Clascoterone

- 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 4, 2025-- 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

- 与安慰剂相比，每日一次口服脂肪酸合成酶（FASN）抑制剂地尼法司他（ASC40）在所有主要、关键次要及次要终点上均实现了高度具有统计学意义且临床意义显著的改善- 地尼法司他显示出良好的安全性和耐受性特征- 就经安慰剂校准后的治疗成功百分比而言，地尼法司他（18.6%）的疗效比美国食品药品监督管理局（FDA）批准的沙瑞环素（sarecycline，9.4%）和多西环素（doxycycline，6.7%）分别高98%和178%- 就经安慰剂校准后的治疗成功百分比而言，地尼法司他（18.6%）的疗效比FDA批准的柯拉特龙（clascoterone）乳膏（11.6%）高60%- 地尼法司他在III期试验中表现出了优越的疗效以及良好的安全性特征，有望实现痤疮治疗的重大突破香港，2025年6月4日--歌礼制药有限公司（香港联交所代码：1672，“歌礼”）今日宣布，同类首创（first-in-class）、每日一次口服小分子脂肪酸合成酶（FASN）抑制剂地尼法司他（ASC40）治疗中重度寻常性痤疮的III期临床试验（NCT06192264）达到所有主要、关键次要及次要终点。该项III期临床试验是一项在中国开展的随机、双盲、安慰剂对照、多中心的临床试验，旨在评估地尼法司他每日一次口服片在480例中重度寻常性痤疮患者中的安全性和疗效。患者被按照1:1的比例随机分至一个活性药物组和一个安慰剂对照组，接受每日一次50毫克地尼法司他口服片或匹配的安慰剂治疗，为期12周。地尼法司他组和安慰剂组基线特征均衡。表1概述了部分基线特征。主要、关键次要及次要终点可见表2。主要终点包括治疗成功百分比（治疗成功的定义为在第12周时，研究者总体评估（Investigator's Global Assessment，IGA）评分较基线下降至少2分，且IGA分级为0分（光洁）或1分（几乎光洁））、总皮损计数相对基线百分比下降，以及炎性皮损计数相对基线百分比下降。第12周时，地尼法司他治疗组治疗成功百分比为33.2%，而安慰剂组为14.6%，p<0.0001；地尼法司他治疗组总皮损计数相对基线百分比下降是57.4%，而安慰剂组为35.4%，p<0.0001；以及，地尼法司他治疗组炎性皮损计数相对基线百分比下降是63.5%，而安慰剂组为43.2%，p<0.0001。第12周时，非炎性皮损计数相对基线百分比下降（关键次要终点），地尼法司他治疗组为51.9%，而安慰剂组为28.9%，p<0.0001。每日一次口服50毫克地尼法司他，为期12周的安全性和耐受性特征良好。地尼法司他和安慰剂的治疗期间发生的不良事件（treatment-emergent adverse events，TEAE）发生率相当。任何类别的与试验药物相关的TEAE发生率均不超过10%。仅两类TEAE的发生率超过5%（皮肤干燥在地尼法司他治疗组和安慰剂组的发生率分别为6.3%和2.9%，干眼症在地尼法司他治疗组和安慰剂组的发生率分别为5.9%和3.8%）。所有与地尼法司他相关的不良事件（AE）均为轻度或中度。没有与地尼法司他相关的3级和4级不良事件，且没有与地尼法司他相关的严重不良事件（SAE）。无死亡病例发生。地尼法司他治疗痤疮的机制是：（1）通过抑制人皮脂细胞的脂肪酸从头合成（DNL），直接抑制面部皮脂生成；和（2）通过减少细胞因子分泌和Th17分化来抑制炎症。皮脂分泌过剩是导致痤疮的主要诱因之一，地尼法司他独特的作用机制可直接减少皮脂分泌过剩，这使得地尼法司他独树一帜，而其他大多数痤疮治疗药物并不针对痤疮的根本原因。歌礼创始人、董事会主席兼首席执行官吴劲梓博士表示：我们对III期试验顶线数据非常满意。地尼法司他片在治疗成功方面表现出色，且总皮损、炎性皮损和非炎性皮损均显著下降。很快我们将向中国国家药品监督管理局（NMPA）递交这一令人振奋的创新疗法。  地尼法司他与其它常用口服和外用痤疮药物对比（非头对头比较），显示出更优越的疗效，详见表3。