FASCINATE-2: Denifanstat Improves Disease Activity, MASH Resolution, Fibrosis

New data from the phase 2b FASCINATE-2 clinical trial of denifanstat in patients with biopsy-confirmed metabolic-dysfunction associated steatohepatitis (MASH) and stage 2 or stage 3 fibrosis demonstrate the oral fatty acid synthase (FASN) inhibitor’s statistically significant and clinically meaningful impact on disease activity, MASH resolution, and fibrosis.¹

Findings were published in The Lancet Gastroenterology and Hepatology and showed statistically significant improvements at week 52 with denifanstat relative to placebo on both of the study’s primary endpoints: MASH resolution without worsening of fibrosis with ≥2-point reduction in nonalcoholic fatty liver disease activity score (NAS), and ≥2-point reduction in NAS without worsening of fibrosis.^1,2

“Patients living with MASH, a complex disease, urgently need treatments that simultaneously address the three main drivers of liver injury: fat accumulation, inflammation, and fibrosis,” Rohit Loomba, MD, MHSc, a professor of medicine, chief of the division of gastroenterology and hepatology, and director of the MASLD Research Center at the University of California San Diego, said in a press release.² “These data support denifanstat’s potential to improve overall liver health by targeting the major pathways responsible for liver injury. Results of the current study include the improvement in fibrosis without worsening of MASH in 49% of F3 MASH patients, a group whose MASH is more advanced. These results highlight denifanstat’s highly differentiated mechanism of action, which is designed to inhibit endogenous FASN activity in hepatocytes, immune cells and stellate cells.”

An oral, selective FASN inhibitor, denifanstat is designed to reduce fat accumulation, inflammation, and fibrosis, considered to be the 3 main drivers of MASH. On October 1, 2024, it received Breakthrough Therapy Designation from the US Food and Drug Administration for the treatment of noncirrhotic MASH with moderate to advanced fibrosis based on positive data from the phase 2b FASCINATE-2 trial.³

A 52-week multicenter, double-blind, randomized, placebo-controlled trial, FASCINATE-2 was conducted at clinical sites in the USA, Canada, and Poland to evaluate the safety and histological impact of denifanstat compared to placebo in 168 biopsy-confirmed MASH patients with moderate-to-severe fibrosis (stage F2 or F3) with NAS ≥4. Patients were randomly assigned in a 2:1 ratio to receive 50 mg denifanstat or placebo taken orally once daily for 52 weeks, stratified by type 2 diabetes, region, and fibrosis stage.^1,3

Of 1087 patients screened between June 2, 2021, and June 28, 2022, 168 eligible participants were randomly assigned to receive denifanstat 50 mg once per day (n = 112) or placebo (n = 56), all of whom received ≥ 1 dose of study treatment. In the ITT population, 42 (38%) of 112 participants in the denifanstat group had a ≥ 2-point improvement in NAS without a worsening of fibrosis versus 9 (16%) of 56 participants in the placebo group (common risk difference, 21.0%; 95% CI, 8.1–33.9; P = .0035). Additionally, 29 (26%) of 112 participants in the denifanstat group showed MASH resolution with a ≥ 2-point improvement in NAS without a worsening of fibrosis compared with 6 (11%) of 56 participants in the placebo group (common risk difference, 13.0%; 95% CI, 0.7–25.3; P = .0173).¹

The most common treatment-emergent adverse events were COVID-19 (17% denifanstat vs 11% placebo), dry eye symptoms (9% vs 14%), and alopecia (19% vs 4%). All adverse events considered to be related to the study drug were of grade 1 or grade 2, and no serious adverse events (12% denifanstat vs 5% placebo) were considered to be drug-related.¹

“Our publication in this esteemed Lancet journal validates the importance of these findings and reinforces the potential impact of denifanstat, our oral fat synthesis inhibitor, to improve patient outcomes, particularly as the disease becomes more severe,” Dave Happel, chief executive officer of Sagimet, said in a press release.² “The data demonstrate significant improvements in all key histological features of the disease, meeting both fibrosis improvement and MASH resolution endpoints as outlined in the FDA draft guidance for Phase 3 clinical trials in MASH. We look forward to building on the encouraging data generated to date which supports the advancement of denifanstat into Phase 3 development. We are committed to addressing the urgent needs of patients living with MASH and anticipate starting our planned Phase 3 program in 2024.”

References

1. ^{Loomba R, Bedossa P, Grimmer K, et al. Denifanstat for the treatment of metabolic dysfunctionassociated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial. The Lancet Gastroenterology & Hepatology. https://doi.org/10.1016/S2468-1253(24)00246-2}
2. ^{Sagimet Biosciences. Sagimet Biosciences Announces Publication of Results from Phase 2b FASCINATE-2 Clinical Trial of Denifanstat in Biopsy-Confirmed F2/F3 MASH in The Lancet Gastroenterology & Hepatology. October 11, 2024. Accessed October 11, 2024. https://ir.sagimet.com/news-releases/news-release-details/sagimet-biosciences-announces-publication-results-phase-2b}
3. ^{Brooks, A. Denifanstat Receives Breakthrough Therapy Designation for Noncirrhotic MASH. HCPLive. October 1, 2024. Accessed October 11, 2024. https://www.hcplive.com/view/denifanstat-receives-breakthrough-therapy-designation-noncirrhotic-mash}