PARIS — Oral treatment with the novel fatty acid synthase inhibitor denifanstat was associated with significant improvements in moderate-to-severe acne in a phase 3 trial presented at the European Academy of Dermatology and Venereology (EADV) 2025 Congress. 

During the 12-week trial, statistically higher proportions of patients treated with the experimental drug than placebo achieved the key efficacy endpoints. These included treatment success as defined by a 2-point or more reduction in the Investigators Global Assessment (IGA) from baseline and an IGA score of 0 or 1, the percentage change in total lesion count (TLC), and the percentage change in the inflammatory lesion count (ILC). 

“The new acne treatment drug denifanstat, which was announced at last week's EADV and is currently in clinical trials, caught my interest,” Tomoko Kobayashi, PhD, director of Kobatomo Dermatology, Tokyo, wrote on X. 

“It's a fatty acid synthase inhibitor that suppresses sebum production, and it's said to produce relatively early improvement even in moderate to severe cases,” Kobayashi added. 

Kobayashi also noted, “The side effects seem to be mild, so I'd like to try it as an alternative to isotretinoin, but I wonder how it will turn out.”

Stopping Sebum Production

Flora Xiang, MD, of Huashan Hospital, Fudan University, Shanghai, and the principal investigator for the trial, said that sebum production was really important in the pathogenesis of acne.

“Overproduction of sebum changes the profile of the cutaneous bacteria of acne and also will enhance or induce the innate immune reaction,” she said during a late-breaking news session where she presented the study’s findings.

Denifanstat acts directly on the fatty acid synthase present in sebocytes, reducing sebum production. It blocks inflammation by lowering cytokine release and suppressing Th17 cell differentiation, Xiang explained. 

Treatment Benefit as Early as 4 Weeks

Following the positive findings of a phase 2 trial, a 50 mg once-daily oral dose of denifanstat was selected for further investigation. The study Xiang presented involved 480 Chinese people aged 18-40 years who had moderate-to-severe acne as indicated by an IGA of 3 or 4. 

Half of those enrolled were randomly allocated to treatment with denifanstat tablets and half to a matching placebo. 

After 12 weeks of treatment, a significantly (P < .0001) greater percentage of denifanstat - than placebo-treated patients met the trial’s primary efficacy endpoints. Respectively, 33.2% vs 14.6% achieved IGA treatment success, the percentage change in TLC from baseline was -57.4% vs -35.4%, and the percentage change in ILC from baseline was -63.5% vs -43.2%. 

Moreover, significantly (again all P < .0001) more treated with denifanstat than placebo met the trial’s various secondary efficacy endpoints. The percentage changes from baseline in non-ILC were a respective -51.9% and -28.9%, and the absolute changes were -58.3% vs -36.2% in TLC and -26.6% vs -18.4% in ILC.

A treatment benefit was seen as early as 4 weeks in the denifanstat arm, progressively improving with time, Xiang reported. 

Treatment-emergent adverse events were reported in similar percentages (58.6% and 56.3%) of denifanstat- and placebo-treated patients. Most of these side effects were mild (grade 1) or moderate (grade 2). 

Xerophthalmia and dry skin were the most commonly reported side effects of denifanstat, occurring in 5.9% and 6.3% of patients vs 3.8% and 2.9% for placebo. 

However, reduced tear film break-up time was more common in the placebo-treated patients, at 2.5% vs 1.3% for denifanstat.

Dry skin “especially at the end of the finger” was also a more frequent finding in the active than placebo treatment arm (6.3% vs 2.9%). 

Multiple Questions

These data garnered lots of questions after Xiang’s presentation. First, she was asked by the co-chair, Margarida Gonçalo, MD, from the University of Coimbra and University Hospital, Portugal, about the wider applicability of the findings since 95% of the study’s population were Han Chinese. 

The response was that denifanstat had already been trialed as a treatment for fatty liver disease and that those studies had been conducted internationally. In fact, it was during those trials that the dry skin side effect was noted, which led to the drug’s investigation as a possible acne treatment.

“There could be a difference in different populations,” Xiang acknowledged, and this would be something to look at in future studies. 

Other questions were whether it would be possible for patients to become pregnant while taking the drug and if there were any teratogenicity data, as pregnancy was a contraindication to isotretinoin’s use.

Xiang said that data is currently unavailable, and she is not sure if there were any data regarding the drug’s teratogenic potential. 

A final question was what would happen after patients stopped the treatment? Was continuous treatment with the drug required to sustain the effects?

“Good question,” Xiang said. “You know the acne patients are really concerned about the relapse.” This is why an open-label extension study has been set up to look at the after-effects of the drug and the need for continued treatment, she said. 

Ascletis BioScience Co., Ltd sponsored the trial and Xiang served as the principal investigator. Denifanstat is being developed by Ascletis as ASC40 for acne in China and by Sagimet for metabolic dysfunction-associated steatohepatitis in the rest of world.

Sara Freeman is a freelance medical journalist based in London, England.