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Novel, first-in-class, fatty acid synthase (FASN) inhibitor, TVB-2640 demonstrates clinically significant reduction in liver fat by MRI-PDFF, and ALT in NASH: a phase 2 randomized placebo controlled TRIAL (FASCINATE-1).
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FASN Inhibitor Cuts Liver Fat, Eases Fibrosis, in Phase 2 NASH Trial
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
TVB-2640, a fatty acid synthase (FASN) inhibitor, lowered de novo lipogenesis in liver of people with nonalcoholic steatohepatitis (NASH) in a 99-person placebo-controlled trial [1]. The once-daily oral agent also quelled markers of fibrosis, liver injury, and inflammation in this 12-week phase 2 trial.
The multicenter US team that conducted this study noted that uncontrolled de novo lipogenesis promotes fat accumulation in the liver that contributes to development of NASH. De novo lipogenesis also plays roles in obesity, metabolic syndrome, and cancer [2]. A leading cause of cirrhosis and liver transplantation, NASH has no FDA-licensed therapy.
TVB-2640 is a first-in-class once-daily FASN inhibitor that lowered de novo lipogenesis in the liver up to 90% in a phase 1b trial that enrolled 12 obese men with metabolic disorders [3]. FASCINATE-1 is a phase 2a multicenter, placebo-controlled trial that randomized 99 adults to 25 or 50 mg of TVB-2640 or to placebo once daily for 12 weeks [4]. Participants had at least 8% liver fat determined by MRI-PDFF* and liver fibrosis indicated by a magnetic resonance elastography (MRE) reading of 2.5 kPa or greater or F1-F3 fibrosis on biopsy. The trial excluded people with evidence of cirrhosis or other chronic liver diseases. The primary endpoints were MRI-PDFF-determined decrease in liver fat and safety.
In the 25-mg, 50-mg, and placebo groups, 54.5%, 63%, and 45% were men and median age stood at 58, 55, and 52. Respective proportions of participants with type 2 diabetes were 76%, 37%, and 55%, and median body mass index stood at 34, 33, and 31 kg/m2 (all indicating obesity).
Two of 33 participants in the 25-mg TVB-2640 group (and no one in the other two groups) had a treatment-emergent adverse event leading them to stop treatment. Proportions of participants with grade 1 drug-related treatment-emergent adverse events were 30% in the 25-mg arm, 26% in the 50-mg arm, and 10% in the placebo arm. Respective proportions with grade 2 drug-related treatment-emergent adverse events were 6%, 3%, and 3%. There were no grade 3 or worse adverse events, and no one in any group had a serious treatment-emergent adverse event.
Numbers of participants randomized and with 12-week efficacy endpoints reported were 33 and 30 for 25 mg of TVB-2640, 35 and 28 for 50 mg, and 31 and 27 for placebo. After 12 weeks of treatment dose-dependent relative changes in liver fat by MRI-PDFF were -28.2% with 50 mg (P < 0.005 vs placebo), -9.6% with 25 mg, and +4.5% with placebo. Respective proportions of participants with at least a 30% relative reduction in liver fat at week 12 were 61% (P < 0.001 vs placebo), 23%, and 11%.
The investigators recorded dose-dependent 12-week drops in alanine aminotransferase, low-density lipoprotein (LDL) cholesterol, cytokeratin-18 and tripalmitin (two lipotoxicity markers), (all differences between 50 mg and placebo statistically significant). The same dose-dependent pattern held true for three markers of fibrosis at week 12: ProC3, TIMP1, and PIIINP, with significant differences between 50 mg of TVB-2640 and placebo. The higher dose of TVB-2640 also significantly improved two markers of hepatic insulin sensitivity relative to placebo, FGF21 and adiponectin.
The investigators proposed that together these liver fat and biomarker changes with 50 mg of TVB-2640 "indicate improvement in several key nodes of NASH pathology." Development of TVB-2640 for NASH is continuing.
*MRI-PDFF, magnetic resonance imaging proton density fat fraction.
References
1. Loomba R, Rinella ME, Harrison SA, et al. Novel, first-in-class, fatty acid synthase (FASN) inhibitor, TVB-2640 demonstrates clinically significant reduction in liver fat by MRI-PDFF, and ALT in NASH: a phase 2 randomized placebo controlled TRIAL (FASCINATE-1). AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 67.
2. Ameera F, Scandiuzzib L, Hasnaina S, Kalbacherc H, Zaidia N. De novo lipogenesis in health and disease. Metabolism. 2014;63:895-902. https://www.sciencedirect.com/science/article/abs/pii/S0026049514001115
3. Sayed-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.
4. ClinicalTrials.gov. Study of TVB 2640 in subjects with non-alcoholic steatohepatitis (NASH). ClinicalTrials.gov identifier NCT03938246.
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