Denifanstat achieves ‘statistically significant’ improvements in liver histology in MASH
Click Here to Manage Email Alerts
Key takeaways:
- At 52 weeks, MASH resolution without worsening of fibrosis was reported among 36% on denifanstat vs. 13% on placebo.
- Improvement in fibrosis by at least one stage was reported among 41% vs. 18%.
Denifanstat, a fatty acid synthase inhibitor, outperformed placebo in metabolic dysfunction-associated steatohepatitis resolution without worsening of fibrosis and fibrosis improvement, according to data presented at EASL Congress.
“Denifanstat is a specific and potent oral inhibitor of fatty acid synthase,” Rohit Loomba, MD, MHSc, chief of the division of gastroenterology and hepatology at University of California, San Diego, and director of the MASLD Research Center, said. “It functions through three independent mechanisms in MASH: It blocks steatosis by inhibiting de novo lipogenesis in hepatocytes, reduces inflammation by preventing immune cell activation and finally blunts fibrosis via inhibiting stellate cell activation.”
In the multicenter, double-blind, randomized, placebo-controlled FASCINATE-2 phase 2b trial, Loomba and colleagues assessed the safety and efficacy of denifanstat vs. placebo in improving fibrosis and MASH resolution after 52 weeks.
They enrolled 168 patients (mean age, 57 years; 68% men) with biopsy-confirmed MASH and fibrosis stage 2 (n = 75) or 3 (n = 93). Patients in the intention-to-treat population were randomly assigned 2:1 to once-daily oral denifanstat 50 mg (n = 112) or placebo (n = 56) and underwent baseline MRI-proton density fat fraction (MRI-PDFF), biomarkers and liver biopsy at baseline, with assessments at weeks 26 and 52.
The primary endpoints were at least a 2-point improvement in nonalcoholic fatty liver disease score (NAS) without worsening of fibrosis or MASH resolution with NAS improvement without worsening of fibrosis. Secondary outcomes included improvement in liver fibrosis of at least one stage without worsening of MASH, digital AI pathology measures and MRI-PDFF response.
Researchers included 126 patients with pre- and post-treatment biopsies in the modified intention-to-treat population.
At 52 weeks, denifanstat achieved “statistically and clinically significant” results compared with placebo, Loomba said, in both the intention-to-treat (ITT) and modified intention-to-treat (mITT) populations, with NAS improvement without worsening of fibrosis reported among 38% of patients on denifanstat vs. 16% on placebo in ITT and 52% vs. 20% in mITT, respectively. In addition, MASH resolution with NAS improvement without worsening of fibrosis occurred among 26% vs. 11% and 36% vs. 13%.
Further, improvement in liver fibrosis by at least one stage without worsening of MASH was reported among 30% vs. 14% in ITT and 41% vs. 18% in mITT and by at least two stages among 20% vs. 2% in mITT. Progression to stage 4 cirrhosis occurred among 5% vs. 11% in mITT.
Adverse events affecting at least 10% of patients included COVID-19 (17% vs. 10.7%), dry eye (8.9% vs. 14.3%) and hair thinning (18.8% vs. 3.6%). Loomba noted hair thinning stabilized with a 2- to 4-week dose-hold and was reversible.
“Denifanstat, a fatty acid synthase inhibitor, was better than placebo for both the subpart H approval pathway endpoints including MASH resolution without worsening of fibrosis and fibrosis improvement without worsening of MASH in this phase 2b trial,” Loomba said. “Denifanstat delivered clinically meaningful and statistically significant improvement in liver histology. We also noticed a two-stage improvement in fibrosis as well as significant improvement in F3 patients.”
He continued: “These results support continued clinical development of denifanstat to phase 3 clinical trials in MASH.”
Collapse
Loomba R, et al. Denifanstat, a fatty acid synthase (FASN) inhibitor, shows significant fibrosis improvement and MASH resolution in FASCINATE-2, a phase 2b 52-week international, randomized, double-blind, placebo-controlled trial in patients with F2 or F3 fibrosis. Presented at: EASL Congress; June 5-8, 2024; Milan (hybrid).
Click Here to Manage Email Alerts