Phase 1 Study of EDP-305, a Novel Once-Daily Oral Farnesoid X Receptor Agonist, in Healthy Subjects and Those with Presumptive Nonalcoholic Fatty Liver Disease

Abstract

Introduction: EDP-305 is a farnesoid X Receptor (FXR) agonist that selectively activates FXR and is currently under investigation for with the treatment of nonalcoholic steatohepatitis (NASH). The primary objective was to assess the safety of EDP-305 in healthy subjects and subjects with presumptive NAFLD. Methods: In this placebo-controlled doubleblind Phase 1 study, healthy subjects (aged 20-55 years) were randomized to single or multiple oral doses of once daily EDP-305 or placebo and subjects with presumptive NAFLD (aged 25-52 years) were randomized to multiple oral doses of once daily EDP-305 or placebo for 14 days. Six cohorts received EDP-305 1 mg, 5 mg, 10 mg, 20 mg, 40 mg or 80 mg in the SAD phase including a food effect cohort that received EDP-305 10 mg. In the MAD phase, 12 cohorts received EDP-305 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg or 20 mg (six cohorts in healthy subjects and six in presumptive NAFLD). Results: In the SAD phase, 38 subjects received EDP-305 and 12 subjects received placebo, and in the MAD phase, 72 subjects received EDP-305 and 24 subjects received placebo. No serious adverse events were reported, and the most common treatment-emergent adverse events (TEAEs) in EDP-305 treated subjects were constipation, headache, and pruritus. The majority of TEAEs were mild to moderate in severity. EDP-305 exposure increased with single and multiple doses in both healthy subjects and those with presumptive NAFLD. EDP-305 exposure was approximately 3-fold higher in fed vs. fasted subjects. Strong FXR target engagement was demonstrated in both healthy and presumptive NAFLD subjects in the MAD phase with FGF19 increases and C4 reductions compared with placebo. Conclusion: EDP-305 was well tolerated, with pruritus the most common treatmentemergent adverse event at EDP-305 doses ≥10 mg and with minimal effects on lipids. Dose proportional PK support once daily dosing. Significant elevations of FGF19 and diminutions in C4 demonstrated potent engagement of the FXR receptor at doses that neither elicit adverse effects on lipids nor result in pruritus. These results supported further evaluation of EDP-305 in patients with NASH.

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.…”

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

“…A relative bioavailability assessment indicated that EDP‐305 tablet has approximately twofold higher exposures compared to the suspension (data on file). Results from phase I studies in healthy subjects and subjects with presumptive NAFLD 4 and a phase II study in subjects with NASH 5 suggest that the optimal therapeutic dosage range for EDP‐305 is 1–2 mg (tablet) once daily. These DDI studies were conducted at clinically relevant doses, and can be applied to future studies in patients with NASH.…”

“…[1][2][3] In phase I studies, EDP-305 was well-tolerated in healthy subjects at single doses up to 80 mg and in subjects with or without presumed nonalcoholic fatty liver disease (NAFLD) at multiple daily doses up to 20 mg for 14 days. 4 In a 12week, phase II study that evaluated the safety, tolerability, and efficacy of EDP-305 in 132 non-cirrhotic patients with fibrotic NASH, treatment with EDP-305 reduced hepatic enzyme levels and liver fat with a tolerability profile that was consistent with other FXR agonists. 5 Results from preclinical studies indicate that EDP-305 has a low potential to inhibit cytochrome (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 isoenzymes or to induce CYP1A2, 2B6, and 3A4 in standard hepatic microsome studies.…”

“…Preclinical studies indicated that EDP‐305 potently regulates the expression of FXR target genes in vivo and is hepatoprotective in multiple rodent models of liver injury and NASH 1–3 . In phase I studies, EDP‐305 was well‐tolerated in healthy subjects at single doses up to 80 mg and in subjects with or without presumed nonalcoholic fatty liver disease (NAFLD) at multiple daily doses up to 20 mg for 14 days 4 . In a 12‐week, phase II study that evaluated the safety, tolerability, and efficacy of EDP‐305 in 132 non‐cirrhotic patients with fibrotic NASH, treatment with EDP‐305 reduced hepatic enzyme levels and liver fat with a tolerability profile that was consistent with other FXR agonists 5 …”

“…In clinical studies, EDP‐305 geometric mean terminal half‐life ( t 1/2 ) values were similar across all dose levels for fasted and fed subjects and ranged from 11.12 to 14.98 h, following single doses, and 9.86 to 21.2 h following multiple doses. 4 In a radiolabeled mass balance study, fecal excretion was the predominant route of elimination for EDP‐305, with observed mean recovery of total radioactivity of 78.7% in feces and 1.42% in urine (unchanged drug). EDP‐305 was not detected in urine, indicating no urinary clearance of EDP‐305 (data on file; Enanta Pharmaceuticals).…”