Clinical trial: A Phase 2 Randomised Platform Study to Assess Monotherapy and Combination Treatment Regimens in Metabolic Dysfunction–Associated Steatohepatitis

Background Drug combinations have potential for additive or synergistic efficacy in patients with metabolic dysfunction–associated steatohepatitis (MASH). Aim To assess the safety, efficacy and pharmacokinetics of single or combination treatments in patients with MASH. Methods In this multicentre, open‐label, platform phase 2 study, patients ( N = 41) were randomised 1:1 to LYS006 20 mg twice‐daily (bid) monotherapy or LYS006 20 mg bid+tropifexor 200 μg once‐daily (qd) combination therapy for 12 weeks. The primary endpoint was safety; secondary endpoints were efficacy and pharmacokinetics. Results Pruritus adverse events (AEs) were reported in 62% of patients in the combination arm. Other AEs were similar between the treatment arms. A greater reduction in alanine aminotransferase (ALT) and liver fat was observed in the combination versus monotherapy arm (ALT: 43% vs. 13% reduction; liver fat: 37% vs. 20% reduction, respectively). No significant impact on biomarkers for liver fibrosis was observed in either treatment arm, but there was an indication for lower plasma exposure to LYS006 upon co‐administration with tropifexor. Conclusions LYS006 20 mg bid monotherapy and LYS006 20 mg bid+tropifexor 200 μg qd therapy were well tolerated with the exception of a high frequency of pruritus in the combination arm, consistent with the now known pharmacologic effect of farnesoid X receptor agonists. The greater reductions in ALT and liver fat in the combination arm versus monotherapy arm were similar to those observed with tropifexor as monotherapy in a previously reported phase 2 clinical trial, and clear additional benefit was not observed in combination treatment with LYS006. This study design allowed for rapid screening of potentially high efficacy drug combinations in MASH. Trial Registration ClinicalTrials.gov identifier: NCT04147195