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标题: A Study Evaluating GS-9620 in Treatment Naive Subjects With Chronic Hepatitis B [打印本页]

作者: kennyu    时间: 2012-5-26 23:33     标题: A Study Evaluating GS-9620 in Treatment Naive Subjects With Chronic Hepatitis B

    A Study Evaluating GS-9620 in Treatment Naive Subjects With Chronic Hepatitis B
                         This study is currently recruiting participants.   
                              Verified December 2011 by Gilead Sciences   
            
      First Received on April 30, 2012.            Last Updated on May 2, 2012        History of Changes      
  

Sponsor:

Gilead Sciences

Information provided by (Responsible Party):

Gilead Sciences

ClinicalTrials.gov Identifier:

NCT01590641

    Purpose  

Dose cohorts may be dosed with one of up to 4 possible total weekly doses (0.3 mg, 1 mg, 2 mg, 4 mg). Dose escalation or repetition will be governed by pre-specified safety and activity rules. Subjects will be confined on either days 1-3 or days 1-3 and 8-10. Follow-up visits are also required periodically through day 43, and potential viral load follow-up visits at weeks 3 and 6 months post last dose. Study procedures involve blood draws for pharmacokinetic, pharmacodynamic, virologic, and safety assessments



      

  
        Condition              Intervention              Phase      
                Hepatitis B
                HBV
              
                Drug: Single Ascending Dose (SAD) Cohorts GS-9620
                Drug: Multiple Ascending Dose (MAD) Cohorts
              
                Phase 1
              
  

  
              
Study Type:

Interventional

Study Design:

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment

Official Title:

A Double-Blind, Randomized, Placebo-Controlled, Single and Multiple- Dose Ranging, Adaptive Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antiviral Activity of GS-9620 in Treatment Naive Subjects With Chronic Hepatitis B Virus Infection


作者: 咬牙硬挺    时间: 2012-5-27 06:44

效果如何呢
作者: kennyu    时间: 2012-5-27 18:16

回复 咬牙硬挺 的帖子

你难道就不会 google + gs-9620 一下吗?

作者: StephenW    时间: 2012-5-27 18:20

回复 咬牙硬挺 的帖子

他们正在招募,将在2013年报告.
作者: scilab    时间: 2012-5-27 19:05

回复 StephenW 的帖子

开始二期临床了?
作者: StephenW    时间: 2012-5-27 20:10

本帖最后由 StephenW 于 2012-5-27 20:11 编辑

回复 scilab 的帖子

说是为第1阶段, 但所有的参与者都是乙型肝炎患者, 不同剂量将被测试.

作者: 候月    时间: 2012-5-27 21:44

GS-9620对黑猩猩慢性HBV感染的疗效
作者:龙华 译
来源:EASL 2011网站
日期:2011-04-03

  已知激活TLR7可促进干扰素和免疫刺激因子生成,并激活先天性和获得性免疫。GS-9620是一种高效选择性口服TLR7小分子量激动剂,开发用于慢性HBV及HCV感染的治疗。美国圣安东尼奥市西南生物医学研究基金会的Lanford等报告了一项在慢性HBV感染黑猩猩中,评价GS-9620疗效的研究结果,显示GS-9620单药治疗可诱导治疗性抗病毒免疫应答,病毒载量降低伴随着细胞因子及趋化因子应答以及肝脏淋巴细胞浸润。而且对于高病毒滴度的动物,随访期间也可见病毒载量持续受抑。这些结果证实GS-9620具有用于慢性HBV感染治疗的潜力。

  研究中,3只有慢性HBV感染大猩猩被给予GS-9620口服,1 mg/kg,每周3次,共4周,随后2 mg/kg,每周3次再治疗4周。使用LC/MS/MS法确定GS-9620血清浓度,检测血清HBV DNA、HBsAg、HBeAg、CBC和血生化,并使用流式细胞仪分析淋巴细胞亚群的激活,通过点阵仪(Luminex)、肝脏组织学检查和免疫组化分析以及干扰素刺激基因(ISG)的诱导,确定肝脏和血液中细胞因子和趋化因子的水平。

