Ascletis Announces Phase III Trial of Denifanstat (ASC40), a First-in-Class, Once-Daily Oral FASN Inhibitor for Acne, Meets All Endpoints

Rhea-AI Summary

Ascletis announces successful Phase III trial results for Denifanstat (ASC40), a first-in-class oral FASN inhibitor for acne treatment. The trial met all endpoints with 33.2% treatment success vs 14.6% for placebo. Denifanstat showed superior efficacy compared to FDA-approved treatments: 98% more effective than sarecycline, 178% more effective than doxycycline, and 60% more effective than clascoterone cream in placebo-adjusted treatment success. The drug demonstrated significant reductions in total lesion count (57.4%), inflammatory lesions (63.5%), and non-inflammatory lesions (51.9%). With a favorable safety profile and only mild to moderate adverse events, Denifanstat's unique mechanism directly targets sebum overproduction, a root cause of acne. The once-daily oral treatment offers potential advantages over topical treatments, which suffer from 30-40% non-adherence rates.

Positive

• Denifanstat met all primary, key secondary, and secondary endpoints in Phase III trial
• Superior efficacy compared to existing treatments: 98% more effective than sarecycline, 178% more than doxycycline, 60% more than clascoterone cream
• Favorable safety profile with no serious adverse events or severe side effects
• Unique mechanism of action targeting root cause of acne through FASN inhibition
• Better potential treatment adherence compared to topical therapies (30-40% non-adherence for topicals)
• No risk of antibiotic resistance unlike current treatments

Negative

• Mild to moderate adverse events including dry skin (6.3%) and dry eye (5.9%)
• Trial conducted only in China, may need additional studies for global approval

Insights

Pharmaceutical Development Expert

Denifanstat shows exceptional Phase III results for acne, outperforming existing treatments with novel mechanism targeting root causes.

The Phase III clinical trial results for denifanstat (ASC40) represent a significant breakthrough in acne therapeutics. This first-in-class FASN inhibitor demonstrated impressive efficacy across all primary and secondary endpoints with high statistical significance (p<0.0001). The treatment success rate of 33.2% versus 14.6% for placebo translates to a substantial 18.6% placebo-adjusted improvement.

What makes denifanstat particularly noteworthy is its novel mechanism of action that directly targets sebum overproduction—a fundamental cause of acne—through FASN inhibition. This approach differentiates it from current treatments that primarily address symptoms rather than underlying causes.

The comparative data is compelling: denifanstat showed 98% greater efficacy than sarecycline and 178% greater efficacy than doxycycline in placebo-adjusted treatment success. It also outperformed clascoterone cream by 60%. These non-head-to-head comparisons suggest denifanstat could potentially become a best-in-class treatment.

The safety profile appears favorable, with mostly mild-to-moderate adverse events and no serious drug-related adverse events reported. The two most common side effects—dry skin (6.3%) and dry eye (5.9%)—are tolerable compared to the more concerning side effects of current treatments like isotretinoin.

As a once-daily oral medication, denifanstat addresses the poor adherence issues commonly seen with topical treatments, potentially improving real-world effectiveness. This combination of superior efficacy, favorable safety, and convenient administration positions denifanstat as a potential game-changer in moderate-to-severe acne management.

• Denifanstat (ASC40), a once-daily oral fatty acid synthase (FASN) inhibitor, demonstrated statistically significant and clinically meaningful improvement compared to placebo in all primary, key secondary, and secondary endpoints
• Denifanstat demonstrated a favorable safety and tolerability profile
• Denifanstat was 98% and 178% more effective than U.S. Food and Drug Administration (FDA)-approved sarecycline and doxycycline with regard to placebo-adjusted percent treatment success, respectively, 18.6% for denifanstat versus 9.4% for sarecycline, 18.6% versus 6.7% for doxycycline
• Denifanstat was 60% more effective than FDA-approved clascoterone cream with regard to placebo-adjusted percent treatment success, 18.6% for denifanstat versus 11.6% for clascoterone cream, respectively
• The exceptional efficacy of denifanstat coupled with its favorable safety profile in the Phase III trial provides a potential major break-through for the treatment of acne

HONG KONG, June 3, 2025 /PRNewswire/ -- Ascletis Pharma Inc. (HKEX: 1672, "Ascletis") announces today that denifanstat (ASC40), a first-in-class, once-daily oral small molecule fatty acid synthase (FASN) inhibitor, meets all primary, key secondary, and secondary endpoints in the Phase III clinical trial for the treatment of moderate to severe acne vulgaris (NCT06192264).

The Phase III clinical trial was a randomized, double-blind, placebo-controlled, multicenter clinical trial in China to evaluate the safety and efficacy of denifanstat once-daily oral tablet in 480 patients with moderate to severe acne vulgaris. Patients were enrolled and randomized into one active treatment arm and one placebo control arm at the ratio of 1:1 to receive 50 mg denifanstat oral tablet once daily or matching placebo for 12 weeks. Baseline characteristics were well balanced between denifanstat and placebo arms. Table 1 summarizes some of baseline characteristics.

