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

Abstract

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).

Fine‐Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease

“…During cholestasis, FXR signaling mediates an adaptive response aiming to reduce bile acid pool size by inhibiting bile acid synthesis and modulating their transport . FXR currently represents a promising target for therapeutic approaches to treat human cholestatic disease . Regulation of FXR involves a dynamic deacetylation process coordinated by SIRT1 and is needed for FXR‐DNA binding and target gene transcription, whereas the same process regulates FXR proteasomal degradation .…”

Primary Biliary Cholangitis

“…Another phase 2 study launched simultaneously evaluated two OCA doses (10 mg and 50 mg) versus placebo as monotherapy in 59 patients with PBC. Serum ALP dropped by 53.9% in the 10‐mg group, 37.2% in the 50‐mg group, and by only 0.8% in the placebo group . Again, pruritus was the most important adverse event, leading to discontinuation of 38% of study subjects in the 50‐mg arm.…”

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug‐induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease

“…As is characteristic of all cholestatic liver diseases, the degree of ALP elevation is higher than the degree of aminotransferase elevation in PBC. ALP typically ranges from 2 to approximately 10 x ULN, although ALP may be normal in the early stages of disease . While mean ALP values most commonly range between 2‐3 × ULN, a recent study from Mexico comparing survival rates of patients treated with ursodeoxycholic acid compared with other treatments, reported that entry ALP prior to the start of either ursodeoxycholic acid or other drugs was 5.2 ± 3.7 × ULN and 4.0 ± 4.5 × ULN (mean ± SD) in the two groups respectively .…”

“…Obeticholic acid has now been listed on livertox.nih.gov as “a suspected rare cause of clinically apparent liver injury occurring mostly in patients with preexisting cirrhosis”0 . In reviewing published clinical trials of obeticholic acid for PBC, it is noted that there were discontinuations due to elevated liver tests, although the profiles of these patients were not publicly available for evaluation …”

“…In a review of PBC clinical trials, new nadir values of liver tests achieved after treatment initiation were not utilised in DILI monitoring or stopping rules, in spite of the fact that nadir levels for ALT and ALP were achieved and stabilised by 1‐3 months of therapy . Although not assessed in any trials, the degree of reduction in ALT and ALP to achieve this nadir value was approximately a mean reduction of 15% from baseline value .…”