Ascletis Announces ASC40, a First-in-Class, Once-Daily Oral FASN Inhibitor, Achieved Endpoints in Phase II Clinical Trial for Acne

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May 02, 2023, 05:11 ET

HANGZHOU and SHAOXING, China, May 2, 2023 /PRNewswire/ -- Ascletis Pharma Inc. (HKEX: 1672, "Ascletis") announces today that ASC40 (Denifanstat), a first-in-class, once-daily oral fatty acid synthase (FASN) inhibitor, achieved primary and key secondary endpoints in Phase II clinical trial for acne vulgaris.

ASC40 is an oral, selective small molecule inhibitor of FASN. Mechanisms of ASC40 for 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.

The Phase II clinical trial was a randomized, double-blind, placebo-controlled, multicenter clinical trial in China to evaluate the safety and efficacy of ASC40 for the treatment of patients with moderate to severe acne. The enrolled 180 patients were randomized into three active treatment arms or one placebo control arm at the ratio of 1:1:1:1 to receive ASC40 (25 mg, 50 mg or 75 mg) or matching placebo orally, once daily for 12 weeks, among which 179 patients received at least one dose of ASC40 or placebo.

Table 1 summarized the topline efficacy data.

Table 2 compared 50 mg ASC40, oral, once-daily treatment to topical clascoterone cream (Winlevi^®), 1%, twice-daily treatment. Clascoterone is a topical androgen receptor inhibitor, which was approved by the U.S. Food and Drug Administration in August 2020.

Table 1. Primary and key secondary efficacy endpoints of 25 mg, 50 mg and 75 mg ASC40, oral, once daily for 12 weeks vs placebo (n=179)

Endpoint	25 mg ASC40, oral, once daily, 12 weeks (n=45)	50 mg ASC40, oral, once daily, 12 weeks (n=44)	75 mg ASC40, oral, once daily, 12 weeks (n=45)	Placebo, oral, once daily, 12 weeks (n=45)
% change from baseline in total lesion count at week 12 (primary endpoint) ^§	-53.1	-61.3	-53.1	-34.2
P value vs placebo	0.006	0.008	0.008	NA
Absolute change from baseline in total lesion count at week 12 (key secondary endpoint)^§	-56.0	-60.5	-46.0	-37.0
P value vs placebo	0.024	0.030	0.083	NA
% change from baseline in inflammatory lesion count at week 12 (key secondary endpoint)^§	-54.4	-65.0	-60.0	-31.4
P value vs placebo	0.006	0.003	0.029	NA
Absolute change from baseline in inflammatory lesion count at week 12 (key secondary endpoint)^§	-25.0	-26.0	-22.0	-13.0
P value vs placebo	0.007	0.003	0.032	NA
Note: § Data are medians.

Table 2. 50 mg ASC40, oral, once daily for 12 weeks vs topical clascoterone cream (Winlevi^®), 1%, twice daily for 12 weeks
(not head-to-head comparison)

Category	ASC40 or placebo, once daily for 12 weeks			Clascoterone cream or placebo (vehicle), twice daily for 12 weeks
	Phase II			Phase II *			Phase III **
	50 mg, oral (n=44)	Placebo, oral (n=45)	Placebo adjusted efficacy	1%, topical (n=70)	Placebo, topical (n=75)	Placebo adjusted efficacy	1%, topical (n=722)	Placebo, topical (n=718)	Placebo adjusted efficacy
Baseline characteristics
Total lesion count ***	101.1	105.0	NA	75.8	74.4	NA	103.6	104.1	NA
Inflammatory lesion count ***	43.4	43.7	NA	28.6	30.5	NA	42.7	42.1	NA
IGA = 3 (moderate), %	65.9	71.1	NA	45.7	70.7	NA	82.7	84.1	NA
IGA = 4 (severe), %	34.1	28.9	NA	28.6	14.7	NA	17.3	15.9	NA
Efficacy
% change from baseline in total lesion count at week 12	-61.3	-34.2	-27.1	NA	NA	NA	-37.2	-25.3	-11.9
Absolute change from baseline in total lesion count at week 12	-60.5	-37.0	-23.5	NA	NA	NA	-39.6	-26.2	-13.4
% change from baseline in inflammatory lesion count at week 12	-65.0	-31.4	-33.6	-41.8	-28.4	-13.4	-45.9	-33.1	-12.8
Absolute change from baseline in inflammatory lesion count at week 12	-26.0	-13.0	-13.0	-12.3	-9.1	-3.2	-19.7	-14.1	-5.6
% treatment success at week 12 ****	19.4	5.1	14.3	10.9	3.4	7.5	19.4	7.8	11.6
Notes: IGA: Investigator's Global Assessment. * The Phase II data of clascoterone cream (1%) in Table 2 are from Study Results of NCT01631474 on www.clinicaltrials.gov. In addition to patients with moderate and severe acne, this Phase II clinical trial enrolled 25.7% and 14.7% patients with mild acne (IGA = 2) in the clascoterone cream (1%) and placebo groups, respectively. The Phase III data of clascoterone cream (1%) in Table 2 combined or averaged the data from two Phase III clinical trials published in the following article: Hebert A, Thiboutot D, Gold L S, et al. Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients with Facial Acne: Two Phase 3 Randomized Clinical Trials [J]. JAMA Dermatology, 2020, 156(6). * Data are means. **** Treatment success is defined as at least a 2-point reduction in IGA from baseline and an IGA of 0 or 1 at week 12.

