Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial

Abstract

Background & aims: Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH.

Methods: This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2-F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks' treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory.

Results: A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. Despite similar weight loss (7-10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: -9.8 to -11.0% vs. -8.0%), liver biochemistry, and non-invasive tests of fibrosis.

Conclusions: In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH.

Clinical trial registration number: NCT03987074.

Lay summary: Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.

Keywords: NASH; cilofexor; fibrosis; firsocostat; non-alcoholic steatohepatitis; semaglutide.

Conflict of interest statement

Conflict of interest NA: advisory board/review panel member for Echosens, Gilead, Intercept, Perspectum, Pfizer and Zydus; grant/research support from Akero, Allergan, Bristol Myers Squibb, Genentech, Gilead, Intercept, Madrigal, NGM Bio, Novo Nordisk, Pfizer, Viking and Zydus; speaker for AbbVie, Alexion, Echosens, Gilead and Intercept. TH: advisory board/review panel member and/or grant/research support from AbbVie, Bristol Myers Squibb, Gilead, Mallinckrodt, Merck and Organovo; speaker for AbbVie, Allergan, Amarex/Cytodyn, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, CARA, Cymabay, DURECT Corporation, Enanta, Galectin, GenFit, Gilead, Grifols, Intercept, Mallinckrodt, Merck, Mirum, Novartis, Novo Nordisk, Pfizer and Salix. AK: grant/research support from Gilead; speaker for Gilead, Intercept and Novartis. RSH, YZ, ANB, RPM: employees and shareholders of Gilead Sciences, Inc., LHD, KB, MSK, CB: employees and shareholders of Novo Nordisk A/S. RL: consultant for 89bio, Eli Lilly, Gilead, Glympse Bio, Ionis, Merck, Metacrine, NGM Bio, Novo Nordisk, Pfizer, Sagimet and Viking; grant/research support from AstraZeneca, Eli Lilly, Gilead, Intercept, Inventiva, Janssen, Madrigal, NGM Bio, Novartis and Novo Nordisk. MN: advisory committees or review panel member for Abbott, EchoSens, Intercept and OWL; grant/research support from Conatus, Galectin, Galmed, Genfit, Gilead, Shire and Zydus; speaker for Echosens, and holds stock in Anaeots. RH, HK and ZK: no interests to declare. Please refer to the accompanying ICMJE disclosure forms for further details.

Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.