ASC-41

--Up to 68.2% mean relative reduction in liver fat content from baseline among biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) patients receiving 12-week treatment of ASC41 --Significant and clinically meaningful reductions in liver fat, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lipids as well as excellent safety and tolerability profile demonstrated by ASC41 in MASH patients HANGZHOU, China, June 10, 2024 /PRNewswire/ -- Gannex Pharma Co., Ltd. ("Gannex"), a wholly-owned company of Ascletis Pharma Inc. (HKEX:1672, "Ascletis") dedicated to the research and development and commercialization of new drugs in the field of metabolic dysfunction-associated steatohepatitis (MASH), today announced a poster presentation at the European Association for the Study of the Liver (EASL) Congress 2024, held June 5-8, 2024 in Milan, Italy. A copy of the poster is available under the Posters/Publications page of Gannex's website at . The poster presentation titled, "ASC41, a selective THRβ agonist significantly reduces liver fat and ALT in biopsy-confirmed MASH patients after 12-week treatment: an interim analysis of a 52-week serial liver biopsy study", describes significant and clinically meaningful reductions in liver fat, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in biopsy-confirmed MASH patients receiving 12-week treatment of ASC41 tablet, among which the data of ALT and AST notably differentiates ASC41 from other thyroid hormone receptor β (THRβ) agonists currently at clinical or commercial stages. In addition, baseline characteristics from Phase II clinical trials were comparable between ASC41, conducted in China, and resmetirom, except for lower body mass index (BMI) and more males for ASC41. Please refer to Table 1 below for more details. Table 1. Baseline Characteristics ASC41, a once-daily oral tablet, is a liver targeted small molecule and is highly THRβ-selective. The oral tablet formulation was developed utilizing Ascletis' in-house proprietary technology. Three Phase I or Ib studies in China were completed in healthy or obese subjects with elevated low-density lipoprotein cholesterol (LDL-C) > 110 mg/dL. A U.S. Phase I study demonstrated no clinically significant drug-drug interactions between ASC41/ASC41-A and most frequently used antidepressants and statins, as well as no significant difference in drug exposure between Americans and Chinese at the same dose. Table 2. Changes from Baseline (CFB) in LFC, Liver Enzymes and Lipids Biomarkers at Week 12 "93.3% of patients