Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis

Abstract

Background & aims: Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.

Methods: In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.

Results: In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].

Conclusions: Readily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.

Trial registration: ClinicalTrials.gov NCT01265498.

Keywords: biomarkers; fibrosis; non-alcoholic steatohepatitis; non-invasive.

Conflict of interest statement

Conflicts of interests:

NC received consulting fees from AbbVie Inc., Domain Therapeutics, Afimmune, Eli Lilly and Company, Cempra, Shire, Axovant, Ardelyx, NuSirt Biopharma, and Tobira (Allergan) Therapeutics, Inc., and grant/research support from Galectin Therapeutics Inc., Cumberland, Gilead Sciences, Inc., and Intercept Pharmaceuticals, Inc. MFA received consulting fees from BHV Pharma, Inc., and TaiwanJ Pharmaceuticals Co. Ltd. and grant/research support from Allergan, Arisaph Pharmaceuticals, Inc., Boehringer-Ingelheim GmbH, Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Exalenz Bioscience Ltd., Galectin Therapeutics Inc., Galmed Pharmaceuticals Ltd., Genfit Corp., Gilead Sciences, Inc., Immuron, Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals, Inc., NIH/NIDDK, Shire, TaiwanJ Pharmaceuticals Co. Ltd., and Tobira Therapeutics, Inc. MFA has also received speaker fees from Alexion Pharma GmbH and advisory/review panel fees from Bristol-Myers Squibb Company, Celgene Corporation, NGM Biopharmaceuticals, Inc., and Pfizer Inc. RL received advisory/review panel fees from Arrowhead Pharmaceuticals, Inc., Galmed Pharmaceuticals Ltd., and Tobira Therapeutics, Inc., and consulting fees from Alnylam Pharmaceuticals, Inc., Celgene Corporation, Corgenix, DeuteRx, Enanta Pharmaceuticals, Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., and Zafgen Inc. RL also received grant/research support from Adheron Therapeutics, Inc., AGA Pharma & Supplements SL, Daiichi Sankyo Company, Ltd., Immuron, KineMed, Inc., Merck & Co., Inc., and Promedior, Inc. KVK received advisory/review panel fees from AbbVie Inc., Enanta Pharmaceuticals, Inc., Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Trio Health, and Verlyx Pharma Inc. and grant/research support from AbbVie Inc., Evidera, Galectin Therapeutics Inc., Gilead Sciences, Inc., Immuron, Intercept Pharmaceuticals, Inc., Merck & Co., Inc., NGM Biopharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Tobira Therapeutics, Inc., and Trio Health. KVK has also received speaker fees from Gilead Sciences, Inc., and Intercept Pharmaceuticals, Inc. AJM has nothing to disclose. SD received consulting fees from Fresenius Kabi. BAN-T received advisory/review panel fees from Allergan, Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galmed Pharmaceuticals, Ltd., Janssen Pharmaceuticals, Inc., Nimbus Therapeutics, Novartis Pharmaceuticals Corporation, Pfizer Inc., Receptos Services, LLC, and Zafgen Inc. and consulting fees from Medimmune. NT received advisory/review panel fees from Biotest Pharmaceuticals Corporation and Eisai Co., Ltd. and consulting fees from Achillion Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Cocrystal Pharma, Inc., and Merck & Co., Inc. NT also received grant/research support from AbbVie Inc., Biotest Pharmaceuticals Corporation, Eisai Co., Ltd., Gilead Sciences, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, and Vertex Pharmaceuticals Inc. BF is an employee of Intercept Pharmaceuticals, Inc. RS is an employee of Intercept Pharmaceuticals, Inc., and receives stock ownership. DS is an employee of Intercept Pharmaceuticals, Inc., and receives stock ownership. AJS received advisory/review panel fees from Abbott, Bristol-Myers Squibb Company, Exalenz Bioscience Ltd., Gilead Sciences, Inc., Genfit Corp., Ikaria, Inc., Novartis Pharmaceuticals Corporation, and Pfizer Inc. and consulting fees from Echosens, Genentech, Inc., HemoShear Therapeutics, LLC, JD Pharma Consultants Pvt. Ltd., Nimbus Therapeutics, Merck & Co., Inc., Salix Pharmaceuticals, Takeda Pharmaceutical Company Ltd., and Zafgen Inc. AJS also received grant/research support from Galmed Pharmaceuticals Ltd., Genentech, Inc., Gilead Sciences, Inc., Ikaria, Inc., Intercept Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Salix Pharmaceuticals, Takeda Pharmaceutical Company Ltd., and Tobira Therapeutics, Inc., and contracting fees from Elsevier B.V. and UpToDate, Inc. AJS also holds a management position at Sanyal Biotechnology and has stock options in Genfit, HemoShear, Exalenz, and Galmed.

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

Figure 1.

Mean and mean change for APRI, FIB-4, and NFS scores over time: Completer population. **p

Figure 2.

Mean change from baseline to Week 72 for APRI, FIB-4, and NFS by baseline fibrosis stage for OCA (teal) and placebo (grey): Completer population. Patients with missing data at a specific time point were not included in the analysis for that time point. The completer population was defined as all patients who were randomly assigned, received treatment and had available biopsy results for both baseline and 72 weeks. APRI, aspartate aminotransferase:platelet ratio index; CI, confidence interval; FIB-4, fibrosis-4; OCA, obeticholic acid; NFS, non-alcoholic fatty liver disease fibrosis score.

Figure 3:

Median percentage change from baseline in APRI, FIB-4, and NFS by improvement in histologic stage at 72 weeks: Completer population. Patients with missing data at a specific time point were not included in the analysis for that time point. The completer population was defined as all patients who were randomly assigned, received treatment and had available biopsy results for both baseline and 72 weeks. APRI, aspartate aminotransferase:platelet ratio index; FIB-4, fibrosis-4; NFS, non-alcoholic fatty liver disease fibrosis score.

Figure 4:

ROC curve for APRI, FIB-4, and NFS at 24 weeks as predictors of histologic improvement in fibrosis at week 72 showing sensitivity and specificity: Completer population. The completer population was defined as all patients who were randomly assigned, received treatment and had available biopsy results for both baseline and 72 weeks. APRI, aspartate aminotransferase:platelet ratio index; FIB-4, fibrosis-4; NFS, non-alcoholic fatty liver disease fibrosis score; ROC, receiver operator characteristic.