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FASN Inhibitor Denifanstat
Improves NASH Markers in 26-Week Analysis
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EASL Congress 2023, June 21-24, Vienna
Mark Mascolini
Denifanstat, an investigational fatty acid synthase (FASN) inhibitor, significantly improved key liver-related markers in people with nonalcoholic steatohepatitis (NASH) in a 26-week interim analysis involving 52 people in the placebo-controlled FASCINATE-2 trial [1]. Liver fat fell by 30% or more in two thirds of people randomized to denifanstat.
A critical mechanism in accumulation of excess liver fat involves the enzymes acetyl-CoA-carboxylase (ACC) and FASN, which turn dietary sugars into the potentially dangerous fatty acid palmitate [2], the most common saturated fatty acid in humans. (See endnote below References.) In the placebo-controlled phase 2a trial FASCINATE-1, 50 mg of oral denifanstat daily for 12 weeks lowered MRI-PDFF-measured liver fat by 28% in people with NASH, and 61% of participants shed at least a 30% of liver fat [2]. (MDR-PDFF is magnetic resonance imaging-derived proton density fat fraction, a noninvasive scan.)
As a FASN inhibitor, denifanstat addresses key drivers of NASH: It blocks steatosis (fat buildup in the liver) by inhibiting new fat formation in liver cells. It quells inflammation by thwarting activation of immune cells. And it stymies fibrosis by slowing activation of stellate cells, which contribute to liver fibrosis.
FASCINATE-2, a phase 2b double-blind, placebo-controlled trial, randomized 168 US, Canadian, and European adults with biopsy-proved NASH to denifanstat at an oral dose of 50 mg daily or placebo [1,3]. Researchers planned an interim analysis at week 26 to analyze noninvasive measures related to liver fat. Participants had to be 18 or older with a screening biopsy showing F2-F3 fibrosis and a NAFLD activity score of 4 or more including a score of at least 1 for steatosis, balloon degeneration, and lobular inflammation.
The planned interim analysis involved the first 52 participants who completed 26 weeks and had an initial MRI-PDFF showing at least 8% liver fat. Of these 52 people, 30 had been randomized to 50 mg of denifanstat and 22 to placebo. Together they averaged 56.4 years in age and 99.6 kg in weight. Almost two thirds (65.4%) of these 52 participants had diabetes, and levels of the liver enzyme alanine aminotransferase (ALT) averaged 62.7 U/L. MRI-PDFF-gauged liver fat averaged 19.3%, and 54% of this group had F3 fibrosis.
After 26 weeks of treatment, significant improvement in the saturated fatty acid triglyceride tripalmitin with denifanstat compared with placebo (-42.0% vs +21.5%, P < 0.002) indicated greater inhibition of FASN activity with denifanstat. MRI-PDFF determined a relative liver fat reduction of 34.1% with denifanstat, significantly greater than the 1.5% dip with placebo (P < 0.001). Absolute change in liver fat came to -6.3% with denifanstat versus 0.9% with placebo (P < 0.001). Two thirds of the denifanstat-treated group (67%) saw their liver fat decline by at least 30% with denifanstat versus 18% getting placebo (P < 0.01). About half of these denifanstat responders had a 50% or greater drop in liver fat.
ALT fell significantly more with denifanstat than with placebo (-16.5 U/L vs -4.0 U/L, P < 0.05). A significantly higher proportion assigned to denifanstat than placebo had both an MRI-PDFF drop of 30% or more and an ALT decline of at least 17 U/L (37% vs 9%, P < 0.05), a combination that correlates with liver biopsy response.
Two markers of liver fibrosis fell significantly more with denifanstat than with placebo: enhanced liver fibrosis (ELF) score (-0.34 vs -0.02, P < 0.05) and PRO-C3 (-8.2% vs -1.5%), P < 0.05). Low-density lipoprotein cholesterol fell significantly more in the denifanstat group (-12.4 mg/dL vs 0.0 mg/dL, P < 0.05). A significantly greater improvement in fibroblast growth factor (FGF)-21 with denifanstat (73.1% vs 0.9%, P < 0.01) suggested more improvement in insulin sensitivity with the FASN inhibitor. (FGF-21 "is a hormone that regulates important metabolic pathways" [4].)
A safety analysis showed no grade 3 or worse drug-related adverse events with denifanstat and no treatment-related serious adverse events. A treatment-emergent adverse event (TEAE) emerged in 46.7% of people randomized to denifanstat versus 27.3% randomized to placebo. TEAEs led 2 people in the denifanstat group and 1 in the placebo group to stop treatment (6.7% vs 4.6%).
The researchers believe their findings "suggest that denifanstat will have a positive impact on histological end points in FASCINATE-2."
References
1. O'Farrell M, Grimmer K, Zetter A, et al. Multicenter, randomized, double-blind, placebo-controlled trial of fatty acid synthase (FASN) inhibitor, denifanstat, versus placebo in the treatment of biopsy-proven NASH: a 26-week interim analysis of the FASCINATE-2 phase 2b trial. EASL Congress 2023, June 2023, Vienna. Abstract OS-061.
2. 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. 2021;161:1475-1486. doi: 10.1053/j.gastro.2021.07.025. https://www.gastrojournal.org/article/S0016-5085(21)03276-5/fulltext
3. ClinicalTrials.gov. Study of TVB-2640 in subjects with nonalcoholic steatohepatitis (NASH). ClinicalTrials.gov identifier NCT04906421. https://clinicaltrials.gov/ct2/show/NCT04906421 .
4. Tezze C, Romanello V, Sandri M. FGF21 as modulator of metabolism in health and disease. Front Physiol. 2019;10. https://doi.org/10.3389/fphys.2019.00419
From FASCINATE-1 article (Reference 2 above):
"Increased intrahepatic fat and the generation of lipotoxic metabolites initiate and drive the progression of NAFLD by damaging hepatocytes, stimulating inflammatory responses, and activating profibrotic stellate cells in the liver. The de novo lipogenesis (DNL) pathway, in which the enzymes acetyl-CoA-carboxylase (ACC) and fatty acid synthase (FASN) convert metabolites of simple dietary sugars into the fatty acid palmitate, plays a major role in creating excess fat in the liver and generating certain lipotoxic molecules. Insulin resistance and blood glucose may further stimulate DNL in NAFLD patients resulting in increased intrahepatic triglyceride levels."
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