At all doses, oral ASC40 with once-daily, 12-week treatment was safe and well tolerated. The incidence rates of test articles-related adverse events (AEs) were comparable among 25 mg (grade 1 = 28.9%; grade 2 = 20.0%), 50 mg (grade 1 = 36.4%; grade 2 = 11.4%), 75 mg (grade 1 = 44.4%; grade 2 = 17.8%) ASC40 and placebo (grade 1 = 35.6%; grade 2 = 13.3%). For all treatment groups, the most common test article-related AE was dry eyes whose incidence rates were similar among 25 mg (grade 1 =17.8%; grade 2 = 6.6%), 50 mg (grade 1 = 22.7%; grade 2 = 2.3%), 75 mg (grade 1 = 15.5%; grade 2 = 11.1%) ASC40 and placebo (grade 1 = 28.9%; grade 2 = 6.6%). There were no ASC40 related grade 3 or 4 AEs and no ASC40 related serious AE (SAEs). No death was reported.

Based on efficacy and safety assessment, 50 mg, oral, once-daily dose is recommended for the Phase III clinical trial which is expected to be initiated in the second half of 2023. The other two doses are being assessed for the Phase III trial.

In the previous Phase IIa clinical trial of non-alcoholic steatohepatitis (NASH) patients with 12-week treatment of 50 mg ASC40, oral, once daily, 61% patients showed clinically meaningful and statistically significant liver fat reduction. Furthermore, statistically significant total cholesterol, low-density lipoprotein cholesterol (LDL-C) and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) reductions were observed at week 12 compared to baseline^[1].

Acne is the eighth most prevalent disease in the world and affects more than 640 million people globally^[2]. Adherence to topical therapies is worse when compared with that for oral agents: an estimated 30% to 40% of patients do not adhere to their topical treatments^[3]. Currently, effective oral treatment for acne are mainly isotretinoin which can cause a lot of severe AEs such as hepatotoxicy, hearing impairment and depression, etc. ASC40 has the potential to be a first-in-class, once-daily, oral acne therapeutic which offers both superior efficacy and patient compliance with good safety profile.

"The FASN inhibitor ASC40 is a first-in-class drug candidate with novel mechanism, demonstrating significant efficacy and good safety in the Phase II clinical trial. I look forward to conducting the Phase III clinical trial as soon as possible." 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 ASC40 Phase II trial for moderate to severe acne.

"I am excited about such strong Phase II clinical data," said Dr. Jinzi J. Wu, Founder, Chairman and CEO of Ascletis, "As FASN inhibition is a novel mechanism for acne and ASC40 is the first-in-class drug candidate for this mechanism, Ascletis once again demonstrates its strong R&D capability to develop innovative medicines for unmet medical needs. I look forward to initiating the Phase III clinical trial for acne in the second half of 2023."

[1] Loomba R, Mohseni R, Lucas K J, et al. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled Ph2a trial [J]. Gastroenterology, 2021.

[2] Tan J K, Bhate K. A global perspective on the epidemiology of acne [J]. Br J Dermatol 2015, 172 Suppl 1(3-12). DOI: 10.1111/bjd.13462.

[3] 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.

About Ascletis

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 manufacturing and commercialization. Led by a management team with deep expertise and a proven track record, Ascletis focuses on three therapeutic areas with unmet medical needs from a global perspective: viral diseases, non-alcoholic steatohepatitis (NASH) and oncology. Through excellent execution, Ascletis rapidly advances its drug pipeline with an aim of leading in global competition. To date, Ascletis has three marketed products, i.e. ritonavir tablets, GANOVO^® and ASCLEVIR^®, and 23 drug candidates in its R&D pipeline. The most advanced drug candidates include ASC22 (HBV functional cure), ASC10 and ASC11(oral small molecules for COVID-19 treatment), ASC40 (recurrent glioblastoma), ASC42 (PBC, primary biliary cholangitis), and ASC40 (acne).

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

SOURCE Ascletis Pharma Inc.