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Abstract Details
A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis
J Hepatol. 2021 Feb 10;S0168-8278(21)00099-4. doi: 10.1016/j.jhep.2021.01.047.Online ahead of print.
Stephen A Harrison1, Mustafa R Bashir2, Kyoung-Jin Lee3, Jennifer Shim-Lopez3, Jonathan Lee3, Brandee Wagner3, Nicholas D Smith3, Hubert C Chen4, Eric J Lawitz5
Author information
1Summit Clinical Research, San Antonio, TX; Pinnacle Clinical Research, San Antonio, TX.
2Duke University Medical Center, Durham, NC.
3Metacrine, Inc., San Diego, CA.
4Metacrine, Inc., San Diego, CA. Electronic address: hchen@metacrine.com.
5Texas Liver Institute, San Antonio, TX; University of Texas Health San Antonio, San Antonio, TX.
Abstract
Background & aims: Farnesoid X receptor (FXR) agonists have been validated to benefit patients with nonalcoholic steatohepatitis (NASH), although improvements in efficacy and/or tolerability remain elusive.
Methods: In this 12-week, randomized, placebo (PBO)-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in three cohorts of subjects with NASH: 80 mg (n=20), 50 mg (n=19), and PBO (n=19).
Results: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs 6% in PBO (P<0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of subjects vs 11% in PBO (P<0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of subjects vs 0% in PBO (P<0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of subjects vs 17% in PBO. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs 2.6% in PBO) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs -1.5% in PBO). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated subjects.
Conclusion: MET409 lowered LFC in 12 weeks in NASH patients and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization.