Ascletis Phase III Denifanstat Trial for Acne Meets All Endpoints

Ascletis Pharma Inc. (HKEX: 1672), a clinical-stage biotechnology company, announced that its first-in-class oral fatty acid synthase (FASN) inhibitor, denifanstat (ASC40), has met all primary, key secondary, and secondary endpoints in a Phase III clinical trial for the treatment of moderate to severe acne vulgaris.

The once-daily oral tablet demonstrated strong efficacy, excellent tolerability, and a unique mechanism of action that addresses the root causes of acne.

Overview of the Phase III Clinical Trial

The Phase III study was a randomized, double-blind, placebo-controlled, multicenter trial conducted in China.

A total of 480 patients with moderate to severe acne vulgaris were enrolled and randomized in a 1:1 ratio to receive either a 50 mg oral tablet of denifanstat or a placebo once daily for 12 weeks.

Baseline characteristics between both arms were well balanced, including total and inflammatory lesion counts and Investigator’s Global Assessment (IGA) scores.

Baseline Characteristics

• Total lesion count: 102.2 (denifanstat) vs 102.1 (placebo)
• Inflammatory lesion count: 42.1 (denifanstat) vs 43.1 (placebo)
• IGA=3 (moderate): 85.8% in both arms
• IGA=4 (severe): 14.2% in both arms

Efficacy Outcomes at Week 12

Denifanstat achieved statistically significant improvements compared to placebo across all efficacy parameters.

Primary Endpoints

• Percent treatment success (defined as IGA 0 or 1 and ≥2-point reduction): 33.2% (denifanstat) vs 14.6% (placebo), with a placebo-adjusted difference of 18.6%, p<0.0001
• Percent reduction in total lesion count: 57.4% vs 35.4%, placebo-adjusted difference of 22.0%, p<0.0001
• Percent reduction in inflammatory lesion count: 63.5% vs 43.2%, placebo-adjusted difference of 20.3%, p<0.0001

Key Secondary and Secondary Endpoints

• Percent reduction in non-inflammatory lesion count: 51.9% vs 28.9%, placebo-adjusted difference of 23.0%, p<0.0001
• Absolute reduction in total lesion count: 58.3 (denifanstat) vs 36.2 (placebo), difference of 22.1
• Absolute reduction in inflammatory lesion count: 26.6 (denifanstat) vs 18.4 (placebo), difference of 8.2

Safety and Tolerability

Denifanstat demonstrated a favorable safety profile over the 12-week treatment period. The incidence of treatment-emergent adverse events (TEAEs) was comparable between the denifanstat and placebo groups. No denifanstat-related TEAEs in any category exceeded 10%.

• Dry skin was observed in 6.3% of denifanstat-treated patients vs 2.9% of placebo
• Dry eye was reported in 5.9% vs 3.8%, respectively

All adverse events related to denifanstat were either mild or moderate. No grade 3 or 4 adverse events or serious adverse events were reported, and there were no deaths.

Unique Mechanism of Action

Denifanstat is a fatty acid synthase (FASN) inhibitor that addresses two core pathophysiological factors in acne:

1. Direct inhibition of facial sebum production via suppression of de novo lipogenesis in human sebocytes
2. Anti-inflammatory effects by reducing cytokine secretion and inhibiting Th17 cell differentiation

Unlike many existing acne therapies, denifanstat directly targets the overproduction of sebum, a root cause of acne. This mechanism offers a differentiated and potentially more effective treatment option compared to both antibiotics and topical therapies.

Comparative Efficacy: Non-Head-to-Head Benchmarking

In a non-head-to-head comparison, denifanstat demonstrated superior efficacy against commonly used acne treatments, including sarecycline, doxycycline, and clascoterone cream.

Placebo-Adjusted Percent Treatment Success

• Denifanstat: 18.6%
• Sarecycline: 9.4%
• Doxycycline: 6.7%
• Clascoterone cream: 11.6%

Denifanstat was 98% more effective than sarecycline, 178% more effective than doxycycline, and 60% more effective than clascoterone cream in placebo-adjusted treatment success.

Placebo-Adjusted Reduction in Lesion Counts

• Inflammatory lesions: 20.3% for denifanstat vs 15.6% (sarecycline), 7.3% (doxycycline), and 12.8% (clascoterone)
• Total lesion count: 22.0% for denifanstat vs 7.6% (doxycycline) and 11.9% (clascoterone)
• Non-inflammatory lesions: 23.0% for denifanstat vs 4.5% (sarecycline) and 11.4% (clascoterone)

These results highlight denifanstat’s consistently higher efficacy across multiple key endpoints.

Potential Clinical Impact

Denifanstat may offer a new therapeutic option for patients with moderate-to-severe acne who are dissatisfied with current treatment options. Unlike antibiotics, it carries no risk of resistance or off-target systemic effects. Compared to isotretinoin, it shows no signs of severe adverse effects such as hepatotoxicity, hearing issues, or depression. The oral, once-daily format is also likely to enhance patient adherence, which is often a limitation with topical therapies.

A previous study cited that 30% to 40% of patients fail to comply with topical acne treatments, underscoring the need for more convenient alternatives like denifanstat.

Regulatory Path Forward

Ascletis plans to submit a marketing application for denifanstat to the China National Medical Products Administration (NMPA) based on the favorable Phase III results. The drug is licensed from Sagimet Biosciences Inc. (Nasdaq: SGMT) for exclusive rights in Greater China.

Expert Commentary

Dr. Leihong Xiang, Chief Physician at Huashan Hospital of Fudan University and principal investigator of the Phase III trial, emphasized the significance of the findings:
“The data demonstrate statistically significant improvements in treatment outcomes for moderate-to-severe acne patients, while maintaining a favorable safety and tolerability profile. Denifanstat's first-in-class mechanism targeting FASN directly addresses a key cause for acne, establishing it as a groundbreaking therapeutic approach in acne treatment.”

About Ascletis Pharma Inc.

Ascletis is a research-driven biopharmaceutical company listed on the Hong Kong Stock Exchange (1672.HK). The company is focused on metabolic diseases and operates across the entire pharmaceutical value chain, including drug discovery, clinical development, and GMP manufacturing. The company has a growing pipeline of clinical-stage candidates aimed at addressing significant unmet medical needs globally.

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