Primary, key secondary, and secondary endpoints can be found in Table 2. Primary endpoints included the percent treatment success (defined as an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-point decrease in IGA from baseline at week 12), the percent reduction from baseline in total lesion count, and the percent reduction from baseline in inflammatory lesion count. At week 12, percent treatment success was 33.2% compared to 14.6% for placebo, p<0.0001, percent reduction from baseline in total lesion count was 57.4% compared to 35.4% for placebo, p<0.0001, and percent reduction from baseline in inflammatory lesion count was 63.5% compared to 43.2% for placebo, p<0.0001. The key secondary endpoint, percent reduction from baseline in non-inflammatory lesion count at week 12, was 51.9% compared to 28.9% for placebo, p<0.0001.

Denifanstat demonstrated a favorable safety and tolerability profile following 12 weeks of once-daily oral administration at 50 mg. The incidence rates of treatment-emergent adverse events (TEAEs) were comparable between denifanstat and placebo. No incidence rates of TEAEs related to study drug in any category exceeded 10%. Only two categories of TEAEs had an incidence rate of more than 5% (6.3% dry skin in denifanstat-treated patients versus 2.9% in the placebo group; 5.9% dry eye in denifanstat-treated patients versus 3.8% in the placebo group). All denifanstat-related adverse events (AEs) were mild or moderate. There were no denifanstat-related grade 3 or 4 AEs and no denifanstat-related serious AEs (SAEs). No deaths were reported.

The mechanisms of action of denifanstat for the treatment of acne are (1) direct inhibition of facial sebum production, through inhibition of de novo lipogenesis (DNL) in human sebocytes; and (2) inhibition of inflammation, through decreasing cytokine secretion and Th17 differentiation. Denifanstat's unique mechanism of action directly reduces one of the main underlying causes of acne which is the overproduction of sebum. This makes denifanstat unique as most other acne treatments do not treat the underlying cause of the condition.

"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.

Table 3 highlights the excellent efficacy of denifanstat in a non-head-to-head comparison to other commonly used oral and topical acne treatments. Denifanstat demonstrated its exceptional efficacy across multiple key metrics compared to sarecycline, doxycycline and clascoterone cream. With regard to the placebo-adjusted percent treatment success and the placebo-adjusted percent reduction from baseline in inflammatory lesion count, denifanstat was 98% and 30% more effective than sarecycline, respectively, 178% and 178% more effective than doxycycline, respectively, and 60% and 59% more effective than clascoterone cream, respectively. With regard to the placebo-adjusted percent reduction from baseline in total lesion count, denifanstat was 189% and 85% more effective than doxycycline and clascoterone cream, respectively. With regard to the placebo-adjusted percent reduction from baseline in non-inflammatory lesion count, denifanstat was 411% and 102% more effective than sarecycline and clascoterone cream, respectively.

Denifanstat has the potential to be a first-in-class, once-daily, oral acne therapeutic, potentially offering both exceptional efficacy and patient compliance with a favorable safety and tolerability profile. Compared to other oral acne treatments, denifanstat provides outstanding efficacy with excellent safety. There is no potential for antibiotic resistance or off target effects which can occur with tetracycline derivatives and no reported denifanstat-related severe AEs such as hepatotoxicity, hearing impairment and depression which are seen with isotretinoin. Denifanstat should also provide better adherence to treatment compared to topical therapies: an estimated 30% to 40% of patients do not adhere to their topical treatments^[1]. Denifanstat is licensed from Sagimet Biosciences Inc. (Nasdaq: SGMT) for exclusive rights in Greater China.

"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. 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." said Prof. Leihong Xiang, Chief Physician of Dermatological Department, Huashan Hospital, Fudan University, Executive Deputy Director of Institute of Dermatology, Fudan University, Deputy Director of Dermatology Division of Chinese Medical Doctor Association and principal investigator of denifanstat Phase III trial for moderate to severe acne.

[1] Purvis CG, Balogh EA, Feldman SR. Clascoterone: How the Novel Androgen Receptor Inhibitor Fits Into the Acne Treatment Paradigm. Ann Pharmacother. 2021;55(10):1297-1299. doi:10.1177/1060028021992055.

