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  The Liver Meeting
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November 13 - 16 - 2021
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FASN Inhibitor TVB-2640 Cuts Liver
Fat 28% in US/China NASH Trial

  AASLD, The Liver Meeting, November 12-15, 2021
Mark Mascolini
TVB-2640, a once-daily oral fatty acid synthase (FASN) inhibitor, reduced liver fat 28% in people with nonalcoholic steatohepatitis (NASH) in a US/China placebo-controlled trial [1]. Twelve weeks of treatment with various doses of TVB-2640 caused 7 adverse events leading to discontinuation in this 142-person trial, but 4 of those 7 came with a high dose not being developed. All drug-related adverse events were grade 1 or 2.
FASN drives fat production in the liver, and that de novo lipogenesis spurs fat accumulation that can lead to nonalcoholic fatty liver disease (NAFLD) and NASH. Research shows that inhibiting FASN lowers steatosis and inflammation while disabling activated stellate cells, which otherwise promote liver fibrosis.
As a once-daily oral drug, TVB-2640 had a similar pharmacokinetic profile in US and Chinese people with NASH and cut de novo lipogenesis up to 90% in a phase 1b trial [2]. The phase 2a randomized, placebo-controlled trial in the United States and China (FASCINATE-1) aimed to assess TVB-2640 efficacy in trimming liver fat measured as magnetic resonance imaging proton density fat fraction (MRI-PDFF) in people with NASH (NCT03938246) [1,3].
The trial tested 50 mg of TVB-2640 once daily in both the US and China and 25 or 75 mg only in the US. In the US researchers randomized 99 people in a 2-to-1 ratio to 25 or 50 mg of TVB-2640 daily or to placebo. Separately, 13 people in the US took 75 mg of TVB-2640 daily or placebo. In China the trial randomized 30 people in a 2-to-1 ratio to 50 mg of TVB-2640 daily or placebo. Participants had to have 8% or greater liver fat and magnetic resonance elastography (MRE) at or above 2.5 kPa or a recent biopsy confirming NASH.
Among people in the 50-mg part of the trial, ages averaged 53 in the US and 33 in China. About 55% in the US and 75% in China were men. US participants weighed more (average 87 vs 78 kg) and had lower alanine aminotransferase (about 27 vs 80 U/L). Median MRI-PDFF measured 15.3% in the US placebo group, 15.8% in the US 50-mg group, 20.6% in the Chinese placebo group, and 16.8% in the Chinese 50-mg group,
MRI-PDFF liver fat dropped significantly after 12 weeks of TVB-2640 in the 50-mg US group (relative change -28% vs +4.5% with placebo) and in the 50-mg Chinese group (relative change =28% vs -11% with placebo) (combined relative change -28% vs +0.7%). In the combined analysis ALT fell 24.3% after 12 weeks of TVB-2640 while rising 9.2% with placebo. "Bad" LDL cholesterol fell in the US 50-mg group while rising with placebo (-11.0% vs +9.0%), but in China LDL cholesterol fell more with placebo than with TVB-2640 (-10.6% vs -2.4%).
In an open-label 13-person group in the US, a TVB-2640 dose of 75 mg daily did not improve response rates much, so the investigators picked 50 mg once daily as the optimal dose for further study
The safety analysis disclosed no dose-related significant adverse events with TVB-2640 versus placebo. Among 56 people who took the 50-mg dose in the US or China, 1 (1.8%) had a treatment-emergent adverse event leading to withdrawal from the study and 23 (43%) had a drug-related adverse event, 18 of them grade 1 and 5 grade 2. There were no treatment-emergent serious adverse events at any dose.
Two machine-learning models developed and tested an algorithm to predict which people with NASH will respond to TVB-2640. A tool that foretold PDFF response included combined baseline values of several serum metabolites: 1-monoetherglycerophosphoethanolamine, gadoleic acid, androsterone sulfate, etiocholanolone sulfate, DL-2-aminocaprylic acid, and D(-)-2-aminobutyric acid.
An international phase 2b double-blind, placebo-controlled trial of TVB-2640 in people with biopsy-confirmed NASH and fibrosis (FASCINATE-2) is underway [4].
1. Loomba R, Harrison SA, Wong VWS, et al. Novel, first-in-class, fatty acid synthase (FASN) inhibitor TVB-2640 demonstrates robust clinical efficacy and safety in a global phase 2 randomized placebo-controlled NASH trial (FASCINATE-1) conducted in the US and China. AASLD, The Liver Meeting, November 12-15, 2021. Abstract 141.
2. Syed-Abdul MM, Parks EJ, Gaballah AH, et al. Fatty acid synthase inhibitor TVB-2640 reduces hepatic de novo lipogenesis in males with metabolic abnormalities. Hepatology. 2020;72:103-118. doi: 10.1002/hep.31000.
3. ClinicalTrials.gov. Study of TVB 2640 in subjects with non-alcoholic steatohepatitis (NASH). ClinicalTrials.gov identifier NCT03938246.
4. ClinicalTrials.gov. Study of TVB-2640 in subjects with nonalcoholic steatohepatitis (NASH). ClinicalTrials.gov identifier NCT04906421.