Obeticholic Acid for Primary Biliary Cholangitis.
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ABSTRACT:
SUBMITTER: Floreani A
PROVIDER: S-EPMC9599277 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Obeticholic Acid for Primary Biliary Cholangitis.
Floreani Annarosa A Gabbia Daniela D De Martin Sara S
Biomedicines 20221002 10
Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease that may progress to fibrosis and/or cirrhosis. Treatment options are currently limited. The first-line therapy for this disease is the drug ursodeoxycholic acid (UDCA), which has been proven to normalize serum markers of liver dysfunction, halt histologic disease progression, and lead to a prolongation of transplant-free survival. However, 30-40% of patients unfortunately do not respond to this first-line therapy. ...[more]
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Project description:Patients with primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid are at risk of disease progression and need additional therapy. Obeticholic acid (OCA) was approved in Canada in May 2017, but its effectiveness in a real-world setting has not been described. We sought to describe our experience with OCA in a Canadian cohort. OCA-naive patients treated at two Canadian centers were included. Clinical and biochemical data were collected at OCA initiation and during follow-up. Primary outcomes were changes in serum alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TB) over the duration of therapy. Secondary outcomes were changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), immunoglobulin M (IgM), platelets, and albumin; and achievement of the primary endpoint of the original phase 3 study that led to OCA approval (A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis [POISE]), dose reductions, discontinuations, and tolerability. Repeated-measures models were used to assess changes in biochemistry over time. Sixty-four patients were included; 4 carried a diagnosis of overlap with autoimmune hepatitis. Mean age was 54.6 years, median ALP was 250 U/L, TB was 13 µmol/L, platelet count was 225 × 109/L, and 24% had liver stiffness measurements ≥16.9 kPa. There was a significant reduction in mean ALP of 55 U/L (P < 0.001), GGT of 138 U/L (P < 0.001), ALT of 11.9 U/L (P < 0.001), AST of 5.7 U/L (P < 0.05), and IgM of 0.70 g/L (P < 0.001) over 12 months; TB remained stable (P = 0.98). Forty-four patients met POISE-inclusion criteria, 39% (n = 17) of whom had 12-month biochemical measurements. In this subset, 18% (n = 3/17) met the 12-month POISE primary endpoint, but considering follow-up to 19 months, 43% achieved this target (n = 9/21). Pruritus was the most commonly reported complaint. Conclusion: Use of OCA was associated with improvement in biochemical surrogates of outcome in PBC in a real-world setting.
| S-EPMC7471421 | biostudies-literature
Project description:Background & aimsObeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions.MethodsPatients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed.ResultsWe analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%).ConclusionsEffectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC.Lay summaryObeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.
| S-EPMC7930359 | biostudies-literature
Project description:Objective: To review the pharmacology, efficacy, and safety of obeticholic acid (OCA) and determine its clinical role relative to other agents in the treatment of patients with primary biliary cholangitis (PBC). Data Sources: A PubMed search (1946 to November 2016) was conducted using the terms INT-747, obeticholic acid, OCA, farnesoid X receptor agonists, FXR agonists, primary biliary cirrhosis, and primary biliary cholangitis. Study Selection and Data Extraction: Phase II and III studies evaluating the use of OCA in PBC patients were included in this review. Data Synthesis: OCA, a farnesoid X receptor (FXR) agonist, is indicated for adult patients with PBC in combination with ursodeoxycholic acid (UDCA) or as monotherapy if unable to tolerate UDCA. Two clinical trials were identified evaluating OCA for the treatment of PBC. Study end points utilized biochemical markers (alkaline phosphatase [ALP] and bilirubin). A phase II study (n = 165) to determine efficacy and safety of OCA at 3 different doses (10 mg, 25 mg, 50 mg) demonstrated statistically significant reductions in ALP (P < .0001 for all OCA groups versus placebo) after 12 weeks. A phase III trial (n = 217) assessed lower OCA doses (5 mg and 10 mg) with a longer study duration (12 months). Statistically significant differences (P < .001) between the 5 to 10 mg group (46%) and the 10 mg group (47%) compared to the placebo group (10%) were found. The primary adverse effect reported in both trials was pruritus. Conclusions: OCA is the first FXR agonist approved for the treatment of PBC. Ongoing research to evaluate clinical outcomes with OCA is currently underway.
| S-EPMC5998444 | biostudies-other
Project description:Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus.ConclusionOCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).
| S-EPMC5947631 | biostudies-literature
Project description:Background & aimsTotal 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.MethodsThis 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.ResultsIn 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).ConclusionsObeticholic 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.