Table 1. Baseline characteristics of Phase III trial of denifanstat

Baseline characteristics	50 mg denifanstat, oral, once daily  (n=240)	Placebo, oral, once daily  (n=240)
Total lesion count	102.2	102.1
Inflammatory lesion count	42.1	43.1
IGA=3 (moderate), %	85.8	85.8
IGA=4 (severe), %	14.2	14.2

Table 2. Efficacy endpoints of 50 mg denifanstat oral, once daily at week 12 versus placebo (intent-to-treat, ITT, analysis)

Efficacy endpoints (1)	50 mg denifanstat, oral, once daily (n=240)	Placebo, oral, once daily (n=240)	Placebo adjusted	p value
Percent treatment success (2) (primary endpoint)	33.2	14.6	18.6	<0.0001
Percent reduction from baseline in total lesion count (primary endpoint)	57.4	35.4	22.0	<0.0001
Percent reduction from baseline in inflammatory lesion count (primary endpoint)	63.5	43.2	20.3	<0.0001
Percent reduction from baseline in non- inflammatory lesion count (key secondary endpoint)	51.9	28.9	23.0	<0.0001
Absolute reduction from baseline in total lesion count (secondary endpoint)	58.3	36.2	22.1	<0.0001
Absolute reduction from baseline in inflammatory lesion count (secondary endpoint)	26.6	18.4	8.2	<0.0001

Notes:

(1)   All efficacy endpoints are least square means.
(2)   Treatment success is defined as an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-point decrease in IGA from baseline at week 12.

Table 3. Denifanstat compared to other commonly used acne treatments (not head-to-head comparison)

Category	Denifanstat  (n=240)	Sarecycline(1) (n=1002)	Doxycycline(2) (n=216)	Clascoterone cream(3) (n=722)
Baseline characteristics
Total lesion count	102.2	72.4	71.7	103.6
Inflammatory lesion count	42.1	30.0	33.6	42.7
IGA=3 (moderate), %	85.8	85.2	93.5	82.7
IGA=4 (severe), %	14.2	14.9	6.5	17.3
Efficacy endpoints at week 12
Placebo-adjusted percent treatment success	18.6	9.4	6.7	11.6
Placebo-adjusted percent reduction from baseline in total lesion count	22.0	NA	7.6	11.9
Placebo-adjusted percent reduction from baseline in inflammatory lesion count	20.3	15.6	7.3	12.8
Placebo-adjusted percent reduction from baseline in non-inflammatory lesion count	23.0	4.5	NA	11.4

Notes:

(1)   The sarecycline data represent an analysis of its two Phase III clinical trials, with values expressed as means. The data are from Moore, A., et al., J Drugs Dermatol 2018 Vol. 17 Issue 9 Pages 987-996. The non- inflammatory lesion count data are from FDA 
(https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209521Orig1s000MultidisciplineR.pdf).
(2)   The doxycycline data at week 16 are from Moore, A., et al., J Drugs Dermatol 2015 Vol. 14 Issue 6 Pages 581-6.
(3)   The clascoterone cream (1%) data represent an analysis of its two Phase III clinical trials, with values expressed as means. The data are from Hebert. A, et al., JAMA Dermatology 2020 Vol. 156 Issue 6, DOI: 10.1001/jamadermatol.2020.0465.

About Ascletis Pharma Inc.

Ascletis is an innovative R&D driven biotech listed on the Hong Kong Stock Exchange (1672.HK), covering the entire value chain from discovery and development to GMP manufacturing. Led by a management team with deep expertise and a proven track record, Ascletis is focused on metabolic diseases by addressing unmet medical needs from a global perspective. Ascletis has multiple clinical stage drug candidates in its metabolic disease pipeline.

For more information, please visit www.ascletis.com.

Contact: 

Peter Vozzo
ICR Healthcare
443-231-0505 (U.S.)
Peter.vozzo@icrhealthcare.com

Ascletis Pharma Inc. PR and IR teams
+86-181-0650-9129 (China)
pr@ascletis.com
ir@ascletis.com 

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SOURCE Ascletis Pharma Inc.

FAQ

What are the Phase III trial results for Denifanstat (SGMT) in acne treatment?

Denifanstat achieved 33.2% treatment success vs 14.6% for placebo, with 57.4% reduction in total lesions, 63.5% reduction in inflammatory lesions, and 51.9% reduction in non-inflammatory lesions after 12 weeks.

How does Denifanstat compare to existing acne treatments?

Denifanstat showed 98% better efficacy than sarecycline, 178% better than doxycycline, and 60% better than clascoterone cream in placebo-adjusted treatment success rates.

What are the side effects of Denifanstat in acne treatment?

The main side effects were mild to moderate, with dry skin (6.3%) and dry eye (5.9%) being the most common. No serious adverse events or severe side effects were reported.

How does Denifanstat work differently from other acne treatments?

Denifanstat uniquely inhibits FASN to directly reduce sebum production and inflammation, addressing the root cause of acne, unlike most other treatments that don't target the underlying cause.

What is the dosing regimen for Denifanstat in acne treatment?

Denifanstat is administered as a once-daily oral tablet at 50mg, offering potentially better treatment adherence compared to topical therapies.