对比沙瑞环素（sarecycline）、多西环素（doxycycline）和柯拉特龙（clascoterone）乳膏，地尼法司他的多个关键指标显示出优越的疗效。就经安慰剂校准的治疗成功百分比和经安慰剂校准的炎性皮损计数相对基线下降百分比而言，地尼法司他的疗效比沙瑞环素分别高98%和30%，比多西环素分别高178%和178%，以及比柯拉特龙乳膏分别高60%和59%。就经安慰剂校准的总皮损计数相对基线下降百分比而言，地尼法司他的疗效比多西环素和柯拉特龙乳膏分别高189%和85%。就经安慰剂校准的非炎性皮损计数相对基线下降百分比而言，地尼法司他的疗效比沙瑞环素和柯拉特龙乳膏分别高411%和102%。地尼法司他有望成为集疗效显著、患者依从性高、安全性和耐受性特征良好等优点于一体的同类首创、每日一次口服的痤疮药物。与其他口服痤疮药物相比，地尼法司他疗效显著且安全性高。无抗生素耐药性风险或脱靶效应（常见于四环素类药物），且未有报告地尼法司他相关的严重的不良事件，如肝毒性、听力障碍和抑郁症（这些见于异维A酸）。与外用药物相比，地尼法司他的患者依从性应当更高：据估计，约有30%至40%的患者不能遵医嘱完成外用治疗[1]。歌礼已从Sagimet Biosciences Inc.（纳斯达克股票代码：SGMT）获得地尼法司他的大中华区独家授权。复旦大学附属华山医院皮肤科主任医师、复旦大学皮肤病学研究所常务副所长、中国医师协会皮肤科医师分会副会长及地尼法司他中重度痤疮III期临床试验主要研究者项蕾红教授表示：地尼法司他的III期临床试验结果令人鼓舞，数据显示其针对中重度痤疮患者的治疗目标实现了统计学显著改善，33.2%的受试者实现治疗成功，总皮损、炎性皮损、非炎性皮损相比基线分别下降57.4%，63.5%和51.9%，且安全性和耐受性良好。地尼法司他通过独特的作用机制——抑制脂肪酸合成酶，靶向痤疮发病机制的关键通路，成为治疗痤疮具有该作用机制的全球首创。  [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.表1. 地尼法司他III期试验基线特征表2. 口服、每日一次50毫克地尼法司他第12周时对比安慰剂的疗效终点（意向治疗集（ITT）分析）注释：（1）所有疗效终点均为最小二乘均值。（2）治疗成功的定义为在第12周时，研究者总体评估（Investigator's Global Assessment，IGA）评分较基线下降至少2分，且IGA分级为0分（光洁）或1分（几乎光洁）。表3. 地尼法司他与其它常用痤疮药物对比（非头对头比较）注释：（1）沙瑞环素数据为两个III期临床试验数据平均值。数据来自Moore, A., et al., J Drugs Dermatol 2018 Vol. 17 Issue 9 Pages 987-996。非炎性皮损的数据来自FDA(https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209521Orig1s000MultidisciplineR.pdf)。（2）多西环素16周数据来自Moore, A., et al., J Drugs Dermatol 2015 Vol. 14 Issue 6 Pages 581-6。 （3）柯拉特龙乳膏(1%) 数据为两个III期临床试验数据平均值。数据来自Hebert. A, et al., JAMA Dermatology 2020 Vol. 156 Issue 6, DOI: 10.1001/jamadermatol.2020.0465。关于歌礼制药有限公司歌礼是一家在香港证券交易所上市（1672.HK）的创新研发驱动型生物科技公司，涵盖了从新药研发至GMP生产的完整价值链。歌礼的管理团队具备深厚的专业知识及优秀的过往成就，在团队的带领下，歌礼聚焦代谢性疾病，致力于解决尚未满足的医疗需求，并以全球化的视野进行布局。歌礼的代谢疾病管线拥有多款临床阶段在研药物。欲了解更多信息，敬请登录网站：www.ascletis.com。关于该临床试验（NCT06192264），可点击“阅读原文”查看详细信息！