Denifanstat Receives Breakthrough Therapy Designation for Noncirrhotic MASH

David Happel

Credit: David Happel on LinkedIn

The US Food and Drug Administration has granted Breakthrough Therapy Designation to Sagimet Biosciences’ denifanstat for the treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced fibrosis.¹

The designation was announced on October 1, 2024, and is supported by positive data from the phase 2b FASCINATE trial demonstrating statistically significant improvements with denifanstat relative to placebo on both primary endpoints of MASH resolution without worsening of fibrosis with ≥2-point reduction in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS), and a ≥2-point reduction in NAS without worsening of fibrosis.¹

“The FDA’s Breakthrough Therapy designation for denifanstat underscores the global incidence of MASH and the continuing need for new therapies,” David Happel, Chief Executive Officer of Sagimet, said in a press release.¹ “As the only fat synthesis inhibitor that directly targets the three main drivers of MASH— fat accumulation, inflammation, and fibrosis— we believe denifanstat is well-positioned to offer a leading treatment option for patients living with MASH.”

An oral, selective fatty acid synthase (FASN) inhibitor, denifanstat is designed to reduce fat accumulation, inflammation, and fibrosis, considered to be the 3 main drivers of MASH.¹ Resmetirom, the only currently FDA-approved MASH therapeutic, is an oral, thyroid hormone receptor (THR)-β selective agonist designed to target key underlying causes of MASH in the liver.²

Positive topline from the phase 2b FASCINATE-2 study of denifanstat in patients with noncirrhotic biopsy-confirmed MASH and moderate to advanced fibrosis were announced on January 22, 2024, and additional 52-week ITT and F3 subgroup efficacy data were presented at the 2024 European Association for the Study of the Liver (EASL) Congress.^3,4

The 52-week randomized, double-blind, placebo-controlled trial evaluated the safety and histological impact of denifanstat compared with placebo in 168 patients with biopsy-confirmed MASH with moderate-to-severe fibrosis (stage F2 or F3) and NAS ≥4. Patients were randomly assigned in a 2:1 ratio to receive 50 mg denifanstat or placebo, taken orally once daily. An end-of-trial biopsy was assessed by a central pathologist for histological endpoints.¹

Topline results showed NASH resolution without worsening of fibrosis with ≥2-point reduction in NAS (NAFLD Activity Score) occurred in 36% of denifanstat-treated patients compared to 13% with placebo (P = .002). Additionally, for the second primary endpoint, a ≥2-point reduction in NAS without worsening of fibrosis was observed in 52% of denifanstat-treated patients compared to 20% with placebo (P = .0001).³

For the trial’s secondary endpoints, denifanstat-treated patients showed statistically significant fibrosis improvement by ≥ 1 stage with no worsening of MASH, and a statistically significantly greater proportion of MRI-derived proton density fat fraction (MRI-PDFF) ≥30% responders relative to placebo. In the ITT population, denifanstat achieved statistically significant results on primary and secondary liver biopsy endpoints, including both histology endpoints recommended in the FDA draft guidance for accelerated approval in MASH. Safety data also showed denifanstat was generally well tolerated.¹

According to a press release from Sagimet Biosciences, the company plans to initiate the phase 3 clinical program for denifanstat in MASH by the end of 2024.¹

References

1. ^{Sagimet Biosciences. Sagimet Receives FDA Breakthrough Therapy Designation for Denifanstat in MASH. October 1, 2024. Accessed October 1, 2024. https://www.globenewswire.com/news-release/2024/10/01/2955945/0/en/Sagimet-Receives-FDA-Breakthrough-Therapy-Designation-for-Denifanstat-in-MASH.html}
2. ^{Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. March 14, 2024. Accessed October 1, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}
3. ^{Sagimet Biosciences. Sagimet Biosciences Announces Positive Topline Results from Phase 2b FASCINATE-2 Clinical Trial of Denifanstat in Biopsy-Confirmed F2/F3 NASH. January 22, 2024. Accessed October 1, 2024. https://ir.sagimet.com/news-releases/news-release-details/sagimet-biosciences-announces-positive-topline-results-phase-2b}
4. ^{Sagimet Biosciences. Sagimet Biosciences Presents Data from ITT and F3 Patient Population in Phase 2b FASCINATE-2 Clinical Trial of Denifanstat at EASL International Liver Congress 2024. June 6, 2024. Accessed October 1, 2024. https://ir.sagimet.com/news-releases/news-release-details/sagimet-biosciences-presents-data-itt-and-f3-patient-population}