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

Abstract

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

Immunotherapy for NAFLD and NAFLD-related hepatocellular carcinoma

“…The improvement in fibrosis was significantly detected in the obeticholic acid 25 mg group (n=71; 23%) compared to the placebo group (n=37; 12%) in a phase 3 trial. In addition, the efficacy and safety of another FXR agonist, tropifexor, has more recently been tested for NASH in a phase 2 trial ( 35 ). Dose-related pruritus was detected, and decreases in hepatic fat fraction and alanine aminotransferase were sustained until 48 th week.…”

Das intestinale Mikrobiom bei gastroenterologischen Krankheitsbildern

“…Ein weiterer Ansatzpunkt ist die direkte Modulation des Farnesoid-X-Rezeptors (FXR) durch Rezeptoragonisten, um die oben beschriebenen Effekte der Dysbiose auf den Gallensäurestoffwechsel zu kompensieren. Hier sind aktuell mehrere Phase-II-Studien erfolgreich abgeschlossen worden [27]. Leider waren die Gruppengrößen meist klein, und ein relevanter klinischer Outcomeparameter wurde nicht erreicht [28].…”

Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study

“…[13] In the phase 2a/b FLIGHT-FXR study, sustained decreases in alanine aminotransferase (ALT) and hepatic fat fraction (HFF) were observed in patients treated with TXR versus placebo. [14] Further, the therapeutic effect of FXR agonism in NASH has been demonstrated in clinical trials, with the bile acid derivative obeticholic acid resulting in fibrosis reduction and improvement in the key features of steatohepatitis. [15,16] Cenicriviroc (CVC), a potent inhibitor of C-C chemokine receptor types 2/5 (CCR2/5), has demonstrated antifibrotic and anti-inflammatory properties in animal models.…”