R. Pencek

Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub‐fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non‐alcoholic fatty liver disease or non‐alcoholic steatohepatitis.

A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis

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. Conclusion: OCA 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).

P374 LONG-TERM TREATMENT OF PRIMARY BILIARY CIRRHOSIS WITH THE FXR AGONIST OBETICHOLIC ACID SHOWS DURABLE EFFICACY

P372 APOPTOSIS INDUCED BY BILIRUBIN AND LITHOCHOLIC ACID IN HUMAN OSTEOBLASTS IS NEUTRALIZED BY URSODEOXYCHOLIC ACID S. Ruiz-Gaspa, M. Dubreuil, N. Guanabens, A. Combalia, P. Peris, A. Monegal, A. Pares. Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd), Liver Unit, Digestive Diseases Institute, Hospital Cĺinic, IDIBAPS, University of Barcelona, Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas, Rheumatology, Department of Orthopedics, Metabolic Bone Diseases Unit, Hospital Cĺinic, University of Barcelona, Liver Unit, Hospital Cĺinic, University of Barcelona, IDIBABPS, CIBERehd, Barcelona, Spain E-mail: silvia.ruiz@ciberehd.org

P1137 : Integrated efficacy summary for obeticholic acid in subjects with primary biliary cirrhosis

Background and Aims: Obeticholic acid (OCA), a modified bile acid and farnesoid x receptor (FXR) agonist, is currently in late-phase development for the treatment of primary biliary cirrhosis (PBC), a rare cholestatic liver disease. In two Phase 2 trials (3 months) and in the Phase 3 POISE trial (12 months) 5mg to 50mg OCA, once daily as monotherapy or add-on to UDCA, produced significant improvements in markers of cholestasis and inflammation. The objective of this integrated analysis was to evaluate the efficacy of ≤10mg OCA, the proposed indicated doses for the treatment of PBC, as monotherapy or in combination with UDCA in an integrated fashion across the 3 trials compared to placebo. Methods: Individual subject data from 3 completed, randomized, controlled double-blind trials of OCA once daily were pooled for this analysis (OCA ≤10mg N=201; placebo N=134; OCA 25mg N=48; OCA 50mg N=57). All placebo subjects were pooled as were OCA doses of 5mg, titration from 5 to 10mg, and 10mg (≤10mg OCA). Inclusion criteria included ALP ≥1.67×ULN or total bilirubin >ULN but <2×ULN. Analyses were repeated based on baseline concomitant UDCA use. Efficacy was evaluated using a composite endpoint shown to correlate with long-term survival (ALP <1.67 ULN with a minimum 15% reduction and a normal bilirubin) (Lammers 2014) and assessment of liver biochemistry and inflammation. Results: Baseline characteristics were generally similar between treatment groups. Baseline ALP was higher in monotherapy subjects compared to UDCA combination subjects. Efficacy data are presented in the Table. At the end of double blind treatment significantly more OCA-treated subjects achieved the composite endpoint compared to placebo when used as monotherapy or in combination with UDCA. OCA treatment was associated with statistically significant and clinically meaningful decreases in ALP as well as GGT, ALT, and AST. While the subjects in the monotherapy group had higher ALP at baseline than the OCA plus UDCA group, the two groups reached similar ALP levels by the end of the double-blind period. Pruritus was the most common adverse event associated with PBC and showed a dose-related increase in incidence with OCA.

PTU-100 Efficacy of obeticholic acid treatment in patients with primary biliary cholangitis with cirrhosis

