Ascletis宣布NASH和HBV的四项临床和临床前研究摘要被国际肝大

StephenW

Ascletis Announced Four Clinical and Preclinical Study Abstracts of NASH and HBV Accepted as Poster Presentations by the International Liver Congress™ 2021

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Ascletis Pharma Inc.

Apr 11, 2021, 20:30 ET
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HANGZHOU, China and SHAOXING, China, April 11, 2021 /PRNewswire/ -- Ascletis Pharma Inc. (HKEX:1672) announces today that four clinical and preclinical study abstracts of NASH and HBV have been accepted by the International Liver Congress™ 2021 as poster presentations. The summary of the four abstracts are shown as below:

1. Title: Significant lipid lowering by ASC41 oral tablet，a liver targeted THR-β agonist，in a Phase I randomized，double-blind，placebo controlled single- and multiple-ascending dose study
(PRNewsfoto/Ascletis Pharma Inc.)

Abstract/poster number: 1851

Category: NAFLD therapy

Results: In the single-ascending dose portion of the study, preliminary data suggest that ASC41 is safe and well tolerated up to a dose of 20 mg. Furthermore, ASC41 tablet formulation showed a dose-proportional pharmacokinetic profile from 1 mg to 20 mg. In the multiple-ascending dose (MAD) portion of the study, preliminary data suggest that after 14 days of once daily oral dosing, subjects demonstrate clinically meaningful and statistically significant reduction in LDL-C and triglycerides compared to placebo, as shown in the table below.

Placebo-adjusted relative change (mean) from baseline after 14 days of once daily oral
dosing of ASC41 tablets

       

1 mg

(n=12)
       

2 mg

(n=12)
       

5 mg

(n=12)

Placebo-adjusted LDL-C

reduction

P-value vs placebo
       

-0.42%

P=0.947
       

-11.94%

P=0.052
       

-19.99%

P=0.002

Placebo-adjusted triglyceride reduction

P-value vs placebo
       

-39.43%

P=0.002
       

-31.06%

P=0.029
       

-34.49%

P=0.015

ASC41 had a benign adverse event profile at all doses following 14-day treatment, with no grade 3 or above adverse events, no serious adverse events or premature discontinuations. Furthermore, ASC41 tablet formulation displayed a dose-proportional pharmacokinetic profile from 1 mg to 5 mg following once daily, 14-day dosing.

Conclusion: These data supported advancement of the ASC41 clinical program for the indication of NASH.

2. Title: Significant improvement of NAFLD activity scores and liver fibrosis by ASC41, a selective THR-β agonist, in high fat diet induced NASH SD rats

Abstract/poster number: 1908

Category: NAFLD therapy

Results: ASC41 demonstrated dose-dependently reductions in liver steatosis, inflammatory cell infiltration, ballooning change and total non-alcoholic fatty liver disease activity score (NAS). ASC41 at 1.5 mg/kg and 4.5 mg/kg showed higher NAS reductions relative to MGL3196 at 5 mg/kg (P=0.01 and P<0.001). ASC41 at 0.5 mg/kg showed a 23.9% reduction in NAS score and a 14.4% reduction in liver fibrosis, similar to MGL3196 at 5 mg/kg. ASC41 at 1.5 mg/kg and 4.5 mg/kg both showed a significant decrease in serum LDL-C.

Conclusion: ASC41 demonstrated NAS reductions and anti-fibrotic benefits in the high fat diet induced NASH SD rats. The current efficacy data supported the advancement of ASC41 into clinical trials in human.

3. Title: Significant improvement of NAFLD activity scores and liver fibrosis by ASC42，a novel non-steroidal FXR agonist，in high fat diet induced NASH mice

Abstract/poster number: 1961

Category: NAFLD therapy

Results: ASC42 demonstrated dose-dependently reductions in liver steatosis, inflammatory cell infiltration, ballooning change and total non-alcoholic fatty liver disease activity score (NAS). ASC42 at 30 mg/kg showed a significantly higher NAS reduction relative to OCA at 30 mg/kg (P<0.001). ASC42 at 3 mg/kg showed a 46.2% reduction in NAS score and a 15.2% reduction in liver fibrosis, similar to OCA at 30 mg/kg. Total glyceride in liver exhibited a dose-proportional decrease in ASC42-treated mice.

Conclusion: ASC42 demonstrated NAS reductions and anti-fibrotic benefits in the mice NASH Model. These data supported the advancement of ASC42 into clinical trials in human.

