Assessment of drug–drug interaction potential with EDP‐305, a farnesoid X receptor agonist, in healthy subjects

Abstract

EDP‐305 is a farnesoid X receptor (FXR) agonist that selectively activates FXR and is a potential treatment for patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Results from preclinical studies indicate that CYP3A4 is the primary enzyme involved in EDP‐305 metabolism and that EDP‐305 has low potential to inhibit or induce cytochrome (CYP) isoenzymes and drug transporters. Four studies were conducted in healthy volunteers to evaluate the drug–drug interaction (DDI) potential of EDP‐305 co‐administered with drugs known to be substrates for drug metabolizing enzymes or transporters, and to assess the effect of inhibitors and inducers of CYP3A4 on EDP‐305. Results suggest caution when substrates of CYP3A4 are administered concomitantly with EDP‐305. A potential for increased exposure is apparent when CYP1A2 substrates with a narrow therapeutic index are administered with EDP‐305. In contrast, substrates of drug transporters can be administered concomitantly with EDP‐305 with a low potential for interactions. Coadministration of EDP‐305 and a combined OC had no relevant effects on plasma concentrations of the combined OC. Co‐administration of EDP‐305 with strong or moderate inhibitors and inducers of CYP3A4 is not recommended. These results indicate low overall likelihood of interaction of EDP‐305 and other substrates through CYP mediated interactions. The interaction potential of EDP‐305 with drug transporters was low and of unlikely clinical significance. The EDP‐305 DDI profile allows for convenient administration in patients with NASH and other patient populations with comorbidities, with minimal dose modification of concomitant medications.

EDP‐297: A novel, farnesoid X receptor agonist—Results of a phase I study in healthy subjects

“…PD effects indicative of FXR activation have shown a more pronounced effect in patients with presumptive NAFLD and NASH when compared with healthy subjects. 25,31,[37][38][39] In this study with EDP-297, target engagement was confirmed by decreases in C4 levels and increases in FGF-19 levels during 14 days of treatment. Increases in liver enzyme levels have been observed with other FXR agonists.…”

“…Consistent with FXR target engagement, FGF‐19 levels increased and C4 levels decreased from baseline during a 12‐week study with EDP‐305, 37 as well as in a 24‐week study with cilofexor, 25 which is similar to effects observed with other FXR agonists. PD effects indicative of FXR activation have shown a more pronounced effect in patients with presumptive NAFLD and NASH when compared with healthy subjects 25,31,37–39 . In this study with EDP‐297, target engagement was confirmed by decreases in C4 levels and increases in FGF‐19 levels during 14 days of treatment.…”

Treatment of liver fibrosis: Past, current, and future

“…Farnesoid-X-receptor (FXR) and the G protein-coupled bile acid receptors are two widely studied bile acids regulating receptors, which play important roles in lipid and glucose metabolism, inflammation, fibrosis, and immune responses. Many FXR ligands have been investigated in clinical trials for NASH and liver fibrosis treatments, such as EDP-305[ 41 , 42 ], cilofexor[ 43 , 44 ], and MET409[ 45 , 46 ]. Hepatic concentrations of conjugated 12α-hydroxylated bile acids, such as taurodeoxycholate and glycodeoxycholate, were significantly increased in patients with NASH and mouse liver fibrosis models[ 47 ].…”