A phase II, randomized, open-label trial depicted that in people having mild-to-moderate fibrosis due to non-alcoholic steatohepatitis (NASH), semaglutide with firsocostat and/or cilofexor was well-tolerated. In exploratory efficacy assessment, the treatment led to additional improvements in liver steatosis and biochemistry when compared to semaglutide alone.

Naim Alkhouri et al. determined safety and effectiveness of semaglutide alone and in combination with cilofexor and/or firsocostat for NASH management. In this proof-of-concept trial, 108 NASH patients were randomly allocated to 24 weeks’ therapy with 2.4 mg once-weekly semaglutide as monotherapy (n=21), semaglutide + 30 mg cilofexor (n=22),  semaglutide + 100 mg cilofexor (n=22), semaglutide + firsocostat (n=22) or semaglutide, cilofexor 30 mg and firsocostat (n=21).

Safety was the major outcome ascertained while all the efficacy outcomes were exploratory. The therapies showed good tolerability. The incidence of side effects was comparable across the groups (73–90%) and most of the events were gastrointestinal. In spite of the same weight loss (7–10%), compared with semaglutide monotherapy, the combination therapy led to higher improvements in liver steatosis estimated by magnetic resonance imaging proton density fat fraction (least-squares mean of absolute changes: −9.8 to −11.0% vs. −8.0%), noninvasive tests of fibrosis, and hepatic biochemistry.

Thus, combining therapies with complementary mechanisms that target different aspects of disease appears to be more beneficial than using single treatments. Additional double-blind, placebo-controlled studies with adequate patient numbers are warranted to determine safety and effectiveness of combination of three different types of drugs, namely semaglutide, firsocostat and cilofexor for NASH management.