EASL2012:GS-9620 INDUCES A PRESYSTEMIC INNATE IMMUNE RESPONSE IN THE ABSENCE OF

StephenW

Abstract               
                                

Title	GS-9620 INDUCES A PRESYSTEMIC INNATE IMMUNE RESPONSE IN THE ABSENCE OF SERUM INTERFERON OR ADVERSE EFFECTS IN BOTH NON-CLINICAL SPECIES AND HUMANS
Speaker:	Abigail   Fosdick
Author:	D. Tumas1, A. Fosdick1*, X. Zheng1, R. Lanford2, J. Hesselgesser1, C. Frey1, W. Grushenka1, R. Halcomb1, U. Lopatin1
Affiliation:	1Gilead Sciences Inc., Foster City, CA, 2Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA. *[email protected]
Background: The side effects associated with interferon-α (IFN-α) make it a challenging therapeutic option for many patients with chronic HBV or HCV infection. Therefore, we are a developing a potent Toll-like receptor 7 (TLR-7) agonist, GS-9620, as an oral immunomodulatory agent capable of inducing an antiviral immune response at the level of the liver and gut associated lymphoid tissue (GALT) without induction of systemic IFN-α or its side effects. (i.e. a “pre-systemic” response). Aim: To demonstrate that low oral doses of the TLR-7 agonist GS-9620 can induce a pre-systemic innate immune response in the liver in the absence of induction of systemic IFN-α. Methods: Single and/or multiple doses of GS-9620 were evaluated in mice, cynomolgus monkeys, chimpanzees (uninfected and HBV infected) and human healthy volunteers (0.3 to 12 mg doses). Pharmacokinetics, pharmacodynamic responses (serum IFN-α, cytokines and interferon stimulated genes (ISGs) in blood and/or liver), and safety parameters were evaluated. Results: At a similar serum Cmax exposure level, oral administration of GS-9620 provides a markedly greater serum IFN-a response than does intravenous administration. In cynomolgus monkeys and normal and HBV-infected chimpanzees, low oral doses of GS-9620 induced ISGs in the liver and/or in circulating blood cells with no increase in serum levels of IFN-α and caused a reduction of viral load in infected animals. In healthy humans, low oral doses of GS‑9620 (< 8 mg) induced a similar pre-systemic ISG response with neither detectable serum IFN-α nor adverse effects including signs or symptoms associated with systemic IFN-α. [Figure 1] Conclusions: In preclinical species, oral administration of GS-9620 induced more IFN-α than intravenous administration relative to GS-9620 exposure. This suggests that cells in the GALT and/or liver can be stimulated to induce a locally restricted TLR7 response following oral administration of GS-9620. In support of this hypothesis, following low oral doses of GS-9620 ISG induction was found in blood cells in the absence of either detectable serum IFN-α or adverse effects associated with systemic levels of IFN-α in normal and chronically HBV-infected non-human primates as well as in healthy human volunteers.

StephenW

标题GS-9620诱导一个PRESYSTEMIC的先天免疫反应的血清干扰素或不良影响的非临床的物种和人类的情况下
主讲人：阿比盖尔福斯迪克
答：Fosdick1：D. Tumas1，十Zheng1 R. Lanford2，研究Hesselgesser1 C Frey1，W·Grushenka1，R. Halcomb1，U。Lopatin1
单位：1Gilead科学公司的Foster City，CA，美国德克萨斯州圣安东尼奥得克萨斯州生物医学研究所，病毒学和免疫学教研室。 * abigail.fosdick @ gilead.com
背景：一边与α-干扰素（IFN-α）的影响，使许多与慢性乙型肝炎病毒或丙型肝炎病毒感染患者的治疗选择一个具有挑战性的。因此，我们是一个发展中的一个强有力的电话像7受体（TLR-7）激动剂，GS-9620，作为一种口服免疫调节剂，能诱导抗病毒免疫反应在肝脏的水平和肠道相关淋巴组织（GALT）没有诱导全身α-干扰素或它的副作用。 （即“预全身”的反应）。
目的：要证明的TLR-7激动剂GS-9620的低剂量口服可诱发前，全身在肝脏中缺乏系统性α-干扰素诱导先天免疫反应。
评估方法：GS-9620单和/或多个剂量的老鼠，猕猴，黑猩猩（未受感染和乙肝病毒感染）和人类的健康志愿者（0.3至12毫克的剂量）。药代动力学，药效学反应（血清α-干扰素，细胞因子和干扰素刺激基因（ISGs）在血液和/或肝），安全参数进行了评价。
结果：在一个类似血清的Cmax暴露水平，口服GS-9620提供了一个显着更大的血清IFN-反应比静脉给药。在猕猴和正常和HBV感染的黑猩猩，低剂量口服GS-9620在肝脏和/或诱导无血清α-干扰素的增加循环血细胞ISGs，造成感染动物的病毒载量减少。人类在健康，GS-9620（<8毫克）口服低剂量诱导标志或相关的症状与全身α-干扰素既不检测血清α-干扰素，也没有不良影响，包括类似的预全身的ISG响应。

图1
[图1]


结论：在临床前的品种，诱导口服GS-9620 GS-9620曝光相对比静脉注射α-干扰素。这表明，在GALT的和/或肝细胞可以刺激引起局部限制TLR7的反应后，口服GS-9620。为了支持这一假说，GS-9620的ISG感应后，低剂量口服血细胞中被发现，无论是检测血清IFN-α或全身α-干扰素水平在正常和慢性乙肝病毒感染的非关联的不利影响的情况下人类的灵长类动物以及在健康人的志愿者。

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