FASCINATE-2 topline data: Denifanstat surpasses placebo for NASH with fibrosis at week 52
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Key takeaways:
- Denifanstat showed statistically significant NASH resolution and fibrosis improvement at 52 weeks.
- Denifanstat achieved more than 2-point reduction in NAS without worsening of fibrosis.
Topline data from the phase 2b FASCINATE-2 trial showed “statistically significant improvement” for denifanstat in biopsy-confirmed nonalcoholic steatohepatitis with stage 2 or stage 3 fibrosis at 52 weeks, Sagimet Biosciences announced.
According to topline data findings, denifanstat an oral selective FASN inhibitor demonstrated superior NASH resolution to placebo without worsening of fibrosis, with a more than 2-point reduction in NAFLD Activity Score (NAS) (36% vs. 13%; P=.002). Additionally, 52% of patients who received denifanstat exhibited a more than 2-point reduction in NAS without worsening of fibrosis vs. 20% of patients who received placebo (P=0001).
“The over-activity of fatty acid synthase and increased de-novo lipogenesis (DNL) plays a critical role in the development of NASH and its progression to cirrhosis,” Rohit Loomba, MD, MHSc, director the MASLD Research Center at University of California San Diego, said in a press release. “Denifanstat is the only FASN inhibitor currently in clinical development for the treatment of NASH with related fibrosis. These data show that blocking fatty acid synthesis in the liver and DNL is a critical approach for NASH resolution and improvements in fibrosis.”
In the FASCINATE-2 phase 2b trial, a 52-week randomized, double-blind, placebo-controlled trial, patients with biopsy-confirmed NASH with moderate-to-severe fibrosis with NAS 4 (n=168) were randomized 2:1 to receive either once-daily oral 50 mg denifanstat or placebo. End-of-trial biopsies were assessed by a central pathologist for histological endpoints, with liver biopsies also analyzed using artificial intelligence-based digital pathology.
Denifanstat also demonstrated superiority for all secondary endpoints.
- Fibrosis improvement of at least one stage with no worsening of NASH in 41% of patients who received denifanstat compared with 18% who received placebo (P=.005)
- NASH resolution with no worsening of fibrosis in 38% of patients who received denifanstat compared with 16% who received placebo (P=.002)
- MRI-PDFF decline from baseline 30% (responders) in 65% of patients who received denifanstat compared with 21% who received placebo (P<.0001)
“Denifanstat is designed to reduce the three main drivers of NASH, including fat accumulation, inflammation, and fibrosis, both independently and in parallel,” Dave Happel, CEO of Sagimet, said in the release. “The week 52 biopsy results showed that denifanstat achieved statistical superiority over placebo in reduction of fibrosis, via two independent processes of traditional histopathology and AI digital pathology.”
He added: “Our next step will be holding an end-of-phase 2 meeting with the FDA and starting our phase 3 program for development of denifanstat in NASH with related fibrosis, which we anticipate to begin in the second half of 2024.”
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