Tropifexor plus cenicriviroc combination versus monotherapy in non-alcoholic steatohepatitis: Results from the Phase 2b TANDEM study

by Selleckchem | Aug 08 2023

Background aims: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for non-alcoholic steatohepatitis. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies.

Approach results: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR140), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR140 + CVC), or TXR 90 μg + CVC 150 mg (TXR90 + CVC), for 48 weeks. The primary and secondary endpoints were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR140; -16%, TXR140 + CVC; - 13%, TXR90 + CVC; + 17%, CVC). Reductions in body weight observed at Week 24 (mean changes from baseline: TXR140, -2.5 kg; TXR140 + CVC, -1.7 kg; TXR90 + CVC, -1.0 kg; CVC, -0.1 kg) were sustained to Week 48. At least one-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR140, CVC, TXR140 + CVC and TXR90 + CVC groups, respectively.

Conclusion: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological endpoints compared with monotherapy.

Comments:

The study described is a randomized, multicenter, double-blind, phase 2b trial that aimed to assess the safety and efficacy of combining tropifexor (TXR) and cenicriviroc (CVC) for the treatment of non-alcoholic steatohepatitis (NASH). The study included 193 patients who were randomly assigned to receive one of four treatment options: TXR 140 μg (TXR140), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR140 + CVC), or TXR 90 μg + CVC 150 mg (TXR90 + CVC). The treatment duration was 48 weeks.

The primary endpoint of the study was to evaluate the safety of the combination therapy, while the secondary endpoint focused on histological improvement. The rates of adverse events (AEs) were similar across all treatment groups. The most frequently reported AE was pruritus (itchiness), with the highest incidence observed in the TXR140 group (40.0%).

In terms of efficacy, the study assessed alanine aminotransferase (ALT) levels and body weight as indicators of improvement. Reductions in ALT levels were observed in the TXR and combination therapy groups, with the greatest decrease seen in the TXR140 group (-21% from baseline to 48 weeks). Reductions in body weight were also observed in all treatment groups, and the changes observed at Week 24 were sustained until Week 48.

Histological improvement was evaluated based on changes in fibrosis stage and resolution of steatohepatitis without worsening of fibrosis. The results showed that at least a one-point improvement in fibrosis stage or steatohepatitis resolution without worsening of fibrosis was observed in a range of 29.7% to 32.5% of patients across the treatment groups.

In conclusion, the combination therapy of TXR and CVC demonstrated a safety profile similar to that of the respective monotherapies, with no new safety concerns identified. TXR monotherapy showed sustained decreases in ALT levels and body weight. However, there was no substantial incremental efficacy observed with the combination therapy in terms of ALT levels, body weight, or histological endpoints compared to monotherapy.