| S-EPMC7317821 | biostudies-literature
Project description:Obeticholic acid (OCA) is approved for the treatment of patients with primary biliary cholangitis (PBC) who are partial responders or intolerant to ursodeoxycholic acid. Reports of serious liver injury have raised concerns about its safety in cirrhosis. We investigated the effects of treatment with OCA on hepatic decompensation and liver-related mortality or transplantation in a cohort with compensated PBC cirrhosis. This was a retrospective cohort study using national data of US veterans with PBC and cirrhosis. We performed a propensity score model using variables associated with OCA prescription to control for baseline risk of decompensation. New OCA users were matched to nonusers. We identified 509 subjects with compensated PBC cirrhosis. We developed a propensity score model using variables associated with OCA prescription; 21 OCA users were matched with 84 nonusers. Over 569 and 3,847 person-months, respectively, of follow-up, 5 (23.8%) OCA users and 22 (26.2%) OCA nonusers decompensated. The C-statistic of the propensity score model was 0.87. On multivariable analysis, after adjusting for potential confounders, OCA use was associated with an increased risk of hepatic decompensation (adjusted hazard ratio, 3.9; 95% confidence interval, 1.33-11.57; P = 0.01). There was no association between OCA use and liver-related mortality or transplantation (adjusted hazard ratio, 1.35; 95% confidence interval, 0.35-5.21; P = 0.66). Conclusion: OCA use was associated with an increase in hepatic decompensation but not liver-related mortality or transplantation in patients with compensated PBC cirrhosis. Additional studies are recommended to prospectively investigate these findings.
| S-EPMC8369937 | biostudies-literature
Project description: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.
| S-EPMC5012622 | biostudies-other
Project description:BackgroundUp to 40% of patients with primary biliary cholangitis (PBC) have an inadequate response to ursodeoxycholic acid (UDCA). Obeticholic acid (OCA) is considered the addition of treatment, but the response rate based on commonly referenced biochemical response criteria and lipids' impact was unclear. Previous studies reported inconsistency results partially due to small sample size. Therefore, we performed a meta-analysis and aimed to explore OCA treatment's response rate and effect on lipids' profiles in PBC patients.MethodsWe performed PubMed, Embase, and Cochrane controlled trials register (updated to JUN 2019) databases and manual bibliographical searches for randomized controlled trials reporting on OCA treatment in PBC patients. Two researchers independently extracted data and assessed the risk of bias of studies. We calculated risk ratio (RR) for the overall complete response rate, and the standardized mean difference (SMD) for the serum lipids changes after OCA treatment, all with 95% confidence intervals (CIs) using fixed-effects models. We registered this meta-analysis with PROSPERO (registration number: CRD42020148550).ResultsThree trials, with 265 patients, were selected for the analysis. OCA was superior to placebo in PBC patients (RR, 1.48; 95% CI, 1.15-1.90). OCA's pooled treatment response rate was 65% (95% CI, 56%-74%), corresponding to Paris I criteria. Besides, OCA significantly decreased total cholesterol (P=0.02) with no heterogeneity (P=0.87, I 2 = 0%) and high-density lipoprotein levels (P < 0.05) with no heterogeneity (P=0.82, I 2 = 0%).ConclusionsThis meta-analysis demonstrated that OCA was a promising additional treatment for PBC patients and might reduce serum cholesterol levels. The longer follow-up studies are needed to give more evidence.
| S-EPMC7822683 | biostudies-literature
Project description:Background & aimsBiochemical markers, including GLOBE score and aspartate aminotransferase-to-platelet ratio index (APRI), are used to stratify risk in patients with primary biliary cholangitis (PBC). This study aimed to evaluate the effects of obeticholic acid (OCA) on categorical shifts in GLOBE score, APRI, and both combined, based on data from POISE, a phase III placebo-controlled trial in patients with PBC who had an incomplete response or were intolerant to ursodeoxycholic acid.MethodsIn a post hoc analysis, baseline and Month 12 data from POISE were used to calculate the APRI and GLOBE score. Patients were stratified into 3 risk groups based on a combination of APRI (0.54) and GLOBE (0.3 or age-specific) thresholds.ResultsThe analysis included 215 patients (47 low risk; 79 moderate risk; 89 high risk). Using the combined GLOBE score (threshold of 0.3) and APRI thresholds, there was improvement in ≥1 risk stage in 37% and 35% of patients in the OCA 5-10 mg and 10 mg groups, respectively, vs. 12% in the placebo group (both p <0.05). Progression occurred in 10% and 0% in the 5-10 mg and 10 mg groups vs. 37% in the placebo group. Results with GLOBE age-specific thresholds were similar.ConclusionsBased on change in APRI and GLOBE score at 12 months, OCA treatment is associated with reduction in the predicted risk of liver-related complications in patients with PBC.Lay summaryPrimary biliary cholangitis (PBC) is a chronic disease affecting the liver. People who suffer from PBC are at risk of serious long-term complications. Information from certain blood tests can be used to estimate the likelihood of experiencing long-term complications. The results of this study showed that based on blood test results, people taking obeticholic acid, with or without ursodeoxycholic acid, for PBC were predicted to have a better outcome than those taking placebo.Clinical trials registrationNCT01473524.
| S-EPMC7724188 | biostudies-literature
Project description:Background & aimsPrimary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.MethodsAESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety.ResultsThe intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged.ConclusionsTreatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.RegistrationClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38.Lay summaryPrimary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.
| S-EPMC8157171 | biostudies-literature