Journal Article

PTU-009 Long-term effects of obeticholic acid in patients with primary biliary cholangitis on inflammatory markers

Trauner, Michael, Hirschfield, Gideon M, Liberman, Alexander, Andreone, Pietro, Vargas, Victor, Drenth, Joost PH, Ryder, Stephen, Nevens, Frederik, Shiffman, Mitchell L, MacConell, Leigh, Bowlus, Christopher L, Malecha, Elizabeth Smoot

2019

Overview

IntroductionObeticholic Acid (OCA) is a potent and selective farnesoid X receptor agonist approved for the treatment of primary biliary cholangitis (PBC). PBC is a chronic liver disease characterized by the immune mediated destruction of bile ducts resulting in cholestasis, cirrhosis and liver failure. The POISE study was a randomized, placebo-controlled phase 3 study investigating daily OCA 5–10 mg in PBC patients with an ongoing open label extension (OLE). The purpose of this analysis was to assess the long-term effects of OCA on key markers of liver damage and inflammation.MethodsPatients enrolled in the double-blind phase had an inadequate response to UDCA or were intolerant of UDCA. Patients were randomized to placebo, OCA 5–10 mg, or OCA 10 mg. Upon completion of the 12-month double-blind phase, 198 patients enrolled in the OLE and received OCA. For this analysis, patients were pooled and assessed from the time of first dose of OCA. Data are shown through 48 months of OCA exposure, for patients randomized to placebo in the double-blind phase, only 36 months of data are included.ResultsAt baseline (N=198), patients were 92% female, mean age was 55 years, PBC disease duration was 9 years, and 93% received UDCA (mean dose: 16 mg/kg/day). As observed in the table, there were sustained and significant reductions in immunoglobulins (Ig) A, G and M throughout 48 months of OCA treatment. In addition, significant reductions were observed in tumor necrosis factor (TNF)-α, c-reactive protein (CRP), and cleaved cytokeratin (CK)-18 throughout the duration of the OLE. No clinically meaningful changes were observed with transforming growth factor (TGF)-β and interleukin (IL)-12, both remained within the normal range.Abstract PTU-009 Table 1Median change from Baseline in Key immune, apoptotic and inflammatory markers*p<0.05; **p<0.01; ***p<0.0001. p-values for the comparisons to baseline were obtained using a Wilcoxon signed rank test. Normal ranges: CRP 0-3 mg/L, TNF-α 8.1 pg/ml, TGF-β 18.3-63.4 ng/ml, Ck-18 80 U/L, IL-12 34-246 pg/mL, IgA 0.7-4 g/L, IgG 7-16 g/L, IgM 0.4-2.3 g/LConclusionsThese results demonstrate that OCA has a durable anti-inflammatory effect in patients with PBC as observed by reductions on key markers of apoptosis (TNF-α and CK-18) and inflammation (CRP). Furthermore, a sustained reduction is observed in IgM, which is classically elevated in PBC patients. The clinical significance of OCA mediated reductions in IgA and IgG continues to remain unknown.

• Publisher: BMJ Publishing Group LTD
• Subject: Apoptosis / Bile ducts / C-reactive protein / Cholangitis / Cholestasis / Cirrhosis / Clinical trials / Cytokeratin / Immunoglobulin A / Immunoglobulin G / Immunoglobulin M / Inflammation / Interleukin 12 / Liver cirrhosis / Liver diseases / Liver failure / Long-term effects / Patients / Transforming growth factor / Tumor necrosis factor-TNF / Tumor necrosis factor-α