持续的疗效和血清转换与Toll样受体激动剂7 GS-9620在慢性乙型

StephenW

Research Article
Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B

• Stephan Menne1, , †, ,
• Daniel B. Tumas2, †,
• Katherine H. Liu3,
• Linta Thampi1,
• Dalal AlDeghaither1,
• Betty H. Baldwin3,
• Christine A. Bellezza3,
• Paul J. Cote1,
• Jim Zheng4,
• Randall Halcomb5,
• Abigail Fosdick6,
• Simon P. Fletcher2,
• Stephane Daffis2,
• Li Li7,
• Peng Yue7,
• Grushenka H.I. Wolfgang6,
• Bud C. Tennant3
  

• 1 Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
• 2 Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States
• 3 Department of Clinical Sciences, Gastrointestinal Unit, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States
• 4 Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States
• 5 Department of Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States
• 6 Department of Drug Safety Evaluation, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States
• 7 Department of Biomarkers, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States
  

Received 23 September 2014, Revised 26 November 2014, Accepted 19 December 2014, Available online 2 January 2015

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doi:10.1016/j.jhep.2014.12.026Get rights and content
  Open Access

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Background & Aims

New therapies for chronic hepatitis B (CHB) are urgently needed since current treatments rarely lead to cure. We evaluated whether the oral small molecule toll-like receptor (TLR7) agonist GS-9620 could induce durable antiviral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to human hepatitis B virus (HBV).

Methods

After evaluating the pharmacokinetics, pharmacodynamics and tolerability of oral GS-9620 in uninfected woodchucks, adult woodchucks chronically infected with WHV (n = 7 per group) were dosed with GS-9620 or placebo for 4 or 8 weeks with different treatment schedules.

Results

GS-9620 treatment induced rapid, marked and sustained reduction in serum viral DNA (mean maximal 6.2 log10 reduction), and hepatic WHV DNA replicative intermediates, WHV cccDNA and WHV RNA, as well as loss of detectable serum WHV surface antigen (WHsAg). GS-9620 treatment also induced a sustained antibody response against WHsAg in a subset of animals. Strikingly, treatment reduced the incidence of hepatocellular carcinoma (HCC) from 71% in the placebo group to 8% in GS-9620-treated woodchucks with sustained viral load reduction. GS-9620 treatment was associated with reversible increases in serum liver enzymes and thrombocytopenia, and induced intrahepatic CD8+ T cell, NK cell, B cell and interferon response transcriptional signatures.

Conclusions

The data demonstrate that short duration, finite treatment with the oral TLR7 agonist GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB, and support investigation of this compound as a therapeutic approach to attain a functional cure in CHB patients.

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Graphical abstract

StephenW

研究论文
持续的疗效和血清转换与Toll样受体激动剂7 GS-9620在慢性乙型肝炎的土拨鼠模型

    斯蒂芬Menne1，†，丹尼尔B. Tumas2，†，凯瑟琳H.柳，林塔Thampi1，达拉尔AlDeghaither1，贝蒂H. Baldwin3，恭A. Bellezza3，保罗J. Cote1，吉姆Zheng4，兰德尔Halcomb5，阿比盖尔Fosdick6，西蒙P.的fletcher2，斯特凡Daffis2，李LI7，彭Yue7，Grushenka HI Wolfgang6，芽C. Tennant3

    微生物学与免疫学，乔治敦大学医学中心，华盛顿特区20057，美国1系
    生物学，吉利德科学系2，公司，333湖滨驱动器，福斯特市，CA 94404，美国
    临床科学系3，胃肠部，兽医，康奈尔大学，纽约州14853，美国学院
    药物代谢，吉利德科学公司，333湖滨驱动器，福斯特市，CA 94404，美国4部
    化学，吉利德科学公司，333湖滨驱动器，福斯特市，CA 94404，美国5系
    药物安全性评价，吉利德科学公司，333湖滨驱动器，福斯特市，CA 94404，美国6系
    生物标志物，吉利德科学公司，333湖滨驱动器，福斯特市，CA 94404，美国7系

    收到2014年9月23日，修订2014年11月26日，接受2014年12月19日，可在线2015年1月2日

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        DOI：10.1016 / j.jhep.2014.12.026
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背景与目的

迫切需要新的治疗慢性乙型肝炎（CHB），因为目前的治疗很少导致治愈。我们评估了口服小分子toll样受体（TLR7）激动剂GS-9620是否可以诱导在慢性感染土拨鼠肝炎病毒（WHV）旱獭耐久抗病毒效力，肝DNA病毒密切相关的人乙型肝炎病毒（HBV）。
方法

评估药代动力学，药效学和口服GS-9620在未感染的土拨鼠耐受性后，成人土拨鼠慢性感染WHV（每组n = 7）给药GS-9620或安慰剂治疗4周或8周的不同的治疗方案。
结果

GS-9620治疗诱导的快速，标记和持续减少血清病毒DNA（平均最大6.2日志10减少），和肝WHV DNA复制中间体，WHV cccDNA的和WHV的RNA，以及可检测的血清WHV表面抗原（WHsAg）的损失。 GS-9620治疗也诱导在动物中的一个子集对WHsAg持续的抗体应答。引人注目的是，治疗的71％，而安慰剂组减少肝细胞癌（HCC）的发生率，以8％的GS-9620处理的土拨鼠用持续的病毒载量下降。 GS-9620治疗与可逆增加血清肝酶和血小板减少，并诱导肝内CD8 + T细胞，NK细胞，B细胞和干扰素反应转录签名。
结论

该数据表明，短的持续时间，与口腔TLR7激动剂GS-9620有限治疗可诱导在慢性乙型肝炎的土拨鼠模型的持续的抗病毒反应，以及该化合物作为治疗方法以达到慢性乙型肝炎患者的官能固化的支持调查。