  结果显示,3只动物接受GS-9620治疗后,病毒载量降低了2.0 log,相应血清HBsAg水平降低了50%~61%,HBeAg降低了58%~93%。病毒载量至少降低1 log的持续时间为64天至121天以上,后者指对治疗前高病毒载量动物的监测结束时。使用1 mg/kg剂量即有显著的药代动力学应答,使用2 mg/kg剂量时药代动力学应答进一步增强,ISG增加超过100倍。治疗增加了活化的血液淋巴细胞和NK细胞数量以及凋亡的肝细胞数量,并使肝脏内淋巴细胞浸润逆转。治疗的耐受性良好,不良反应是可逆的,并符合免疫介导的对嗜肝病毒感染的应答。


作者: 咬牙硬挺    时间: 2012-5-28 23:16

感谢楼上的帖子,期待一下似乎可以
作者: 希望奇迹    时间: 2012-5-29 08:01

充满希望!
作者: StephenW    时间: 2012-6-14 07:50

本帖最后由 StephenW 于 2012-6-14 07:51 编辑

Public release date: 13-Jun-2012


Contact: Mika Ono

[email protected]

858-784-2052
Scripps Research Institute

Scripps research scientists show lack of single protein results in persistent viral infection        

                                           IMAGE:                 Michael B. A. Oldstone, Ph.D., is a Professor in the Scripps Research Institute Department of Immunology and Microbial Science.
        
              Click here for more information.                     


LA JOLLA, CA – June 13, 2012 -- Scientists from The Scripps Research Institute have shown a single protein can make the difference between an infection clearing out of the body or persisting for life. The results also show where the defects occur in the immune system without the protein and offer the possibility that targeting this signaling pathway could be beneficial for treatment of persistent viral infections in humans.  Currently hundreds of millions of people around the world are afflicted with persistent viral infections such as HIV, HCV, and HBV.
        The new study is published in the June 14, 2012 issue of the journal Cell Host & Microbe.
        In the new study, a team led by Scripps Research Professor Michael Oldstone showed what happened when a mouse engineered without the protein TLR7 was infected with lymphocytic choriomeningitis virus (LCMV), a virus employed to study the response of the immune system to microbes. While normal mice infected with a LCMV variant called Cl 13 could clear a persistent infection in 60 to 90 days, TLR7-deficient mice were unable to purge the infection throughout their lives.
        "It is well known that RNA from many viruses, including influenza, HIV, and hepatitis C, induce signaling through TLR7," said Kevin Walsh, a research associate in Oldstone's lab and the first author of the study. "We demonstrated that TLR7 plays a significant role in the generation of immune responses required to clear persistent LCMV infection."
        'Biological Warfare'
        In terms of the constant biological warfare between host and microbes, the body is not so much a temple as it is a medieval city. An infectious agent can invade through the skin or mucosa, essentially scaling the walls. Once it's inside it has to deal with the body's first responders, called Toll-like receptors (TLR). These receptors are a pattern-recognition system to alert the immune system.  TLRs form the first line of defense specifically by recognizing molecules of the invading pathogen.
        Ten TLRs have been identified in humans. One of these, TLR7, is located inside the cell within endosomes and the RNA of viruses are detected after they have entered the cell. "TLR7 is a very important receptor in terms of viruses," noted Oldstone.
        In the current study, the researchers chose to use LCMV to understand the role of TLR7. LCMV is, according to Oldstone, "has been, and continues to be a Rosetta Stone to explain basic concepts in immunology and virology."
        Once it was clear that the absence of TLR7 compromised the immune system's ability to clear LCMV infection, Oldstone, Walsh, and their colleagues explored what was happening downstream of the receptor.
        Interestingly, the research demonstrated that even when immune memory cells, which "learn" to fight an infection and impart long-term immunity, were transferred from TLR7-sufficient mice to TLR7-deficient mice, those deficient mice still couldn't clear the infection.
        "The environment within TLR7-deficient mice suppressed the ability of these memory cells to clear the infection," said Walsh.
        Surprisingly Tired Cells
        The team noticed several unexpected things.  First, in the TLR7-deficient mice, there was a profusion of tired T cells. "You see more T cells in TLR7-deficient mice early after infection, but they don't actually clear the infection," said Walsh. "Even though there were more of them, they were less functional."  Second, immune system B cells were severely hampered; specifically, the differentiation and maturation of B cells to plasma cells, cells responsible for generating antiviral antibody, was aborted.  Thus, both essential arms of the immune system, cellular and humoral, required to clear viral infection were compromised.
        Exhausted T cells produce fewer molecules to attack and destroy infected cells. Exhaustion occurs in TLR7-sufficient environments, too—but in those cases there is a resurrection of the T cells 60 to 90 days following infection with LCMV Cl 13, which allows the body to purge the virus. In the TLR7-deficient environment, this resurrection never happens. The exhausted T cells linger, as does the infection. T cell exhaustion is also found in HIV and hepatitis B and C infection.
        "A number of phenomena that LCMV uses to cause a persistent infection is the same that HIV, hepatitis C and B use," said Oldstone. "That's what makes our observation important.  It means that if you understood what is in the environment with loss of TLR7 signaling and how to correct that, you'd have a better chance of treating those persistent human infections. We know how to treat it in the mouse, and people are working very hard to do the treatments in humans."
        

