Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study

Abstract

Background & aims: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study.

Methods: Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study.

Results: Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable.

Conclusions: Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. CLINICALTRIALS.

Gov number: NCT02548351 LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy.

Keywords: ALT; Biomarker; FIB-4; FibroMeter; cirrhosis; elastometry; enhanced liver fibrosis (ELF); liver fibrosis; non-alcoholic steatohepatitis; non-invasive tests; randomized controlled trials.

Conflict of interest statement

Conflict of interest MR was a consultant over the past 36 months for Alnylam, Amgen, AMRA, BMS, Boehringer Ingelheim, Centara, Coherus, Enanta, Galecto, Intercept Pharmaceuticals, Inc., Madrigal, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Fractyl, Gelesis, Siemens, Thetis, Terns, Rivus, 3vbio (Sagimet), 89Bio, and Novartis. She currently has no active consulting contracts. J-FD reports advisory committee participation for AbbVie, Bayer, Bristol-Myers Squibb, Falk, Genfit, Genkyotex, Gilead Sciences, HepaRegeniX, Intercept Pharmaceuticals, Inc., Lilly, Merck, Novartis; speaking and teaching fees from Bayer, Bristol-Myers Squibb, Intercept Pharmaceuticals, Inc., Genfit, Gilead Sciences, Novartis, Roche. QMA reports support from Intercept Pharmaceuticals, Inc. in relation to the present study; research funds as Coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multi-stakeholder consortium includes industry partners, in addition, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer Ltd; royalties or licenses from Elsevier Ltd; consulting fees from 89Bio, Allergan/Tobira, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Madrigal, MedImmune, Medpace, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Roche, Servier, Terns, The Medicines Company, Viking Therapeutics; honoraria from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape; member of advisory board for Medpace (NorthSea Therapeutics). ZG has no conflicts to report. ZY reports consulting fees and research grants from Gilead Sciences, Intercept Pharmaceuticals, Inc., BMS, Novo Nordisk, Viking, Terns, Siemens, Quest, AbbVie, Madrigal, Merck, and Novartis. SAH reports consulting/advisory, stock ownership/equity from Akero, Galectin, Genfit, Madrigal, Metacrine, Histoindex and NGM Bio; grants from Axcella, Cirius, CymaBay, Galectin, Galmed, Genfit, Gilead, HighTide, Madrigal, NGM, Novartis, Novo Nordisk, Pfizer, and Second Genome; consulting/advisory for Alentis, Axcella, Bristol-Meyers Squibb, CiVi, CLDF, Corcept, Echosens, , Gilead, HighTide, Medpace, Novartis, Novo Nordisk, Perspectum, Prometric, Viking, Hepagene, Hepion, and Terns. RL reports research grants from Intercept Pharmaceuticals, Inc., Boehringer -Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer, Siemens; consulting fees from Anylam/Regeneron, Amgen, Ar Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Inipharm, Intercept, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, 89Bio, Viking Therapeutics; advisory committee participation for Intercept Pharmaceuticals, Inc.; co-founder of Liponexus, Inc. AJS is President of Sanyal Biotechnology; he reports stock options in Sanyal Bio, Exhalenz, Akarna, GenFit, Hemoshear, Durect, Indalo, Tiziana, Rivus; paid consultant to 89Bio, Albireo, Amgen, Ardelyx, Boehringer Ingelheim, Bird Rock, Bristol-Myers, Conatus, Covance, Echosens-Sandhill, ENYO, Genentech, General Electric, Genfit, Gilead, Hemoshear, HistoIndex, Inventiva, Janssen, Lilly, Madrigal, Mallinckrodt, Merck, NGM Bio, Nimbus, NorthSea, Novartis, Novo Nordisk, Owl, PathAI, Perspectum, Pfizer, Poxel, Prosciento, Regeneron, Rivus, Roche, Salix, Sanofi, Second Genome, Servier, Siemens, Takeda, Terns, Tiziana, Zydus; unpaid consultant to Immuron, Intercept Pharmaceuticals, Inc., Galectin, Sequana, Fractyl; Durect, Indalo, Allergan, Chemomab, Affimune, Teva, BASF, AMRA, Perspectum, Biocellvia; advisory board member for Immuron; royalties from Elsevier and UptoDate; grant support from Gilead, Mallinckrodt, Salix, Novartis, Galectin, Bristol-Myers, Sequana; receipt of equipment from Echosens-Sandhill; ongoing research collaboration with Echosens-Sandhill, Owl, Second Genome, Siemens; his institution has received grant support from Conatus, Gilead, Mallinckrodt, Boehringer Ingelheim, Novartis, Bristol-Myers, Merck, Lilly, Novo Nordisk, Fractyl, Madrigal, Inventiva, Covance; his institution has received fees from AstraZeneca. MB reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. at the time of the study. AT reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. MN reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. at the time of the study. RS reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. at the time of the study. TG reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. at the time of the study. AV reports employment at Intercept Pharmaceuticals, Inc. at the time of the study. VR reports consulting fees from Galmed, Genfit, Madrigal, NGM, Bristol-Myers Squibb, Boehringer Ingelheim, Theratechnologies, Terns; advisory committee participation for Intercept Pharmaceuticals, Inc. Please refer to the accompanying ICMJE disclosure forms for further details.

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