For patients with nonalcoholic steatohepatitis (NASH), treatment with TVB-2640, a fatty acid synthase inhibitor, may significantly decrease liver fat and improve biochemical, inflammatory, and fibrotic biomarkers in a dose-dependent manner after 12 weeks, according to results from an investigation published in Gastroenterology.

In a randomized, placebo-controlled, single-blind study (FASCINATE-1; ClinicalTrials.gov Identifier: NCT03938246) across 10 sites in the US, a team of researchers aimed to assess the safety and efficacy of TVB-2640 on liver fat and biomarkers for liver and metabolic health in patients with NASH. The primary endpoints of the study were safety and relative change in liver fat after treatment.

A total of 99 patients with 8% or more liver fat and liver fibrosis were included in the analysis. Of the cohort, 31 patients were randomly assigned to placebo, 33 patients received 25 mg of TVB-2640, and 35 patients received 50 mg of TBV-2640 (orally, once-daily for 12 weeks). All 99 patients were included in the safety assessment and the 85 patients who had end-of-treatment magnetic resonance imaging proton density fat fraction treatment were in the efficacy and biomarker analysis.


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Using measures of serum tripalmitin to assess fatty acid synthase inhibition, results suggested the tripalmitin levels increased by 26% among patients in the placebo group, decreased by 21% among patients treated with 25 mg of TVB-2640 (P <.01), and decreased by 40% among patients treated with 50 mg of TVB-2640 (P <.0001). Compared with baseline, by week 4 there was a median 21% decrease in tripalmitin with a dose of 50mg of TVB-2640 (P <.05). This was untested for the 25 mg dose.

Of the 99 patients, at least 1 treatment-emergent adverse event was reported in 62 patients (63%), nearly all of which were mild or grade 1. On-treatment serious adverse events were not reported in either of the dose groups.

Compared with baseline values, liver fat was elevated by 4.5% in the placebo group, while decreasing by 9.6% among patients treated with 25 mg of TVB-2640 (P =.053)  and by 28.1% among patients treated with 50 mg of TVB-2640 (P =.001). Relative reductions of liver fat (≥30%) were observed for 11% of patients in the placebo cohort, 23% of patients in the 25 mg cohort, and 61% of patients in the 50 mg cohort (P <.001).

Metabolic, proinflammatory, and fibrotic markers were all improved in the dose groups. Alanine aminotransferase and cytokeratin-18 levels were reduced with TVB-2640 treatment; however, these levels increased in patients treated with placebo.

Some limitations of the study included the small sample size and the short dosing time. The researchers noted that future studies should analyze the effects of TVB-2640 on liver histology.

“TVB-2640 potently reduced liver fat in NASH patients with a majority achieving an [magnetic resonance imaging proton density fat fraction] response within 12 weeks of treatment,” the researchers noted. “This effect combined with biomarkers showing reduction in liver injury, improvement in metabolic function, reduction of pro-inflammatory lipotoxins, evidence of reduced fibrogenesis, and a favorable effect on serum lipids combine to provide a compelling foundation for larger randomized clinical trials with histologic end points,” concluded the investigators.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Loomba R, Mohseni R, Lucas KJ, et al. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology. Published online July 23, 2021. doi:10.1053/j.gastro.2021.07.025