1Virginia Commonwealth University School of Medicine, Richmond, VA, USA. email@example.com.
2Novartis Pharma AG, Basel, Switzerland.
3Texas Liver Institute, University of Texas Health, San Antonio, TX, USA.
4Diabetes and Endocrinology Consultants, Morehead City, NC, USA.
5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea.
6Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore.
7Hepatitis Centre and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan.
8Diagnostic and Therapeutic Interventional Ultrasound Unit, IRCCS, Azienda Ospedaliero-Universitaria, Bologna, Italy.
9University of Modena and Reggio Emilia, Modena, Italy.
10Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.
11Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
12National Research Institute, Los Angeles, CA, USA.
13Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
14Centro Medico Viamonte, Buenos Aires, Argentina.
15Shimane University Hospital, Izumo, Japan.
16Gastrointestinal Specialists of Georgia, Marietta, GA, USA.
17Advanced Liver Therapies, Baylor College of Medicine, Houston, TX, USA.
18Seoul National University College of Medicine and Liver Research Institute, Seoul, Korea.
19JA Hiroshima General Hospital, Hiroshima, Japan.
20Life Care Clinic Hiroshima, Hiroshima, Japan.
21HistoIndex Pte. Ltd, Singapore, Singapore.
22Inova Fairfax Hospital, Falls Church, VA, USA.
23Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 μg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-μg dose groups ranged from -10.7 to -16.5 U l-1 versus placebo (-7.8 U l-1) and tropifexor 140- and 200-μg groups were -18.0 U l-1 and -23.0 U l-1, respectively, versus placebo (-8.3 U l-1)) and % HFF (tropifexor 10-90-μg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-μg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164.