; Biomedical Research; Chenodeoxycholic Acid; Cholangitis; Cholangitis, Sclerosing; Clinical Trials, Phase III as Topic; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases

Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease. Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo.. This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database.. If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.

Topics: Animals; Autoimmune Diseases; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Cholestasis; End Stage Liver Disease; Genome-Wide Association Study; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Chronic liver disease and cirrhosis are a leading cause of morbidity and mortality in the United States. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis and which has been designated an orphan condition, is a chronic autoimmune disease resulting in the destruction of the small bile ducts in the liver. Without effective treatment, disease progression frequently leads to liver failure and death. Until May 2016, the only FDA-approved treatment for PBC was ursodiol (UDCA), an oral hydrophilic bile acid, which can slow progression of liver damage due to PBC. However, 1 out of 3 patients taking UDCA has an inadequate biochemical response, leading to increased risk of disease progression, liver transplantation, and mortality. Given this unmet clinical need, new therapies are in development for the treatment of PBC. To provide pharmacists with an overview of the latest research on the pathophysiology of PBC and potential new treatment options and to highlight medical and specialty pharmacy approaches to managing access to drugs to treat orphan diseases such as PBC, a 2-hour satellite symposium was presented in conjunction with the 2015 Academy of Managed Care Pharmacy (AMCP) Nexus meeting. Although obeticholic acid was approved by the FDA for the treatment of PBC in May 2016, this development occurred after the symposium presentation. The symposium was supported by an independent educational grant from Intercept Pharmaceuticals and was managed by Analysis Group. Robert Navarro, PharmD, moderated the CPE-accredited symposium titled "Medical and Specialty Pharmacy Management Update on Primary Biliary Cirrhosis." Expert panelists included Christopher L. Bowlus, MD; James T. Kenney, RPh, MBA; and Gary Rice, RPh, MS, MBA, CSP.. To summarize the educational satellite symposium presentations and discussions.. Autoimmune liver diseases, including PBC, are responsible for 15% of all liver transplants performed and an equal percentage of deaths related to liver disease. UDCA is the only FDA-approved therapy for treatment of PBC and is considered the standard of care. Nevertheless, many patients do not respond to UDCA, creating the need for new therapeutic options to improve clinical outcomes for PBC patients with inadequate response to treatment. While several agents are being studied in combination with UDCA, monotherapy with the novel agent obeticholic acid, a farnesoid X receptor agonist, has also shown promising results. Health plans are anticipated to assign any newly introduced therapy for the treatment of PBC to specialty pharmacy given its orphan disease status. This assignment enables the health plan to receive disease education, which is particularly important when new drugs are indicated for orphan diseases, and assistance with designing appropriate prior authorization criteria. The clinical value of any new therapeutic options that will inform formulary decisions and prior authorization criteria will be assessed based on evidence of efficacy, safety, and tolerability, among other factors, such as the potential to reduce or delay medical resource utilization (e.g., liver transplant). Key considerations for prior authorization of a new therapy will be determining which PBC patients are appropriate candidates for the new therapy and developing criteria for that determination. These are likely to include clinical diagnostic criteria and degree of response to prior treatment with UDCA. Initially, any new therapy would likely be positioned as noncovered until appropriate prior authorization criteria are established.. PBC is a chronic liver disease with significant morbidity and mortality, as well as a significant burden on the health care system if the disease progresses to the point at which a liver transplant is needed. Although UDCA, the current standard of care, has improved outcomes for many patients, others have an inadequate response to this treatment. This symposium discussed these issues and also addressed the overall treatment paradigm for orphan drug therapies, key implications for patient management, and the role of specialty pharmacy management and any associated needs both in general and specifically for new therapeutic options for PBC.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Congresses as Topic; Disease Progression; Drug Resistance; Drug Therapy, Combination; Education, Pharmacy, Continuing; End Stage Liver Disease; Evidence-Based Medicine; Formularies as Topic; Humans; Insurance Coverage; Insurance, Pharmaceutical Services; Liver Transplantation; Middle Aged; Prescription Fees; Rare Diseases; Receptors, Cytoplasmic and Nuclear; Satellite Communications; Ursodeoxycholic Acid

