科学研究

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Boyle, JG, et al., Clinical Science (2018) 132 1699–1709


甘莱成立于2019年9月,专注于开发代谢功能障碍相关脂肪性肝炎(MASH)领域相关创新药,满足国内外患者需求。甘莱为歌礼制药有限公司(1672.HK)旗下全资子公司。


甘莱有两款分别针对脂肪酸合成酶(FASN)、甲状腺激素ß受体(THRß)的处于临床阶段的代谢功能障碍相关脂肪性肝炎候选药物。

ASC40:口服脂肪酸合成酶(FASN)抑制剂


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ASC40在MASH患者中治疗的疗效及安全性

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Rohit Loomba et al. 2020, Hepatology 72; 103.EASL 2020 Oral Presentation


• ASC40显著抑制肝内新生脂肪合成(DNL),通过12周治疗可使61%的患者肝内脂肪水平降低超过30% 

• ASC40降低肝内炎症反应程度,降低血清ALT水平 

• ASC40改善TIMP1、PIIINP等纤维化标志物水平,延缓肝脏纤维化进程


ASC41:肝脏靶向THR-β受体激动剂

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• ASC41为肝脏靶向前体药物在肝脏内经CYP3A4代谢为有效活性成分ASC41-A

• ASC41-A靶向肝内THR-β受体,低剂量暴露于其他表达THR的器官,如甲状腺、肌肉、大脑、脂肪 

• 相较于MGL-3196, ASC41对THR-β 受体结合亲和力以及处理能力更强(6倍/22倍)

• 2 种不同的MASH动物模型试验中,ASC41显示出与10倍剂量Resmetirom (MGL-3196)相同的NAS评分和肝纤维化改善


ASC41 I 期临床试验数据


• 研究对象为65位低密度脂蛋白胆固醇(LDL-C)大于110 mg/dL的具有非酒精性脂肪性肝病(NAFLD)特征的受试者 

• 在单剂量递增的研究中,随着给药剂量从1 mg到20 mg,ASC41的体内药物暴露量(药代动力学)呈线性关系,且在高达20 mg的剂量组中仍表现出良好的安全性和耐受性 

• 在多剂量递增的临床研究中,经过14天每日口服一次ASC41片剂治疗后,给药组受试者的低密度脂蛋白胆固醇(LDL-C)和甘油三酯(TG)指标相对安慰剂组表现出具有临床意义和统计学显著性的降低,如下图所示:


ASC41 1期临床试验.png


• 在14天治疗中,ASC41在所有剂量组中无3级或以上不良事件、严重不良事件或提前停药事件发生 

• 在14天每日口服一次ASC41片剂的研究中,随着给药剂量从1 mg到5 mg,ASC41片剂的体内药物暴露量(药代动力学)呈线性关系






学术发表


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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欧洲肝病学会(EASL)年会   (International Liver Congress™ 2024)海报6/2024

ASC41, a thyroid hormone receptor β agonist, showed little drug interaction, significant lipid reduction and comparable pharmacokinetic profiles among Chinese and US healthy subjects and patients with non-alcoholic fatty liver disease (NAFLD): results from two phase 1 studies

2023年美国肝病研究协会(AASLD)年会(The Liver Meeting® 2023)海报11/2023
A Phase Ib Study to Evaluate the   Safety, Tolerability and Pharmacokinetics of ASC 41 a THR-β Agonist, for   28-days in Overweight and Obese Subjects with Elevated LDL-C, a Population   with Characteristic s Of NAFLD2021年美国肝病研究协会(AASLD)年会(The  Liver Meeting® 2021)海报11/2021

Significant lipid lowering by ASC41, an oral tablet, liver-targeted THRβ agonist, in a phase I randomized, double-blind, placebo controlled single- and multiple-ascending dose study

欧洲肝病学会(EASL)年会   (International Liver Congress™ 2021)海报04/2021

Significant Improvement of NAFLD Activity Scores and Liver Fibrosis by ASC41, a Selective THR-β Agonist, in High Fat Diet Induced NASH SD Rats

欧洲肝病学会(EASL)年会   (International Liver Congress™ 2021)海报04/2021

Novel, first-in-class, fatty acid synthase inhibitor, TVB-2640 versus placebo demonstrates clinically significant reduction in liver fat by MRI-PDFF in NASH

2020年美国肝病研究协会(AASLD)年会(The   Liver Meeting® 2020)口头报告11/2020

Novel, first-in-class, fatty acid synthase inhibitor, TVB-2640 versus placebo demonstrates clinically significant reduction in liver fat by MRI-PDFF in NASH

欧洲肝病学会(EASL)年会(International Liver Congress™ 2020)口头报告08/2020

The FASN inhibitor TVB-2640 is efficacious in a new 3D human liver microtissue model of NASH

欧洲肝病学会(EASL)年会(International Liver Congress™ 2020)海报08/2020
Fatty Acid Synthase Inhibitor TVB-2640 Reduces   Hepatic de Novo Lipogenesis in Males With Metabolic AbnormalitiesHepatology   2020论文07/2020
Progressive   Reductions in Hepatic DNL with Increasing Doses of TVB-2640, a First-in-Class   Pharmacologic Inhibitor of FASNKeystone Symposium on Organ Crosstalk in Obesity and NAFLD海报01/2018
Establishing the foundation for a novel, first-in-class, fatty acid synthase inhibitor, TVB-2640, for the treatment of NASH欧洲肝病学会(EASL)年会 (International Liver Congress™   2017)海报04/2017