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

Background & Aims: Non-alcoholic steatohepatitis (NASH) increases the risk of liver-related and cardiovascular complications. Due to its complex pathophysiology, combining therapies with different mechanisms might be advantageous. This trial aimed to assess the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, both alone and in combination with cilofexor, a farnesoid X receptor agonist, and/or firsocostat, an acetyl-coenzyme A carboxylase inhibitor, in patients with NASH.

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

Results: A total of 108 patients were randomized into one of the following groups: semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22), or semaglutide with cilofexor 30 mg and firsocostat (n = 21). The treatments were generally well tolerated, with adverse events occurring at similar rates across groups (73-90%), mostly of a gastrointestinal nature. Although weight loss was similar across groups (7-10%), combinations of semaglutide with cilofexor and/or firsocostat led to greater improvements in liver steatosis as measured by MRI-PDFF (least-squares mean absolute changes: -9.8% to -11.0% vs. -8.0% with semaglutide alone), as well as in liver biochemistry and non-invasive fibrosis tests.

Conclusions: In patients with mild-to-moderate fibrosis due to NASH, the combination of semaglutide with firsocostat and/or cilofexor was generally well tolerated and showed additional improvements in liver steatosis and biochemistry compared to semaglutide alone. However, given the small scale and open-label nature of this trial, further double-blind, placebo-controlled studies with larger patient populations are needed to fully evaluate the efficacy and safety of these combination therapies in NASH.