Ascletis Pharma Inc. announced that denifanstat (ASC40), a first-in-class once-daily oral fatty acid synthase (FASN) inhibitor, successfully met all primary, key secondary, and secondary endpoints in its Phase III clinical trial for moderate to severe acne vulgaris. The randomized, double-blind, placebo-controlled multicenter trial enrolled 480 patients in China and demonstrated statistically significant and clinically meaningful improvements across all measured outcomes.
Phase III Trial Results Demonstrate Superior Efficacy
The 12-week trial randomized patients 1:1 to receive either 50 mg denifanstat oral tablet once daily or matching placebo. At week 12, denifanstat achieved a treatment success rate of 33.2% compared to 14.6% for placebo (p<0.0001), where treatment success was defined as an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-point decrease from baseline.
The drug also demonstrated significant reductions in lesion counts across all categories. Total lesion count decreased by 57.4% from baseline compared to 35.4% for placebo (p<0.0001), while inflammatory lesion count reduced by 63.5% versus 43.2% for placebo (p<0.0001). The key secondary endpoint of non-inflammatory lesion count reduction showed a 51.9% decrease compared to 28.9% for placebo (p<0.0001).
Favorable Safety Profile with Minimal Adverse Events
Denifanstat demonstrated a favorable safety and tolerability profile throughout the 12-week treatment period. The incidence rates of treatment-emergent adverse events (TEAEs) were comparable between denifanstat and placebo groups, with no category exceeding 10% incidence. Only two adverse event categories occurred in more than 5% of patients: dry skin (6.3% versus 2.9% for placebo) and dry eye (5.9% versus 3.8% for placebo).
All denifanstat-related adverse events were classified as mild or moderate, with no grade 3 or 4 adverse events and no serious adverse events reported. No deaths occurred during the trial period.
Novel Mechanism Targets Root Cause of Acne
Denifanstat operates through a unique dual mechanism of action that directly addresses acne's underlying pathophysiology. The drug inhibits facial sebum production through inhibition of de novo lipogenesis in human sebocytes and reduces inflammation by decreasing cytokine secretion and Th17 differentiation. This approach directly targets sebum overproduction, one of the main underlying causes of acne, distinguishing it from most existing treatments that do not address the condition's root cause.
Comparative Efficacy Analysis Shows Superior Performance
In non-head-to-head comparisons with FDA-approved acne treatments, denifanstat demonstrated exceptional efficacy across multiple metrics. The drug showed 98% greater effectiveness than sarecycline and 178% greater effectiveness than doxycycline regarding placebo-adjusted percent treatment success, with denifanstat achieving 18.6% versus 9.4% for sarecycline and 6.7% for doxycycline. Compared to clascoterone cream, denifanstat was 60% more effective, achieving 18.6% versus 11.6% placebo-adjusted treatment success.
For inflammatory lesion count reduction, denifanstat was 30% more effective than sarecycline, 178% more effective than doxycycline, and 59% more effective than clascoterone cream. The drug's performance in non-inflammatory lesion count reduction was particularly notable, showing 411% greater effectiveness than sarecycline and 102% greater effectiveness than clascoterone cream.
Clinical Significance and Regulatory Path Forward
"We are extremely pleased with the topline results of our Phase III trial. Denifanstat tablets demonstrated impressive efficacy beyond treatment success, showing significant reductions in total lesion count, inflammatory lesion count, and non-inflammatory lesion count. We are excited to be submitting this innovative treatment with the China National Medical Products Administration (NMPA) soon," said Jinzi Jason Wu, Ph.D., Founder, Chairman and CEO of Ascletis.
Prof. Leihong Xiang, Chief Physician of Dermatological Department at Huashan Hospital, Fudan University, and principal investigator of the trial, emphasized the clinical significance: "The Phase III clinical trial results for denifanstat are highly encouraging. The data demonstrate statistically significant improvements in treatment outcomes for moderate-to-severe acne patients, with percent treatment success of 33.2%, total lesion count reduction of 57.4% from baseline, inflammatory and non-inflammatory lesion counts decreasing by 63.5% and 51.9%, respectively, while maintaining a favorable safety and tolerability profile."
Addressing Treatment Adherence and Safety Concerns
Denifanstat offers potential advantages over existing therapies in terms of both safety and patient compliance. Unlike tetracycline derivatives, the drug carries no risk of antibiotic resistance or off-target effects. It also avoids the severe adverse events associated with isotretinoin, such as hepatotoxicity, hearing impairment, and depression. The once-daily oral formulation may improve treatment adherence compared to topical therapies, as an estimated 30% to 40% of patients do not adhere to their topical acne treatments.
Denifanstat is licensed from Sagimet Biosciences Inc. for exclusive rights in Greater China, positioning Ascletis to advance this potentially breakthrough therapy through regulatory approval and commercialization in the region.
