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FXR Agonist EDP-305 Lowers ALT and Liver Fat in NASH
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EASL 2020, Digital International Liver Congress, August 27-29, 2020
Mark Mascolini
EDP-305, a non-bile acid farnesoid X receptor (FXR) agonist, lowered alanine aminotransferase (ALT) and reduced liver fat in a 12-week phase 2a trial [1]. Treatment-related discontinuations proved greater with the higher dose of EDP-305 than with the lower dose.
French, US, and Canadian researchers who conducted this study note that NASH appears to be the fastest-growing cause of cirrhosis, liver cancer, and liver transplantation, yet no medications are licensed to treat NASH. As a farnesoid X receptor agonist, EDP-305 could affect hepatic metabolism, as well as inflammatory and fibrogenic processes, in people with fatty liver disease. In a 2-week phase 1 trial, EDP-305 proved generally safe at two doses and suitable for once-daily oral dosing [2].
The double-blind placebo-controlled ARGON-1 trial randomized participants in a 2-2-1 ratio to 1 mg of EDP-305 daily, 2.5 mg of EDP-305 daily, or placebo for 12 weeks. Primary objectives were to assess change in ALT at week 12 and to evaluate safety and tolerability of the drug.
To be eligible for the trial, participants had to have (1) histologic evidence of NASH with fibrosis and elevated ALT, or (2) a phenotypic diagnosis of NASH based on elevated ALT and diagnosis of type 2 diabetes, and (3) a liver fat fraction above 8% by MRI-PDFF (magnetic resonance imaging-derived proton density fat fraction). Participants could not have another chronic disease, histologic or clinical evidence of cirrhosis, HbA1c at or above 9%, or significant alcohol use.
The intention-to-treat population included 55 people randomized to EDP-305 1 mg, 53 randomized to EDP-305 2.5 mg, and 24 randomized to placebo. Those three groups were similar in age (average 51.5, 52.3, 50.8), and they differed marginally in proportion of women (52.7%, 54.7%, 45.8%), proportion of whites (76.4%, 88.7%, 70.8%), body mass index (34.5, 33.8, 36.1 kg/m2), ALT (91.9, 79.5, 78.5 U/L), MRI-PDFF percent liver fat (22.1%, 19.0%, 20.3%), and proportion taking metformin for diabetes (63.6%, 56.6%, 70.8%).
By week 12 average ALT fell 27.9 U/L with 2.5 mg of EDP-305 (P = 0.049 vs placebo), 21.7 U/L with 1 mg of EDP-305 (not significantly different from placebo), and 15.4 U/L with placebo. Improvements in other markers of liver injury-AST and GGT-also proved greater with the 2.5-mg dose than with placebo.
Average MRI-PDFF absolute drop in liver fat was significantly greater with 2.5 mg of EDP-305 than with placebo (7.1% vs 2.4%, P < 0.001). Average liver fat fell 3.3% with 1 mg of EDP-305 (not significantly different from placebo). Proportions of participants with an absolute MRI-PDFF change from baseline of at least 5%, and with a percent MRI-PDFF change from baseline of at least 30%, were 42.9% and 44.9% with 2.5 mg of EDP-305, 31.4% and 25.5% with 1 mg of EDP-305, and 20% and 25% with placebo.
Average 12-week drop in ALT with at least a 30% drop in MRI-PDFF liver fat was 35.3 U/L with 2.5 mg of EDP-305, 31.8 U/L with 1 mg of EDP-305, and 15.9 U/L with placebo.
Through 12 weeks, a measure of EDP-305 target engagement (ALP) was greater with 2.5 mg of EDP-305 than with 1 mg of the drug or with placebo. Improvement in two other measures of target engagement (C4 and FGF19) also proved greater with 2.5 mg of EDP-305 than with 1 mg or placebo.
Treatment-emergent pruritus affected 47.2% of participants taking 2.5 mg of EDP-305, 9.1% taking 1 mg, and 4.2% taking placebo. Most treatment-emergent adverse events were mild or moderate. Serious adverse events affected 1 person taking placebo, 1 taking 1 mg of EDP-305, and no one taking 2.5 mg. But the discontinuation rate was higher with 2.5 mg (22.6%) than with 1 mg (1.8%) or placebo (8.3%). Pruritus-related discontinuations occurred in 20.8% randomized to 2.5 mg versus 1.8% assigned to 1 mg.
"Bad" LDL cholesterol rose through 12 weeks with 1 or 2.5 mg of EDP-305 while falling with placebo. "Good" HDL cholesterol fell more with 2.5 mg of EDP-305 (about 8%) than with 1 mg (about 2%) or placebo (no change).
References
1. Ratziu V, Rinella M, Neuschwander-Tetri B, et al. EDP-305, a non-bile acid farnesoid X receptor (FXR) agonist, showed statistically significant improvements in liver biochemistry and hepatic steatosis in the phase 2a ARGON-1 study. EASL 2020, Digital International Liver Congress, August 27-29, 2020. Abstract AS078.
2. ClinicalTrials.gov. A study to assess the safety, tolerability, pharmacokinetics and efficacy of EDP-305 in subjects with non-alcoholic steatohepatitis. ClinicalTrials.gov identifier NCT03421431.
https://clinicaltrials.gov/ct2/show/NCT03421431 .
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