receiving treatment with ASC41 experienced at least 30% relative reduction from baseline in liver fat content as assessed by magnetic resonance imaging, proton density fat fraction (MRI-PDFF), which we believe is a strong predictor of fibrosis reduction." said Dr. Jinzi J. Wu, Founder, Chairman and CEO of Ascletis, "Reductions in liver inflammatory biomarkers ALT and AST, important for assessing hepatic injury and malfunction, LDL-C, total cholesterol (TC) and triglyceride (TG), which may reduce the risk of cardiovascular-related events, combined with an excellent safety and tolerability profile support our belief that ASC41 is a potentially best-in-class THRβ agonist. We look forward to continuing the clinical development of ASC41." ASC41 was generally well tolerated, with adverse events (AEs) being grade 1 in majority across all cohorts in the Phase II clinical trial, including the placebo cohort (see Table 3). No treatment-related serious adverse event (SAE) was reported in any patients receiving ASC41 treatment or placebo. As in prior studies, ASC41 demonstrated excellent gastrointestinal (GI) tolerability. Table 3. Safety Data About ASC41 ASC41, a once-daily oral tablet in clinical development for the treatment of MASH, is a liver targeted small molecule which is converted into its active metabolite, ASC41-A, a potent and highly selective THRβ agonist. ASC41 tablet was developed using Ascletis' in-house proprietary formulation technology. The patent of ASC41 tablet formulation has been granted in the U.S. About the Phase II Clinical Trial The randomized, double-blind, placebo-controlled and multi-center Phase II clinical trial (ClinicalTrials.gov: NCT05462353) is being conducted in China and is expected to enroll approximately 180 liver biopsy-confirmed MASH patients to be randomized into two treatment cohorts of ASC41 tablet (2 mg or 4 mg), once-daily and one placebo control cohort at the ratio of 1:1:1 for 52-week treatment and 4-week follow-up. Enrollment included patients with at least 7.5% liver fat content at baseline as measured by MRI-PDFF, as well as F2 and F3 liver fibrosis. The study allows up to 15% of enrolled patients to have F1 liver fibrosis. Two liver biopsies will be performed, one at baseline and the other at the end of 52-week treatment. MRI-PDFF will be performed at baseline, Week 12 and Week 52, respectively. The pre-specified interim analysis was conducted when 42 enrolled patients completed 12-week treatment of ASC41 tablet or placebo. Primary objective is a histological reduction in nonalcoholic fatty liver disease (NAFLD) activity score (NAS) ≥ 2 points that results from reduction of necro-inflammation (inflammation or ballooning) without worsening fibrosis. Secondary objectives include MASH resolution and fibrosis improvement. 