4. Title: Significant in-vitro and in-vivo inhibition of HBsAg and HBV pgRNA with ASC42，a novel non-steroidal FXR agonist

Abstract/poster number: 1917

Category: Viral hepatitis A, B, C, D, E: virology

Results: In PHH model, the control compound ETV showed the expected inhibitory activity on HBV DNA, but had no inhibition on HBV pgRNA and HBsAg, while ASC42 inhibited HBsAg, HBV pgRNA, and HBV DNA dose-dependently, with EC50 of 0.79μM, 0.09μM and 0.62μM, respectively (Figure 1A-D). In AAV/HBV mice model, after ETV (0.1 mg/kg) monotherapy, HBV DNA in mice plasma decreased significantly, while HBV pgRNA and HBsAg showed no obvious reduction. ASC42 demonstrated a dose-dependent inhibition of HBV pgRNA, HBsAg, HBV DNA in mice plasma. High-dose group of ASC42 (60 mg/kg) inhibited HBV pgRNA, HBsAg, and HBV DNA by 0.60 log10 copy/μl (P<0.01), 0.38 log10 IU/μl (P =0.002), and 0.77 log10 copy/μl (P <0.05), respectively, relative to vehicle control group (Figure 1 E-F).

Conclusion: These in-vitro and in-vivo studies demonstrated that ASC42, a FXR agonist, significantly inhibited HBV DNA, HBV pgRNA and HBsAg, indicating that ASC42 has therapeutic potential to functional cure of HBV infection. The results support the advancement of ASC42 into clinical trials in human.

About Ascletis

Ascletis is an innovative R&D driven biotech and listed on Hong Kong Stock Exchange (1672.HK). Ascletis is committed to developing and commercializing innovative drugs in the areas of NASH, cancer lipid metabolism and oral checkpoint inhibitors, viral hepatitis and HIV/AIDS for unmet medical needs in China and globally. Led by a management team with deep expertise and a proven track record, Ascletis has developed into a fully integrated platform covering the entire value chain from discovery and development to manufacturing and commercialization.

Ascletis has three marketed products and seventeen R&D pipeline drug candidates or combination therapies (eleven of them developed in-house). 1. NASH: Gannex, a wholly-owned company of Ascletis, is fully dedicated to the R&D and commercialization of new drugs in the field of NASH. Gannex has three clinical stage drug candidates against three different targets – FASN, THR-beta and FXR, and three pre-clinical stage combination therapies. 2. Cancer lipid metabolism and oral checkpoint inhibitors: focus on a pipeline of oral inhibitors targeting FASN which plays a key role in cancer lipid metabolism and a pipeline of oral PD-L1 small molecule inhibitors as the next generation checkpoint inhibitors. 3. Viral hepatitis: (i) Hepatitis B: focus on breakthrough therapies for HBV clinical cure with subcutaneously injected PD-L1 antibody - ASC22 and Pegasys® as cornerstone drugs. (ii) Hepatitis C: successfully launched all oral regimen of ASCLEVIR® and GANOVO® combination (RDV/DNV regimen); and ASC18 fixed dose combination (FDC) is an upgraded version of RDV/DNV regimen with bridging study finished. 4. HIV/AIDS: ASC09F is a FDC treatment of HIV targeting protease. The clinical trial application of ASC09F has been approved. For more information, please visit www.ascletis.com.

SOURCE Ascletis Pharma Inc.

StephenW

Ascletis宣布NASH和HBV的四项临床和临床前研究摘要被国际肝大会2021接受为海报展示

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Ascletis Pharma Inc.

美国东部时间2021年4月11日，20：30
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美通社-PR Newswire / 2021年4月11日，中国杭州和绍兴/-Ascletis Pharma Inc.（HKEX：1672）今天宣布，NASH和HBV的四项临床和临床前研究摘要已被2021年国际肝病大会接受为海报展示。四个摘要的摘要如下所示：

1.标题：肝脏靶向THR-β激动剂ASC41口服片剂在I期随机，双盲，安慰剂控制的单次和多次递增剂量研究中显着降低了脂质
（PRNewsfoto / Ascletis Pharma Inc.）

摘要/海报号：1851

类别：NAFLD治疗

结果：在研究的单次上升剂量部分中，初步数据表明ASC41是安全的，并且耐受剂量高达20 mg。此外，ASC41片剂的剂量动力学曲线与剂量成正比，范围为1毫克至20毫克。在该研究的多次上升剂量（MAD）部分中，初步数据表明，与口服安慰剂相比，每天一次口服给药14天后，受试者表现出LDL-C和甘油三酸酯的临床意义降低，并具有统计学意义以下。

每日一次口服14天后，由安​​慰剂调整过的相对于基线的相对变化（平均值）
ASC41片剂的剂量



1毫克

（n = 12）


2毫克

（n = 12）


5毫克

（n = 12）

安慰剂调整的LDL-C

减少

P值与安慰剂


-0.42％

P = 0.947


-11.94％

P = 0.052


-19.99％

P = 0.002

安慰剂调整的甘油三酸酯减少

P值与安慰剂


-39.43％

P = 0.002


-31.06％

P = 0.029


-34.49％

P = 0.015

ASC41在14天治疗后所有剂量下均具有良性不良事件，无3级或以上不良事件，无严重不良事件或过早停药。此外，ASC41片剂在每天一次，14天给药后显示出从1毫克到5毫克的剂量比例药代动力学特征。