Total bilirubin is a predictor of survival in primary biliary cholangitis, with the main elevated component being direct bilirubin. The purpose of this post hoc analysis was to assess the efficacy and safety of obeticholic acid across quartiles of varying baseline levels of direct bilirubin in the phase 3, randomized, placebo-controlled Primary Biliary Cholangitis Obeticholic Acid International Study of Efficacy.. This analysis assessed patients on the basis of their baseline direct bilirubin level (divided by quartile). Biochemistry and safety outcomes were evaluated within each quartile over time.. In the quartile with the highest baseline direct bilirubin (>5.47 µmol/L), there was a significant reduction in both direct and total bilirubin at Month 12 compared with placebo. Least squares mean (standard error) change from baseline in direct bilirubin at Month 12 was 4.17 (1.42) µmol/L for placebo, -3.48 (1.63) µmol/L for obeticholic acid 5-10 mg and -3.66 (1.51) µmol/L for obeticholic acid 10 mg (P < .0001, obeticholic acid vs placebo); the corresponding values for total bilirubin at Month 12 were 4.38 (1.55) µmol/L for placebo, -4.53 (1.83) µmol/L for obeticholic acid 5-10 mg and -5.06 (1.64) µmol/L for obeticholic acid 10 mg (P < .0001, obeticholic acid vs placebo).. Obeticholic acid treatment was associated with significant reductions in total and direct bilirubin, particularly in patients with high baseline direct bilirubin. Because raised direct bilirubin levels, even within the normal range, are predictive of survival in primary biliary cholangitis, these results suggest substantial benefits of obeticholic acid in at-risk patients.

Topics: Bilirubin; Chenodeoxycholic Acid; Cholangitis; Humans; Liver Cirrhosis, Biliary; Liver Function Tests

The aim of this study was to evaluate the long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis using 3-year interim data from the 5-year open-label extension of the pivotal phase 3 POISE trial.. In the double-blind phase of POISE, 217 patients with primary biliary cholangitis with inadequate response to or intolerance to ursodeoxycholic acid were randomised to receive placebo, obeticholic acid 5 to 10 mg, or obeticholic acid 10 mg once daily for 12 months. During the open-label extension phase, patients received variable, adjusted doses of obeticholic acid. Markers of cholestasis and liver injury, alkaline phosphatase (ALP), and total and direct bilirubin were evaluated, and safety was assessed for up to 48 months of treatment with obeticholic acid. All analyses in the open-label extension were done in the safety population, defined as any patient randomised in the double-blind phase who received at least one dose of obeticholic acid during the open-label extension. This trial is registered at ClinicalTrials.gov (NCT01473524) and with EudraCT (2011-004728-36).. 193 patients were treated during the open-label extension. In this 3-year interim analysis, ALP concentrations were significantly reduced compared with baseline at 12 months (mean change -105·2 U/L [SD 87·6]), 24 months (-101·0 U/L [98·5]), 36 months (-108·6 U/L [95·7]), and 48 months (-95·6 U/L [121·1]; p<0·0001 for all yearly time points). Total bilirubin concentrations were stabilised, with significant reductions versus baseline at 12 months (mean change -0·9 μmol/L [SD 4·1]; p=0·0042) and 48 months (-0·8 μmol/L [3·8]; p=0·016). Stabilisation was also noted for direct bilirubin, with a significant change from baseline at 12 months (mean change -0·5 μmol/L [SD 3·0]; p=0·021). However, changes in total and direct bilirubin were not significant at other time points. Obeticholic acid was generally well tolerated, with pruritus (149 [77%] patients) and fatigue (63 [33%]) being the most common adverse events. No serious adverse events were considered related to obeticholic acid.. Interim analyses suggest long-term efficacy and safety of obeticholic acid in patients with primary biliary cholangitis who are intolerant to or inadequately responsive to ursodeoxycholic acid.. Intercept Pharmaceuticals.

Topics: Alkaline Phosphatase; Bilirubin; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Dose-Response Relationship, Drug; Double-Blind Method; Fatigue; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Pruritus; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholangitis; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholangitis; Humans; Liver Cirrhosis, Biliary

Topics: Chenodeoxycholic Acid; Cholangitis; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Drug Administration Schedule; Female; Humans; Jaundice; Middle Aged; Ursodeoxycholic Acid

Topics: Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Cholangitis; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; United States; United States Food and Drug Administration

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

Topics: Alanine Transaminase; Alkaline Phosphatase; Autoantibodies; Bilirubin; Biomarkers; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Disease Progression; Gastroenterology; Humans; Liver Cirrhosis, Biliary; Mitochondria; Predictive Value of Tests; Risk Assessment; Risk Factors; Sensitivity and Specificity; Societies, Medical; Treatment Outcome; United Kingdom; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholangitis; Gastrointestinal Agents; Humans; Liver; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Treatment Outcome

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Drug Therapy, Combination; Humans; Treatment Outcome; Ursodeoxycholic Acid

