Obeticholic acid is associated with improvements in AST-to-platelet ratio index and GLOBE score in patients with primary biliary cholangitis

Abstract

Background & aims: Biochemical 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.

Methods: In 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.

Results: The 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.

Conclusions: Based 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 summary: Primary 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 registration: NCT01473524.

Keywords: AE, adverse event; ALP, alkaline phosphatase; APRI; APRI, aspartate aminotransferase-to-platelet ratio index; AST, aspartate aminotransferase; Cholestasis; DB, double-blind; FXR, farnesoid X receptor; IQR, inter-quartile range; LLN, lower limit of normal; LN, natural logarithm; LT, liver transplant; OCA, obeticholic acid; OR, odds ratio; PBC; PBC, primary biliary cholangitis; Risk stratification; UDCA, ursodeoxycholic acid; ULN, upper limit of normal.

Conflict of interest statement

Maren H. Harms has received speaker fees from Zambon BV. Gideon M. Hirschfield has received consultancy fees from CymaBay, Gilead, GSK, Intercept, and Novartis, as well as grant funding from Gilead and Falk Pharma. Annarosa Floreani declares no conflicts of interest that pertain to this work. Marlyn J. Mayo has served on advisory committees or review panels for GSK, and has received grant/research support from Gilead, CymaBay, Intercept, Mallinckrodt, Novartis, Target, GSK, and Genfit. Albert Parés has received grant funding, personal fees, and advisory board fees from Intercept; personal fees and advisory board fee from Novartis; and personal fees from CymaBay and Inova Diagnostics. Alexander Liberman and Leigh MacConell are employees and shareholders of Intercept. Elizabeth Smoot Malecha is an employee of Intercept. Richard Pencek is a shareholder and former employee of Intercept. Bettina E. Hansen has received grant funding and personal fees from Intercept, CymaBay, and Albireo, and has received personal fees from Mirum and ChemoMab. Please refer to the accompanying ICMJE disclosure forms for further details.

© 2020 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

Figures

Graphical abstract

Fig. 1

Changes in APRI. Double-blind p value for comparing OCA with placebo was obtained using an ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomisation strata factor. The dashed red line represents the APRI threshold of 0.54. ∗p <0.05. ∗∗p <0.01. ∗∗∗p <0.0001. ANCOVA, analysis of covariance; APRI, aspartate aminotransferase-to-platelet ratio index; BL, baseline; LS, least square; OCA, obeticholic acid; UDCA, ursodeoxycholic acid.

Fig. 2

Categorical changes in APRI after OCA treatment. Progression was defined as baseline APRI ≤0.54 and on treatment APRI >0.54; improvement was defined as baseline APRI >0.54 and on treatment APRI ≤0.54. Patients with evaluations at both baseline and double-blind Month 12 were included. p values were obtained using the Cochran-Mantel-Haenszel test. ∗p <0.05. ∗∗p <0.01. APRI, aspartate aminotransferase-to-platelet ratio index; OCA, obeticholic acid; UDCA, ursodeoxycholic acid.

Fig. 3

Categorical changes in GLOBE score after OCA treatment. (A) GLOBE score by overall threshold (0.3). (B) GLOBE score by age-specific threshold. Age-specific threshold was defined as follows, for age based on consent date: −0.52 for p value was obtained using the Cochran-Mantel-Haenszel test. ∗p <0.05. ∗∗p <0.01. ∗∗∗p <0.001. OCA, obeticholic acid; UDCA, ursodeoxycholic acid.

Fig. 4

Risk category shifts using APRI and GLOBE thresholds combined. (A) Risk category shifts using APRI and GLOBE (0.3) thresholds combined. (B) Risk category shifts using APRI and GLOBE (age-specific) thresholds combined. Progression was defined as a shift from a lower to higher risk category and improvement from a higher to lower risk category. Low risk: both scores ≤ threshold; moderate risk: one of the scores > threshold; high risk: both scores > threshold. p values were obtained using the Cochran-Mantel-Haenszel test. ∗p <0.05. ∗∗p <0.01. ∗∗∗p <0.001. ∗∗∗∗p <0.0001. APRI, aspartate aminotransferase-to-platelet ratio index; DB, double-blind; OCA, obeticholic acid; UDCA, ursodeoxycholic acid.