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 focuses on three therapeutic areas with unmet medical needs from a global perspective: viral diseases, MASH and oncology. Through excellent execution, Ascletis rapidly advances its drug pipeline with an aim of leading in global competition. To date, Ascletis has multiple clinical stage drug candidates in its R&D pipeline. The most advanced drug candidates include ASC22 (CHB functional cure), ASC40 (acne), ASC40 (recurrent glioblastoma), ASC40 (MASH), ASC41 (MASH) and ASC61 (advanced solid tumors). For more information, please visit . About Gannex Pharma Co., Ltd. Founded in 2019, Gannex is a clinical-stage, wholly-owned company of Ascletis, dedicated to the R&D and commercialization of new drugs in the field of MASH. Gannex has two clinical-stage drug candidates against two different targets, i.e. THRβ (ASC41) and fatty acid synthase (FASN) (ASC40). For more information, please visit . SOURCE Ascletis Pharma Inc.

非酒精性脂肪性肝炎（NASH）也称代谢性脂肪性肝炎（MASH），是非酒精性脂肪肝病（NAFLD）的一种严重形式，对肝细胞产生应激和损伤，可进展为肝硬化、肝衰竭和肝细胞癌。当下患脂肪肝的人群愈发广泛，进展为NASH的患者比例高达约15%-25%。但是由于发病机制复杂以及临床终点认证困难，NASH领域长期面临着“病人多，药少”的窘境。直至今年，FDA批准了生物医药公司Madrigal开发的口服小分子药物Resmetirom，成为FDA批准上市的首款NASH新药。如今，窘境迎曙光，而且还有多种类型的NASH新药已处于不同临床阶段。据不完全统计，有8家中国药物研发企业的11条候选药物管线已进入到2期及以后的临床研究中，有望为NASH患者带来更多治疗选择。其中，有以下特点值得关注：集中在主要靶点：目前所开发的NASH药物管线主要集中在5大主流靶点：FXR，THR-β，GLP-1R，FGF21和PPAR。THR-β成药性已得到验证：今年刚刚获批上市的Resmetirom正是THR-β激动剂。自此，该靶点的成药性得以验证，临床数据更优的候选管线将备受关注。开发路径以小分子制剂为主流：进入2期临床及以后的管线中，大部分为小分子制剂。仅正大天晴的AP025和东阳光药的HEC88473为融合蛋白。而且维亚臻生物的VSA006是其中仅有的小核酸类型的候选药物。拉尼兰诺，AP025正大天晴成立于1997年，是一家从事医药创新和高品质药品的研发、生产与销售的创新型医药集团，为中国生物制药的附属核心企业，致力于为患者提供更佳的健康解决方案和优质可负担的医药资源。公司于2022年9月授权引进Inventiva的核心产品拉尼兰诺（lanifibranor），用于治疗非酒精性脂肪性肝炎（NASH）和其他潜在的代谢疾病。拉尼兰诺是一种口服小分子药物，通过激活三种过氧化物酶体增殖物激活受体（PPAR）亚型在体内调节抗纤维化、抗炎症通路，有益于血管和代谢变化。PPAR是能调节与脂质代谢、血糖稳态和胰岛素信号转导相关的多个过程的核素受体。作为一种PPAR激动剂，该产品在以中等效力靶向所有三种PPAR亚型， 包括平衡激活PPARα和PPARδ、部分激活PPARγ。FDA和CDE均已授予拉尼兰诺用于NASH的突破性疗法认证。此外，公司于同年授权引进了安源医药的NASH新药AP025。AP025是安源医药依托于自主知识产权构建融合蛋白的连接肽技术研发出的一款全人源长效FGF21融合蛋白。拉尼ZSP1601众生睿创（Raynovent）成立于2018年10月，是众生药业的控股子公司。公司专注于呼吸系统和代谢性疾病领域创新药物研发与商业化。基于对呼吸系统和代谢性疾病病理生理的理解与洞见，众生睿创聚焦于研发流感、新冠、禽流感、特发性肺纤维化、NASH、2型糖尿病和体重管理等重大疾患和公共卫生问题的全新疗法。公司开发的用于治疗NASH的一类小分子创新药物ZSP1601目前正在开展2b期临床研究，ZSP1601是一种泛磷酸二酯酶（PDE）抑制剂，具有全新作用机制和全球自主知识产权，有成为“First-In-Class”药物的潜力。