Primary Biliary Cholangitis, previously known as Primary Biliary Cirrhosis, is a rare disease, which mainly affects women in their fifth to seventh decades of life. It is a chronic autoimmune disease characterized by a progressive damage of interlobular bile ducts leading to ductopenia, chronic cholestasis and bile acids retention. Even if the disease usually presents a long asymptomatic phase and a slow progression, in many patients it may progress faster toward cirrhosis and its complications. The 10year mortality is greater than in diseases such as human immunodeficiency virus/Hepatitis C Virus coinfection and breast cancer. Ursodeoxycholic acid is the only treatment available today, but even if effective in counteracting the disease progression for the majority of patients, in approximately 40% is not able to decrease effectively the alkaline phosphatase, a surrogate marker of disease activity. Recently, obeticholic acid received the European Medicines Agency conditional approval, as add on treatment in patients non responders or intolerant to ursodeoxycholic acid. The present paper illustrates the opinion of a working group, composed by clinical pharmacologists, gastroenterologists/hepatologists with specific expertise on Primary Biliary Cholangitis and patient associations, on the state of the art and future perspectives of the disease management. The agreement on the document was reached through an Expert Meeting.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Cholestasis; Disease Progression; Drug Therapy, Combination; End Stage Liver Disease; Humans; Ursodeoxycholic Acid

Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters.. Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin).. OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E. In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin).. Intercept Pharmaceuticals, Inc.

Topics: Adult; Aged; Aged, 80 and over; Caffeine; Chenodeoxycholic Acid; Cholangitis; Cytochrome P-450 Enzyme System; Dextromethorphan; Digoxin; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Midazolam; Middle Aged; Omeprazole; Rosuvastatin Calcium; Warfarin

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Humans; Ursodeoxycholic Acid

In a double-blind, randomized, placebo-controlled study including 217 patients with primary biliary cholangitis, the authors show that obeticholic acid (a potent farnesoid X agonist) administered with ursodeoxycholic acid or as monotherapy significantly decreases serum alkaline phosphatase and bilirubin when compared to placebo. Pruritus (and serious adverse effects) was observed more frequently in obeticholic acid-treated patients than in controls, in spite of a decrease in serum bile acid concentration. These results are encouraging, but more studies are needed on clinical efficacy and safety before obeticholic acid can be widely recommended.

Topics: Chenodeoxycholic Acid; Cholangitis; Double-Blind Method; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is a chronic, progressive autoimmune liver disease that mainly affects middle-aged women. Obeticholic acid (OCA), which was recently approved by the Food and Drug Administration for PBC treatment, has demonstrated positive effects on biochemical markers of liver function. Our objective was to evaluate the long-term clinical impact and cost-effectiveness of OCA as a second-line treatment for PBC in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA. We developed a mathematical model to simulate the lifetime course of PBC patients treated with OCA+UDCA versus UDCA alone. Efficacy data were derived from the phase 3 PBC OCA International Study of Efficacy trial, and the natural history of PBC was informed by published clinical studies. Model outcomes were validated using the PBC Global Study. We found that in comparison with UDCA, OCA+UDCA could decrease the 15-year cumulative incidences of decompensated cirrhosis from 12.2% to 4.5%, hepatocellular carcinoma from 9.1% to 4.0%, liver transplants from 4.5% to 1.2%, and liver-related deaths from 16.2% to 5.7% and increase 15-year transplant-free survival from 61.1% to 72.9%. The lifetime cost of PBC treatment would increase from $63,000 to $902,000 (1,330% increment). The discounted quality-adjusted life years with UDCA and OCA+UDCA were 10.74 and 11.78, respectively, and the corresponding costs were $142,300 and $633,900, resulting in an incremental cost-effectiveness ratio of $473,400/quality-adjusted life year gained. The results were most sensitive to the cost of OCA.. OCA is a promising new therapy to substantially improve the long-term outcomes of PBC patients, but at its current annual price of $69,350, it is not cost-effective using a willingness-to-pay threshold of $100,000/quality-adjusted life year; pricing below $18,450/year is needed to make OCA cost-effective. (Hepatology 2017;65:920-928).

Topics: Adult; Biopsy, Needle; Chenodeoxycholic Acid; Cholangitis; Cohort Studies; Cost-Benefit Analysis; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunohistochemistry; Male; Middle Aged; Prospective Studies; Quality-Adjusted Life Years; Risk Assessment; Severity of Illness Index; Time; Treatment Outcome

Topics: Chenodeoxycholic Acid; Cholangitis; Humans