Denifanstat a ‘promising oral therapy’ for the treatment of MASH, related fibrosis
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Key takeaways:
- More patients treated with denifanstat vs. placebo achieved improvement in NAS without worsening of fibrosis, as well as MASH resolution.
- No serious adverse events were drug-related.
Patients treated with denifanstat 50 mg vs. placebo achieved significant improvements in metabolic dysfunction-associated steatohepatitis resolution and fibrosis, according to study results in The Lancet Gastroenterology & Hepatology.
“Denifanstat, an oral [fatty acid synthase] inhibitor, has been shown to improve liver fat and markers of inflammation and insulin resistance in early phase trials in patients with MASLD,” Rohit Loomba, MD, MHSc, chief of the division of gastroenterology and hepatology and director of the MASLD Research Center at UC San Diego Health, told Healio. “Therefore, we examined the efficacy of denifanstat vs. placebo over 52 weeks of [treatment] in patients with stage 2 or 3 fibrosis with MASH using improvement in liver histology as the primary endpoint.”
In the international, multicenter, phase 2b FASCINATE-2 trial, 168 adult patients (mean age, 57 years; 60% women) were randomly assigned to once-daily denifanstat 50 mg (n = 112) or placebo (n = 56) for up to 52 weeks and grouped by type 2 diabetes status, region and fibrosis stage. All patients received at least one dose of the study treatment and were included in safety analysis.
Co-primary endpoints included at least a 2-point improvement in nonalcoholic fatty liver disease activity score (NAS) without worsening of fibrosis and MASH resolution with at least a 2-point improvement in NAS without worsening of fibrosis.
According to analysis of the intention-to-treat population, 38% of the treatment group vs. 16% of the placebo group achieved the endpoint of improvement in NAS without worsening of fibrosis, for a common risk difference of 21% (95% CI, 8.1-33.9). In addition, 26% vs. 11%, respectively, achieved MASH resolution with improvement in NAS without worsening of fibrosis, for a common risk difference of 13% (95% CI, 0.7-25.3).
“Denifanstat at 50 mg orally once daily led to significant improvements in MASH resolution, as well as at least one-stage improvement in fibrosis, among patients with biopsy-proven MASH with stage 2 or 3 fibrosis,” Loomba said.
Further, 30% of treated patients vs. 14% on placebo exhibited fibrosis improvement by at least one stage, measured via Nonalcoholic Steatohepatitis Clinical Research Network score, without worsening of steatohepatitis (common risk difference = 11.8%; 95% CI, –1.3 to 24.8).
“Denifanstat also increased the level of polyunsaturated fatty acids in triglycerides and reduced LDL cholesterol, suggesting it might have beneficial cardiometabolic effects, and was generally well-tolerated,” Loomba noted.
The most common treatment-emergent events among patients on denifanstat vs. placebo were COVID-19 (17% vs. 11%), symptoms of dry eye (9% vs. 14%) and alopecia (19% vs. 4%), and no serious adverse events (12% vs. 5%) were drug-related.
“Denifanstat is a promising oral therapy in development for the treatment of MASH-related fibrosis,” Loomba told Healio. “A large, multicenter, international, phase 3, randomized, placebo-controlled clinical trial is needed to compare the efficacy of denifanstat vs. placebo to validate these findings in improving MASH resolution without worsening fibrosis and one-stage improvement in fibrosis without worsening of MASH.”
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