此前，ZSP1601的早期临床数据表明其药代动力学特性和安全性良好，在炎症、肝脏脂肪、纤维化等多个指标获得积极的结果，结果已于2023年10月发表在Nature communications期刊。众生睿创已完成多轮融资，最新的C轮融资于2022年12月完成，融资额达3.7亿元，由宜德基金和倚锋资本共同领投，万联广生、广州国聚创投跟投，众生药业及清池资本继续追加投资。▲众生睿创融资历史（图片来源：即刻药数）西格列他微芯生物于2001年3月成立，是小分子创新药研发企业。微芯生物以满足临床未被满足的需求为首任，致力于为患者提供可承受的创新机制的治疗药物。公司自主设计、合成、筛选和开发的西格列他是新一代过氧化物酶增殖体活化相关受体（PPAR）全激动剂，可适度平衡激活PPARα、γ和δ三个受体亚型。该药物已于2021年获得中国国家药品监督管理局（NMPA）批准上市，用于治疗2型糖尿病，也成为全球首个获批治疗2型糖尿病的PPAR全激动剂。目前，其单药治疗NASH的2期临床研究（CGZ203研究）已完成数据清理并锁库，已达成试验首要疗效终点。HTD1801君圣泰是一家全球一体化的新型生物技术公司，专注代谢性疾病、消化系统疾病等领域的重大未满足临床需求。公司立足源头创新，以患者的综合临床获益和整体健康改善为目标，开发“First-in-Class”、多功能、多适应症的原创新药。基于自主知识产权，公司已构建丰富产品管线，在全球推进多项中、后期临床试验，开发代谢异常性脂肪性肝炎（MASH）、2型糖尿病（T2DM）、严重高甘油三酯血症（SHTG）、原发性硬化性胆管炎（PSC）和原发性胆汁性胆管炎（PBC）等适应症。公司的核心产品管线HTD1801作为肠肝抗炎及代谢调节剂，靶向调节对人体代谢过程中至关重要的多个通路，包括与代谢及消化系统疾病相关的通路。HTD1801是由两个活性成分小檗硷及熊去氧胆酸组成的含离子键的盐，这两种活性成分在中医治疗肠道及肝脏疾病上有悠久的用药历史；通过公司的研究发现，以盐的形式协同作用具有独特的微观结构以形成明确且更优的特性。HTD1801目前正在开展代谢异常性脂肪性肝炎（MASH）的全球多中心2b期临床试验，并且已获得FDA快速通道资格认定。公司于2023年12月港股IPO，募得资金2.78亿港元用于其核心产品管线的开发。IPO之前，公司历经多轮融资。▲君圣泰融资历史（图片来源：即刻药数）ASC40，ASC41成立于2013年，歌礼是一家创新研发驱动型生物科技公司，涵盖了从新药研发至生产和商业化的完整价值链。公司聚焦三大临床需求尚未满足的医疗领域：病毒性疾病、非酒精性脂肪性肝炎和肿瘤，并以全球化的视野进行布局。歌礼目前拥有多款在研药物，其中有两款针对NASH的治疗：ASC40和ASC41。ASC40是歌礼从Sagimet授权引进的脂肪酸合成酶（FAS）抑制剂，2b期临床试研究结果达到了双重主要终点，NASH各项关键标志物有统计学意义上的显著减少，包括肝脏脂肪含量、炎症和纤维化标志物。ASC41是一款小分子肝脏靶向性前体药物，其活性代谢产物可选择性激活甲状腺激素受体β（THR-β），目前处于2期临床研究中并取得了积极的期中结果：12周时，高剂量ASC41组患者的肝脏脂肪含量较基线的相对降幅平均值高达68.2%，安慰剂组降幅为13.1%。HEC88473，HEC96719东阳光药是一家专注于抗病毒、内分泌及代谢性疾病、心血管疾病等治疗领域产品开发、生产及销售的中国制药企业。目前公司有两款在研管线针对NASH的治疗：HEC88473和HEC96719，均处于2期临床研究阶段。HEC88473是东阳光自主研发的Fc融合蛋白双重激动剂，将GLP-1和FGF21分子连接形成双靶蛋白，GLP-1单靶点药物主要应用于2型糖尿病患者血糖调节和减重治疗，而FGF21主要表达于肝脏，是NASH的重要靶点，在糖脂代谢调节中起着关键的作用；有望产生降糖、减重协同效果。HSK31679海思科是一家专注于新药研发，集生产制造及销售推广为一体的专业化医药集团，总部位于成都。公司研发聚焦围手术期、肿瘤、免疫、糖尿病及并发症等疾病领域，目前已经建立一系列自主知识产权药物管线，多个创新药项目正处于临床试验阶段。其中公司自主研发的HSK31679是一种高选择性甲状腺激素β受体（THR-β）激动剂，通过与甲状腺激素β受体结合，影响脂代谢过程中的关键步骤，起到降血脂和肝脏脂肪的作用。临床拟用于治疗NASH，目前处于2期临床研究中。VSA006维亚臻成立于2022年，是由Arrowhead Pharmaceuticals与维梧资本共同成立一家合资公司。Arrowhead Pharmaceuticals授予维亚臻在大中华区开发和商业化该公司4种针对心脏代谢疾病的在研RNA干扰（RNAi）药物的独家权利。目前公司产品管线拥有三款处于临床研发阶段，针对心血管及代谢领域的小核酸药物。此外，公司拥有自主研发能力，将在肝内及肝外递送技术、以及更广阔的治疗领域进行探索。其中VSA006是维亚臻自主开发的一款靶向肝细胞内羟基类固醇17-β脱氢酶13（HSD17β13）的小干扰RNA（siRNA）药物。全基因组关联研究表明， HSD17β13的功能缺失基因突变可以降低NASH患者从肝炎进展为肝纤维化或肝癌的风险。已完成的早期临床研究试验评估了VSA006对正常健康志愿者和确诊或临床怀疑NASH患者的影响，结果表明VSA006治疗耐受性良好，无治疗相关严重不良事件或停药。VSA006可显著降低肝脏HSD17β13 mRNA和蛋白水平，同时有效降低患者丙氨酸转氨酶（ALT）水平。成立之初，维梧资本曾投资6000万美元，作为合资公司的初始资金。▲维亚臻融资历史（图片来源：即刻药数）读者们请星标⭐创鉴汇，第一时间收到推送免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转发/复制至其他平台。转发授权请在「创鉴汇」微信公众号留言联系我们。更多数据内容推荐点击“在看”，分享创鉴汇健康新动态