###

In addition to Oldstone and Walsh, authors of the paper, "Toll-like receptor 7 is required for effective adaptive immune responses that prevent persistent virus infection," were John R. Teijaro, Megan J. Welch, Daniel M. Fremgen, and Karl von Tiehl of Scripps Research; Elina I. Zuniga of the University of California, San Diego; Shawn D. Blackburn and E. John Wherry of the University of Pennsylvania School of Medicine; and Richard A. Flavell of Yale University.
        This research was supported by the US National Institutes of Health.

作者: StephenW    时间: 2012-6-14 07:52

公开发布日期:2012年6月13日

联系人:米卡小野
[email protected]
858-784-2052
斯克里普斯研究所
斯克里普斯研究所的科学家缺乏单一的蛋白质结果表明,在持续性病毒感染



图像:迈克尔BA Oldstone,博士,是一个在斯克里普斯研究所的免疫学和微生物学教授。

拉霍亚加州 -  2012年6月13日 - 来自斯克里普斯研究所的科学家已经证明可以使一个单一的蛋白质之间的清理身体,或坚持对生命的感染的差异。研究结果还表明,在免疫系统中的缺陷的蛋白质发生不和提供的可能性,针对这一信号通路可能是有利于人类的持久性病毒感染的治疗。目前,数百名世界各地的数以百万计的人患有如艾滋病毒,丙肝病毒和乙肝病毒持续感染。

这项新的研究发表在2012年6月14日的Cell杂志上的主机和微生物问题。

由斯克里普斯研究的迈克尔Oldstone教授领导的研究小组在新的研究表明,发生了什么事时,鼠标的设计没有蛋白质TLR7的淋巴细胞性脉络丛脑膜炎病毒(LCMV),来研究微生物免疫系统的反应病毒感染。虽然可以清除持久性感染,在60至90天称为CL 13 1下LCMV变种感染正常小鼠,TLR7的基因缺陷小鼠无法清除其整个生命的感染。

“众所周知,许多病毒,包括流感,艾滋病毒和丙型肝炎RNA,通过TLR7的诱导信号,说:”凯文·沃尔什,在Oldstone的实验室的研究助理和研究的第一作者。 “我们证明,TLR7的发挥需要清除持久LCMV感染的免疫反应产生的一个重要的角色。”

“生物战”

在不断宿主和微生物之间的生物战方面,身体是没有这么多的寺庙,因为它是一个中世纪的城市。传染性病原体可以通过皮肤或粘膜侵入,实质上扩大了墙壁。一旦这里面有处理身体的第一反应,被称为Toll样受体(TLR)。这些受体是模式识别系统,以提醒免疫系统。 TLRs的形成第一道防线,特别是通过识别入侵的病原体的分子。

已确定在人类十大TLRs的。其中之一,TLR7的,位于内侧的内细胞内涵体和病毒的RNA进入细胞后,他们已经检测。 “TLR7的是非常重要的受体在病毒方面,指出:”Oldstone。

目前的研究中,研究人员选择使用下LCMV了解的TLR7的作用。下LCMV是,根据Oldstone的“,一直是并将继续是一个罗塞塔石碑,说明在免疫学和病毒学的基本概念。”

