Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial.

Autor: Sanyal AJ; Virginia Commonwealth University School of Medicine, Richmond, VA, USA. arun.sanyal@vcuhealth.org., Lopez P; Novartis Pharma AG, Basel, Switzerland., Lawitz EJ; Texas Liver Institute, University of Texas Health, San Antonio, TX, USA., Lucas KJ; Diabetes and Endocrinology Consultants, Morehead City, NC, USA., Loeffler J; Novartis Pharma AG, Basel, Switzerland., Kim W; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea., Goh GBB; Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore., Huang JF; Hepatitis Centre and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan., Serra C; Diagnostic and Therapeutic Interventional Ultrasound Unit, IRCCS, Azienda Ospedaliero-Universitaria, Bologna, Italy., Andreone P; University of Modena and Reggio Emilia, Modena, Italy.; Azienda Ospedaliero-Universitaria di Modena, Modena, Italy., Chen YC; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan., Hsia SH; National Research Institute, Los Angeles, CA, USA., Ratziu V; Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France., Aizenberg D; Centro Medico Viamonte, Buenos Aires, Argentina., Tobita H; Shimane University Hospital, Izumo, Japan., Sheikh AM; Gastrointestinal Specialists of Georgia, Marietta, GA, USA., Vierling JM; Advanced Liver Therapies, Baylor College of Medicine, Houston, TX, USA., Kim YJ; Seoul National University College of Medicine and Liver Research Institute, Seoul, Korea., Hyogo H; JA Hiroshima General Hospital, Hiroshima, Japan.; Life Care Clinic Hiroshima, Hiroshima, Japan., Tai D; HistoIndex Pte. Ltd, Singapore, Singapore., Goodman Z; Inova Fairfax Hospital, Falls Church, VA, USA., Schaefer F; Novartis Pharmaceutical Corporation, East Hanover, NJ, USA., Carbarns IRI; Novartis Pharma AG, Basel, Switzerland., Lamle S; Novartis Pharma AG, Basel, Switzerland., Martic M; Novartis Pharma AG, Basel, Switzerland., Naoumov NV; Novartis Pharma AG, Basel, Switzerland., Brass CA; Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2023 Feb; Vol. 29 (2), pp. 392-400. Date of Electronic Publication: 2023 Feb 16.
DOI: 10.1038/s41591-022-02200-8
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: