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  The International Liver Congress™
EASL - European Association for the
Study of the Liver
Aug 27-29
Digital ILC 2020
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Nidufexor Lowers ALT and Liver Fat at 12 Weeks in NASH Patients
  EASL 2020, Digital International Liver Congress, August 27-29, 2020
Mark Mascolini
Twelve weeks of nidufexor for people with nonalcoholic steatohepatitis (NASH) lowered alanine aminotransferase (ALT), liver fat, and weight in a phase 2 comparison with placebo [1]. This non-bile acid FXR agonist had good target engagement and achieved dose-proportional systemic exposure in this 121-person trial.
Bile acids produced by cholesterol can alter gene expression in the liver and small intestine by activating nuclear receptors including farnesoid X receptor (FXR) [2]. Signaling through FXR plays roles in hepatic metabolic, inflammatory, and fibrogenic processes. Researchers are studying several FXR agonists for treatment of NASH, including nidufexor [3].
An international team conducted this phase 2 randomized, double-blind, placebo-controlled trial to explore the safety, pharmacokinetics, and efficacy of nidufexor dosed at 50 or 100 mg daily for 12 weeks in people with NASH.
The CLMB763X2201 trial enrolled 121 people with biopsy-confirmed or phenotypic NASH randomized in a 2-to-1 ratio to 50 or 100 mg of nidufexor once daily or placebo. Cohort 1 had an ALT at or above 60 U/L (men) or 40 U/L (women) and received 100 mg of nidufexor or placebo. Cohort 2 had an ALT at or above 43 U/L (men) or 28 U/L (women) and got 50 mg of nidufexor or placebo. Participants had to be at least 18 years old and have a hepatic fat fraction at or above 10%. They could not have type 1 or uncontrolled type 2 diabetes (HbA1c >/= 9.5%), calculated estimated glomerular filtration rate below 60 mL/min, or other forms of chronic liver disease, cirrhosis, decompensation, or a significant history of alcohol consumption.
Average age was similar across the 100-mg, 50-mg, and combined placebo groups (51.3, 49.5, 51.6), and similar proportions were women (59%, 52%, 60%) and white (86%, 84%, 78%). The 100-mg, 50-mg, and combined placebo groups were also similar in average body mass index (34, 34.5, 35.1 kg/m2) and hepatic fat fraction (19.5%, 19.9%, 20.5%). The 100-mg nidufexor group had a higher average ALT (72.4 U/L) than the 50-mg group (53.2 U/L) or the placebo group (63.0 U/L).
Fifteen of 37 people (40.5%) in the 100-mg nidufexor group stopped treatment (11 for adverse events), as did 5 of 44 (11.4%) randomized to 50 mg and 7 of 40 (17.5%) randomized to placebo (4 for adverse events).
ALT dropped quickly with either nidufexor dose and stayed lower through 12 weeks when compared with placebo. The adjusted mean changes from baseline through 12 weeks were significantly greater with nidufexor than with placebo (P < 0.05).
Relative change in percent hepatic fat was greater with 100 mg than with 50 mg of nidufexor, and both declines were greater than with placebo. About 70% of people assigned to 100 mg of nidufexor, 50% assigned to 50 mg, and under 5% assigned to placebo had at least a 30% drop in hepatic fat measured by MRI-PDFF (magnetic resonance imaging-derived proton density fat fraction). Average percent change in body weight was significantly greater with 100 mg of nidufexor (-1.44 kg) or 50 mg (-2.02 kg) than with placebo (P < 0.01).
Total cholesterol and "bad" LDL cholesterol did not change through 12 weeks with nidufexor or placebo. "Good" HDL cholesterol fell marginally with the FXR agonist but not with placebo.
Systemic exposures measured by area under the curve and maximum concentration were proportionately greater with 100 than 50 mg of nidufexor.
Twelve of 37 people (32%) randomized to 100 mg of nidufexor had an adverse event leading to dose reduction or discontinuation, compared with none randomized to 50 mg and 4 of 40 (10%) randomized to placebo. Two people on the 100-mg dose (5.4%) and 3 on the 50-mg dose (6.8%) had serious adverse events. The most frequent adverse events (with 100 mg, 50 mg, and placebo) were pruritus (54.1%, 29.5%, 15.0%), nausea (18.9%, 11.4%, 5.0%), increased urine protein/creatinine ratio (18.9%, 18.2%, 7.5%), and hyperglycemia (10.8%, 9.1%, 0%). Most adverse events were grade 1 or 2.
There are no licensed therapies for NASH.
1. Aspinall R, Shennak M, Stoica G, et al. Nidufexor, a non-bile acid FXR agonist, decreases ALT and hepatic fat fraction in patients with NASH after 12 weeks dosing. EASL 2020, Digital International Liver Congress, August 27-29, 2020. Abstract GS07.
2. Matsubara T, Li F, Gonzalez FJ, et al. FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 2013;368(1-2):17-29. doi: 10.1016/j.mce.2012.05.004.
3. Chianelli D, Rucker PV, Roland J, et al. Nidufexor (LMB763), a novel FXR modulator for the treatment of nonalcoholic steatohepatitis. J Med Chem. 2020;63:3868-3880. https://doi.org/10.1021/acs.jmedchem.9b01621.