它曾经是清楚的TLR7的情况下,削弱免疫系统的能力,以清除LCMV感染,Oldstone,沃尔什,和他们的同事探讨发生了什么事的受体下游。

有趣的是,研究表明TLR7的自给自足的小鼠转移TLR7的缺陷小鼠免疫记忆细胞,其中“学习”,以对抗感染和传播长期免疫力,即使被这些缺陷小鼠仍然无法清除感染。

“内TLR7的基因缺陷小鼠的环境,抑制这些记忆细胞的能力,以清除感染,”沃尔什说。

令人惊讶的是疲惫的细胞

该小组发现了一些意想不到的事情。首先,在TLR7的基因缺陷小鼠,有丛生的疲惫的T细胞。 “你看到更多的T细胞在TLR7的基因缺陷小鼠在感染后早期,但它们实际上并不清除感染,”沃尔什说。 “即使有更多的人,他们是功能少。”二,免疫系统的B细胞受到严重阻碍;具体地说,浆细胞的分化和成熟B细胞,细胞产生抗病毒抗体,被中止。因此,破坏免疫系统的两个基本武器,细胞免疫和体液,需要清除病毒感染。

耗尽的T细胞产生较少的攻击和摧毁感染细胞的分子。用尽发生TLR7的自给自足的环境,但在这些案件中,有一个T细胞的复活下LCMV CL 13,从而使人体清除病毒感染后的60至90天。在TLR7的缺乏的环境中,这种复活从未发生过。精疲力竭的T细胞流连忘返,作为感染。还发现,在艾滋病毒和乙型和丙型肝炎病毒感染的T细胞耗竭。

他说:“一些现象,下LCMV使用造成持续感染艾滋病毒,丙型肝炎和B使用Oldstone,说:”是相同的。 “这是什么使我们的观察是重要的。这意味着,如果你的理解是什么样的TLR7信号的损失,以及如何纠正这种环境中,你就会有一个更好的治疗那些持久的人类感染的机会。”我们知道如何对待它在小鼠,人很努力做人类的治疗方法。“
###

“梅根研究韦尔奇,约翰·R·Teijaro,丹尼尔研究Fremgen,和卡尔在除了要Oldstone和沃尔什的论文作者,有效,防止持续性病毒感染的适应性免疫反应的要求,”Toll样受体7斯克里普斯研究所的冯Tiehl;埃利娜一祖尼加,圣迭戈加利福尼亚大学的肖恩D.布莱克本和E.宾夕法尼亚大学医学院的约翰·惠里和耶鲁大学的理查德·A·弗拉维尔。

这项研究是由美国国立卫生研究院的支持。
作者: MP4    时间: 2012-6-14 20:37

scripps又出招了。
作者: cwy121    时间: 2012-6-14 21:36

还是人家美国牛逼,即使人家称霸人家也有那资本,现在你说中国能整出来啥,培养的学生都是贪污腐败,无能的后备军——简直是前赴后继!
不喜欢美国的霸气,但是你不能不服人家的科学水平。中国应该好好的反思,不是一味的抹黑,一味的政治斗争。期待好消息。
作者: lin12345    时间: 2012-6-15 09:29

多谢分享
作者: kennyu    时间: 2012-6-19 23:22

回复 StephenW 的帖子

我现在其实不是非常怀疑GS9620的疗效。因为,从gilead的研发策略上看,明显能感觉到乙肝治疗进入了后抗病毒时代。也就是说,抗病毒作为一个标准治疗步骤被固定下来,而进口缩短抗病毒的时间及用药的副作用是下一步的研发重点。gilead现在在研的两款药物就重点关注这两点。

我比较担心gs9620的副作用,我曾经看到过一个美国小公司做TLR-9的agonist,(治疗哮喘?还是黑色素瘤?)结果病人会出现淋巴组织增生。。。。

这种药物对免疫系统的影响是未知的,也是风险所在。

作者: StephenW    时间: 2012-6-19 23:50

本帖最后由 StephenW 于 2012-6-19 23:51 编辑

回复 kennyu 的帖子

你是对的,副作用是重要的考虑因素。据Medhelp的studyforhope,Gilead公司尝试一系列的剂量,希望能找到“甜蜜点(sweet spot)”。




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