Introduction Obeticholic acid (OCA) is a potent and selective farnesoid X receptor (FXR) agonist under investigation for treatment of primary biliary cholangitis (PBC) and other chronic liver diseases. POISE was a double-blind, placebo-controlled, randomised Phase 3 study examining the efficacy of OCA in PBC. The objective of this post-hoc analysis was to assess the efficacy of OCA in the subset of patients with cirrhosis who were at higher risk of progression to liver-related outcomes or death. Method We randomised and dosed 216 patients 1:1:1 with placebo (PBO) (n=73), OCA 5–10 mg (n=70, titrated to 10 mg after 6 months based on response and tolerability) or OCA 10 mg (n=73). Inclusion criteria included PBC diagnosis, ALP≥1.67x ULN and/or total bilirubin (BILI) >ULN to <2x ULN, stable UDCA dose or intolerance to UDCA. Patients were considered to have cirrhosis if they met one of the following criteria: biopsy-proven cirrhosis, transient elastography of ≥16.9 kPa, or history of cirrhosis. The primary composite endpoint was an ALP<1.67x ULN with ≥15% reduction in ALP and BILI ≤ULN after 12 months. Results Cirrhosis was present in approximately 17% of patients in POISE: PBO, n=13; OCA 5–10 mg, n=13; OCA 10 mg, n=10. At month 12, 54% (p<0.05) of patients in the OCA 5–10 mg group and 40% (p=0.06) in the OCA 10 mg group met the primary composite endpoint compared to 8% of PBO patients with cirrhosis. The table shows significant differences in ALP and BILI between PBO and both OCA groups after 12 months. BILI increased on PBO; however, it remained stable in both OCA groups after 12 months of treatment. Pruritus was the most common adverse event in patients with cirrhosis, affecting 23%, 69%, and 80% of patients in the PBO, OCA 5–10 mg, and OCA 10 mg groups, respectively. Conclusion In this post-hoc analysis, no additional safety concerns due to OCA were observed in the subgroup of OCA-treated patients with cirrhosis, and OCA treatment resulted in significant improvements in biochemical markers associated with disease progression. The percentage of patients achieving the primary composite endpoint on OCA was comparable in patients with cirrhosis and non-cirrhotic patients. These results suggest that OCA may play a beneficial role in preservation of the functional capacity of residual liver tissue in cirrhotic patients. Disclosure of Interest J Vierling: None Declared, G. Hirschfield: None Declared, D. Jones: None Declared, R. Groszmann: None Declared, K. Kowdley: None Declared, R. Pencek Conflict with: Intercept Pharmaceuticals, Inc., Conflict with: Intercept Pharmaceuticals, Inc., T. Marmon Conflict with: Intercept Pharmaceuticals, Inc., Conflict with: Intercept Pharmaceuticals, Inc., L. MacConell Conflict with: Intercept Pharmaceuticals, Inc., Conflict with: Intercept Pharmaceuticals, Inc. Abstract PTU-100 Table 1 Effect of OCA treatment on ALP and total bilirubin in patients with cirrhosis

PTU-080 Efficacy and Safety of Obeticholic Acid (OCA) in PBC Patients with Advanced Disease as Evidenced by Abnormal Bilirubin: An Integrated Analysis

Introduction ALP and bilirubin are both strongly associated with need for liver transplant or death in patients with primary biliary cirrhosis (PBC, also known as primary biliary cholangitis). Elevation of ALP precedes elevations in bilirubin, which is of particular concern since bilirubin is the major predictor of adverse disease outcome. Obeticholic acid (OCA, 6 ethyl chenodeoxycholic acid) is a selective potent FXR agonist developed for treatment of PBC. Given the particular concern in patients with abnormal bilirubin, the intent of this analysis was to evaluate the efficacy and safety of OCA in patients with an elevated bilirubin. Methods The clinical development of OCA in PBC has included three randomised, double-blind, placebo-controlled studies (2 Phase 2 trials and 1 Phase 3). Abnormal bilirubin was not a common feature in the individual studies, therefore, data from all three studies was pooled. All studies included key biochemical and clinical assessments at 3 months of OCA therapy; data was also available for a subset of subjects at 12 months.Abstract PTU-080 Figure 1 Results ALP was markedly elevated at baseline in patients with abnormal bilirubin and OCA treatment was associated with significant ALP reductions. Bilirubin levels increased in the placebo arm and decreased with OCA, although the difference was not statistically significant over this short 3 month timeframe. At 12 months there was a significant reduction in bilirubin vs. placebo. Consistent with the overall population, pruritus was the most common event in placebo and OCA-treated patients. The safety profile of OCA was consistent with the overall development program. Hepatic disorders (eg, increased bilirubin, PBC, and postal hypertension) and serious adverse events increased in incidence with abnormal bilirubin levels but were likely due to progression of the underlying disease. Conclusion OCA treatment in patients with advancing disease, as evidenced by abnormal bilirubin, was associated with significant improvements in ALP and bilirubin, parameters shown to correlate with improved clinical outcome. Disclosure of Interest None Declared