结论：这些数据支持了用于指示NASH的ASC41临床计划的进展。

2.标题：高脂饮食诱导的NASH SD大鼠通过选择性THR-β激动剂ASC41显着改善NAFLD活性评分和肝纤维化

摘要/海报号：1908

类别：NAFLD治疗

结果：ASC41表现出剂量依赖性地降低了肝脂肪变性，炎性细胞浸润，球囊改变和总非酒精性脂肪肝疾病活动评分（NAS）。与5 mg / kg的MGL3196相比，1.5 mg / kg和4.5 mg / kg的ASC41显示出更高的NAS降低（P = 0.01和P <0.001）。与0.5 mg / kg的MGL3196相似，0.5 mg / kg的ASC41显示NAS得分降低23.9％，肝纤维化降低14.4％。 1.5 mg / kg和4.5 mg / kg的ASC41均显示血清LDL-C显着降低。

结论：ASC41在高脂饮食诱导的NASH SD大鼠中表现出NAS减少和抗纤维化的作用。当前的功效数据支持ASC41进入人体临床试验的进展。

3.标题：新型非甾体FXR激动剂ASC42在高脂饮食诱导的NASH小鼠中显着改善NAFLD活性评分和肝纤维化

摘要/海报编号：1961

类别：NAFLD治疗

结果：ASC42证明剂量依赖性地降低了肝脂肪变性，炎性细胞浸润，球囊改变和总非酒精性脂肪肝疾病活动评分（NAS）。相对于30 mg / kg的OCA，30 mg / kg的ASC42显示出NAS降低显着更高（P <0.001）。与30 mg / kg的OCA相似，3 mg / kg的ASC42显示NAS得分降低46.2％，肝纤维化降低15.2％。肝脏中的总甘油酯在ASC42处理的小鼠中呈剂量比例降低。

结论：ASC42在小鼠NASH模型中显示出NAS减少和抗纤维化的益处。这些数据支持了ASC42在人体临床试验中的发展。

4.标题：新型非甾体FXR激动剂ASC42对HBsAg和HBV pgRNA的显着体内和体外抑制作用

摘要/海报编号：1917

类别：甲，乙，丙，丁，戊型病毒性肝炎：病毒学

结果：在PHH模型中，对照化合物ETV对HBV DNA表现出预期的抑制活性，但对HBV pgRNA和HBsAg无抑制作用，而ASC42剂量依赖性地抑制HBsAg，HBV pgRNA和HBV DNA，EC50为0.79μM，分别为0.09μM和0.62μM（图1A-D）。在AAV / HBV小鼠模型中，ETV（0.1 mg / kg）单药治疗后，小鼠血浆HBV DNA显着下降，而HBV pgRNA和HBsAg没有明显降低。 ASC42在小鼠血浆中显示了对HBV pgRNA，HBsAg，HBV DNA的剂量依赖性抑制。高剂量ASC42组（60 mg / kg）抑制HBV pgRNA，HBsAg和HBV DNA 0.60 log10 copy /μl（P <0.01），0.38 log10 IU /μl（P = 0.002）和0.77 log10 copy /μl （P <0.05）分别相对于媒介物对照组（图1 EF）。

结论：这些体外和体内研究表明，FXR激动剂ASC42可以显着抑制HBV DNA，HBV pgRNA和HBsAg，表明ASC42对功能性治愈HBV感染具有治疗潜力。结果支持ASC42进入人体临床试验的进展。

关于Ascletis

Ascletis是一家创新的研发驱动型生物技术，已在香港联合交易所（1672.HK）上市。 Ascletis致力于在NASH，抗癌脂质代谢和口服检查点抑制剂，病毒性肝炎和HIV / AIDS等领域开发创新药物并将其商业化，以满足中国乃至全球的医疗需求。在拥有深厚专业知识和可靠记录的管理团队的带领下，Ascletis已发展成为一个完全集成的平台，涵盖了从发现，开发到制造和商业化的整个价值链。

Ascletis有3种上市产品和17种研发中的候选药物或联合疗法（其中11种是在公司内部开发的）。 1. NASH：Gannex是Ascletis的全资公司，完全致力于NASH领域中新药的研发和商业化。 Gannex针对三种不同目标（FASN，THR-beta和FXR）具有三种临床阶段候选药物，以及三种临床前阶段联合疗法。 2.癌症脂质代谢和口服检查点抑制剂：专注于针对FASN的一系列口服抑制剂，FASN在癌症脂质代谢中起关键作用，以及作为下一代检查点抑制剂的口服PD-L1小分子抑制剂。 3.病毒性肝炎：（i）乙型肝炎：专注于突破性疗法，以皮下注射的PD-L1抗体-ASC22和Pegasys®作为基础药物，可用于HBV临床治愈。 （ii）丙型肝炎：成功实施了ASCLEVIR®和GANOVO®联合治疗的所有口服方案（RDV / DNV方案）； ASC18固定剂量组合（FDC）是RDV / DNV方案的升级版，已完成桥接研究。 4. HIV / AIDS：ASC09F是FDC治疗HIV靶向蛋白酶。 ASC09F的临床试验应用已获得批准。有关更多信息，请访问www.ascletis.com。

消息来源Ascletis Pharma Inc.

StephenW

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