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

• Published in: Nature medicine Vol. 29; no. 2; pp. 392 - 400
• Main Authors: Sanyal, Arun J., Lopez, Patricia, Lawitz, Eric J., Lucas, Kathryn J., Loeffler, Juergen, Kim, Won, Goh, George B. B., Huang, Jee-Fu, Serra, Carla, Andreone, Pietro, Chen, Yi-Cheng, Hsia, Stanley H., Ratziu, Vlad, Aizenberg, Diego, Tobita, Hiroshi, Sheikh, Aasim M., Vierling, John M., Kim, Yoon Jun, Hyogo, Hideyuki, Tai, Dean, Goodman, Zachary, Schaefer, Felicity, Carbarns, Ian R. I., Lamle, Sophie, Martic, Miljen, Naoumov, Nikolai V., Brass, Clifford A.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2023; Nature Publishing Group
• Subjects: 692/308; 692/308/153; Adverse events; Agonists; Alanine; Alanine transaminase; Aspartate aminotransferase; Benzothiazoles; Biomedical and Life Sciences; Biomedicine; Cancer Research; Double-Blind Method; Humans; Infectious Diseases; Liver; Metabolic Diseases; Molecular Medicine; Neurosciences; Non-alcoholic Fatty Liver Disease; Placebos; Pruritus; Receptors; Safety; Transaminases; Treatment Outcome
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-022-02200-8

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 The FLIGHT-FXR trial, testing farnesoid X receptor agonist tropifexor in nonalcoholic steatohepatitis, demonstrated sustained decreases in alanine aminotransferase levels and hepatic fat fraction, but not aspartate aminotransferase, with dose-dependent pruritus being the most common adverse event.