1Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
2Diabetes and Endocrinology Consultants, North Carolina, USA.
3Department of Gastroenterology Hepatology, Antwerp University Hospital, Antwerp, Belgium.
4InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
5European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
6Mayo Clinic, Rochester, MN, USA.
7Virginia Commonwealth University, VA, USA.
8Sorbonne Université, Hôpital Pitié Salpêtrière, ICAN Paris, France.
9Liver Unit, Hospital Italiano de Buenos Aires, Argentina.
10University of Chicago, Pritzker School of Medicine, IL, USA.
11University of Chicago, IL, USA.
12University of California at San Diego, CA, USA.
13California Liver Research Institute, CA, USA.
14Metabolic Liver Research Program, I. Department of Medicine, University Medical Center Mainz, Germany.
15Houston Research Institute, Houston, TX , USA.
16Digestive Health Research and ObjectiveHealth, Nashville, TN, USA.
17Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.
18Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
19Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey.
20Department of Gastroenterology, School of Medicine, Recep Tayyip Erdogan University, Rize, Turkey.
21Novartis Pharma AG, Basel, Switzerland.
22Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
23AbbVie, CA, USA.
24HistoIndex Pte. Ltd, Singapore.
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 (TXR 140 ), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR 140 + CVC), or TXR 90 μg + CVC 150 mg (TXR 90 + 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 TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; - 13%, TXR 90 + CVC; + 17%, CVC). Reductions in body weight observed at Week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + 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 TXR 140 , CVC, TXR 140 + CVC and TXR 90 + 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.