Oral acne drug denifanstat shows deeper results through 52 weeks | 2026 Fall Clinical Derm

Denifanstat, an investigational once-daily oral pill, more than doubled the rate of clear or almost-clear skin compared with placebo in patients with moderate to severe acne, 33.2% vs. 14.6% at 12 weeks, according to a phase 3 poster presented today at the Fall Clinical Dermatology Conference.

Acne is driven by four connected factors: excess sebum (skin oil), clogged pores (hyperkeratinization), growth of C. acnes bacteria and inflammation, according to authors of the data. Denifanstat, developed by Sagimet Biosciences, blocks fatty acid synthase (FASN), an enzyme that drives de novo lipogenesis (DNL), the process skin cells use to make new fats. FASN also plays a role in inflammatory signaling and the activation of Th17 immune cells.

The poster was led by Julie Harper, M.D., clinical associate professor of dermatology at the University of Alabama at Birmingham, with co-authors affiliated with Sagimet and Ascletis Pharma, Sagimet's license partner in China. The researchers set out to review how FASN inhibitors affect fat production in human skin cells and how denifanstat performed in a recent phase 3 trial in China.

The phase 3 trial (ASC40-303), run by Ascletis, randomized 480 patients with moderate to severe acne to denifanstat 50 mg or placebo once daily for 12 weeks. Patients averaged around 22 years old, and 67.1% to 70.4% in each group were female. In both groups, 85.8% had moderate acne and 14.2% had severe acne, with an average of about 102 total lesions at baseline.

The three primary endpoints were treatment success, defined as an Investigator's Global Assessment (IGA) score of clear or almost clear with at least a 2-point improvement and percent change in total and inflammatory lesion counts. Change in noninflammatory lesions was a key secondary endpoint.

Researchers adjusted the treatment success analysis for baseline acne severity and the lesion count analyses for baseline total lesion count. After 12 weeks, 240 patients entered a 40-week open-label extension (ASC40-304) in which all received denifanstat. In separate analysis, researchers measured how denifanstat and other FASN inhibitors affected fat production in human sebocytes, the skin's oil-producing cells, and in liver cells.

At 12 weeks, total lesion counts dropped 57.4% with denifanstat vs. 35.4% with placebo. Inflammatory lesions fell 63.5% vs. 43.2%, and noninflammatory lesions fell 51.9% vs. 28.9%. The researchers also reported significant improvement as early as week 4. Dry eye occurred in 10.9% of denifanstat patients vs. 8% on placebo, and dry skin in 6.3% vs. 2.9%.

In the extension, which included 124 former placebo patients and 116 who stayed on denifanstat, treatment success reached 55.6% and 57.8% by week 52. Total lesions fell 70.7% and 73.0%, inflammatory lesions fell 75.8% and 78.1%, and noninflammatory lesions fell 65.5% and 68.3%, respectively.

Out of the 239 patients who received denifanstat for up to 52 weeks, dry skin occurred in 7.1% and dry eye in 5.9%, falling to 2.5% and 2.1% during the extension alone. All denifanstat-related adverse events were mild or moderate. In the separate analysis, denifanstat cut new fat production in sebocytes by half at 84 nM with serum and 73 nM without, compared with 210 nM in liver cells. Two other FASN inhibitors, TVB-3567 and TVB-3664, lowered triglycerides in sebocytes by 49.2% to 60.3%. FASN inhibition also lowered the inflammatory protein IL-1β, and denifanstat at 100 nM reduced Th17 cells from 30.0% to 10.3% while raising regulatory T cells from 0.06% to 26.1%.

David Happel, CEO of Sagimet, told Managed Healthcare Executive that blocking sebum matters because sebum production provides the “fuel for basically everything that's going to happen afterwards.”

“What I think caught everybody's attention was the continuing deepening response that we see with (denifanstat) and these patients,” Happel said. “The longer the patients take it, the better they become.”

He also noted that patients who switched from placebo caught up to those treated from the start within about 12 weeks. Denifanstat doesn’t permanently change the disease, and acne can begin to return about four weeks after stopping, which gives dermatologists flexibility to keep patients on it long term or restart as needed, he added.

The drug could reduce reliance on oral antibiotics, which carry resistance concerns and side effects, he said.

“It should dramatically reduce, if not replace entirely, antibiotic usage," he said, adding that an oral option could also help patients with acne on the chest and back, where topicals are hard to apply without help.

He expressed that this drug is the first novel mechanism for an oral acne drug in 44 years, since isotretinoin was approved back in 1982. Happel also said acne develops the same way across populations, so Sagimet expects similar results from its U.S. phase 3 trial, which began screening patients this month.

Authors of the poster concluded that the clinical results and lab evidence together support FASN inhibition as a new oral approach to acne, one that targets several drivers of the disease by reducing fat production, sebum and inflammation.