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An investigational oral fatty acid synthase (FASN) inhibitor was associated with significant improvements in metabolic dysfunction-associated steatohepatitis (MASH) in a phase II clinical trial.

In 168 patients with MASH and stage F2-F3 fibrosis randomized to a daily dose of denifanstat or placebo, 26% of those in the treatment group experienced MASH resolution at 52 weeks with no worsening of fibrosis compared with 11% of the placebo group (common risk difference 13%, 95% CI 0.7-25.3, P=0.0173), said researchers led by Rohit Loomba, MD, of the University of California San Diego Altman Clinical and Translational Research Institute in La Jolla.

In addition, 38% of the treatment group experienced a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without fibrosis worsening versus 16% of the placebo group (common risk difference 21%, 95% CI 8.1-33.9, P=0.0035), Loomba's team reported in .

"Treatment with denifanstat resulted in statistically significant and clinically meaningful improvements in disease activity, MASH resolution, and fibrosis," the study authors concluded. "The results of this phase IIb trial support the advancement of denifanstat to phase III development."

"The mechanism of action of the novel molecule denifanstat directly targets liver steatosis, inflammation, and fibrosis (the three main drivers of liver injury) in individuals with MASH," Loomba and colleagues wrote. "This study is the first clinical trial with a FASN inhibitor and biopsy-based histological endpoints to evaluate the potential of denifanstat and its unique mechanism of action to improve liver disease."

"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," the study authors added.

One of the most common adverse events was alopecia, experienced by 19% of the treatment group versus 4% of the placebo group. Other common treatment-emergent events included dry eye symptoms and COVID-19 infection.

Based on the results of the trial, drugmaker earlier this month that the FDA granted breakthrough therapy designation to denifanstat for the treatment of MASH with moderate to advanced liver fibrosis.

In an , Sven Francque, MD, PhD, and Luisa Vonghia, MD, PhD, of the Antwerp University Hospital in Belgium, said denifanstat should be advanced to a phase III trial based on the current results, although there might be potential downsides to the drug. "Overall, the side effect profile does not raise many concerns, although hair thinning (which accounted for 11 [50%] of 22 discontinuations) might be an issue," they wrote.

In addition, the drug's effect on lipid profiles should be examined more closely, they suggested. In the treatment group, LDL cholesterol decreased by 15%, but triglycerides increased by 32%. "As this increase is more balanced towards polyunsaturated fatty acids, it might not represent an increased cardiovascular risk, but whether it harbors a cardiovascular benefit needs further study, and a more detailed analysis of the final circulating lipidome is needed."

The was a double-blind, randomized, placebo-controlled, phase IIb trial conducted at clinical sites in the U.S., Canada, and Poland. After a screening period of up to 90 days, adult participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned 2:1 to receive 50 mg oral denifanstat (n=112) or placebo (n=56) once per day for 52 weeks. The study was conducted from June 2021 to June 2022.

A majority of participants were women (60%) and 89% were white. Their mean age was 57. Participants were biopsied at baseline and again at the end of treatment. Biopsies were analyzed by a blinded pathologist and artificial intelligence-assisted digital pathology. The two primary efficacy endpoints, evaluated at week 52, were a 2-point or greater improvement in NAS without a worsening of fibrosis, or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis, assessed by intention-to-treat (ITT).

The number needed to treat for MASH resolution or fibrosis improvement was six in the ITT population and four in a modified ITT population that included participants with a minimum 42 weeks of treatment, the researchers reported.

Limitations of the study included the relatively small number of participants, Loomba and colleagues said. In addition, the majority were white, with approximately a third being of Hispanic heritage, which could limit the conclusions to broader populations. Finally, the study was conducted during waves of COVID-19, which led to a large percentage of participants being infected.

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