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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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TVB-2640 Lowers Liver Fat, Improves Fibrosis, in Phase 2a NASH Trial
  EASL 2020, Digital International Liver Congress, August 27-29, 2020
Mark Mascolini
TVB-2640, a fatty acid synthase inhibitor, reduced liver fat in a dose-dependent manner and improved adiponectin and fibrosis markers in a placebo-controlled trial enrolling people with nonalcoholic steatohepatitis (NASH) [1]. The novel agent caused no pruritus, thrombocytopenia, or hypertriglyceridemia.
Although NASH remains the most common cause of cirrhosis and the second most frequent cause of liver transplantation in the United States, no drugs have been licensed to treat this disease. De novo lipogenesis (DNL) and lipotoxicity play important roles in NASH pathogenesis. TVB-2640 inhibited hepatic DNL up to 90% in a phase 1b trial [2].
The phase 2a placebo-controlled trial aimed to evaluate the efficacy of TVB-2640 in decreasing liver fat measured by magnetic resonance imaging-derived protein density fat fraction (MRI-PDFF) in people with NASH.
Participants had at least 8% liver fat and magnetic resonance elastography (MRE) at or above 2.5 kPa or a recent biopsy. The trial excluded people with cirrhosis or other chronic liver disease. Researchers randomized 99 participants 1-to-1-to-1 to 25 or 50 mg of TVB-2640 once daily or to placebo. The primary endpoint was liver fat reduction by MRI-PDFF at week 12.
The 25-mg and 50-mg TVB-2640 groups were a little older than the placebo group (median 58 and 55 vs 52), and they had higher proportions of men (54.5% and 62.9% vs 45.2%) and marginally higher body mass index (34.0 and 32.8 vs 31.2 kg/m2). Baseline liver fat by MRI-PDFF was somewhat lower in the 25-mg TVB-2640 group (14.3%) than in the 50-mg group (15.8%) or the placebo group (15.3%). Proportions of people with type 2 diabetes ranged from 37.1% in the 50-mg TVB-2640 group to 54.8% in the placebo group and up to 75.8% in the 25-mg group.
At week 12 MRI-PDFF showed dose-dependent reductions in mean relative liver fat (-28.2% with 50 mg, -9.6% with 25 mg, and +4.5% with placebo (P < 0.005 for 50 mg TVB-2640 vs placebo) and mean absolute liver fat (-5.1% with 50 mg, -1.8% with 25 mg, and -0.3% with placebo, P < 0.001 for 50 mg TVB-2640 vs placebo). There were significantly more MRI-PDFF responders (at least 30% drop in MRI-PDFF from baseline) in the 50-mg TVB-2640 group (61%) than in the placebo group (11%) (P < 0.001).
More people taking 50 mg of TVB-2640 or 25 mg had at least a 17 U/L drop in alanine aminotransferase (ALT) at week 12 than did the placebo group (50% and 30% vs 18%), and higher proportions taking the fatty acid synthase inhibitor reached a normal ALT at week 12 (58% and 33% vs 27%).
Compared with the placebo group, LDL cholesterol fell significantly more through 12 weeks with 50 mg of TVB-2640 than with placebo (P < 0.005), and adiponectin rose significantly more with 50 mg of TVB-2640 than with placebo (24.1% vs 8.1%, P < 0.05). Fibrosis markers PIIINP and TIMP1 fell more with TVB-2640, and for TIMP1 the difference was significant between TVB-2640 at 50 mg and placebo (P < 0.05).
Rates of grade 1 or grade 2 treatment-emergent adverse events were similar with placebo and 25 mg or 50 mg of TVB-2640 (grade 1: 45.1%, 54.5%, 31.4%; grade 2: 13.0%, 9.0%, 17.1%). Two treatment-emergent adverse events led to drug withdrawal in the 25-mg TVB-2640 arm, while none did in the 50-mg arm or the placebo group. No one taking placebo had a grade 2 treatment-emergent adverse event, compared with 1 person (3%) taking 25 mg of TVB-2640 and 1 (2.9%) taking 50 mg of TVB-2640.
No treatment-emergent serious adverse events arose during the trial. Pruritus, thrombocytopenia, or hypertriglyceridemia did not develop in any study participants.
The researchers propose that their findings justify trials of TVB-2640 efficacy in improving NASH resolution and fibrosis in people with biopsy-proved NASH.
1. Loomba R, Rinella M, Harrison SA, et al. Novel first-in-class, fatty acid synthase inhibitor, TVB-2640 versus placebo demonstrates clinically significant reduction in liver fat by MRI-PDFF in NASH: A phase 2 randomized controlled trial (FASCINATE-1). EASL 2020, Digital International Liver Congress, August 27-29, 2020. Abstract AS074.
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. Epub 2020 May 7.