AASLD2018[456]对口服的药效学反应 管理选择性Toll样 受体8激动

StephenW

456
Pharmacodynamic Response to Oral
Administration of the Selective Toll-like
Receptor 8 Agonist GS-9688 in Healthy
Volunteers
Ethan Grant1, Adarsh Joshi2, Natarajan Ayithan3, Stephane
Daffis4, Jacky Woo5, Tina Lam6, Richard L Mackman7, Simon
Fletcher4, Anuj Gaggar8, Audrey H. Lau9, Shyamasundaran
Kottilil10 and Bhawna Poonia11, (1)Biomarker Sciences, Gilead
Sciences, Inc., (2)Biostatistics, Gilead Sciences, Inc., (3)
Division of Clinical Care and Research, Institute of Human
Virology, University of Maryland School of Medicine, (4)
Virology, Gilead Sciences, Inc., (5)Gilead Sciences, Inc., (6)
Biomarker Operations, Gilead Sciences, Inc., (7)Medicinal
Chemistry, Gilead Sciences, Inc., (8)Gilead Sciences, Inc,
Foster City, California, USA, (9)Clinical Research, Gilead
Sciences, Inc., (10)Division of Clinical Care and Research,
Institute of Human Virology, University of Maryland School
of Medicine, Baltimore, MD 21201, (11)Division of Clinical
Care and Research, Institute of Human Virology, Institute of
Human Virology, University of Maryland School of Medicine,
Baltimore, MD 21201
Background: GS-9688 is an oral selective small molecule
agonist of toll-like receptor 8 (TLR8) currently in clinical
development for the treatment of chronic hepatitis B (CHB).
A single ascending dose Phase 1a study (GS-US-389-2021)
in healthy volunteers demonstrated that oral GS-9688
induced a dose-dependent increase in serum IL-12p40 and
IL-1RA. Here we describe an extensive evaluation of the
pharmacodynamic (PD) response in this study. Methods:
Healthy volunteers (n=11 placebo; n=12 per GS-9688 group)
received a single oral dose of GS-9688 (placebo, 0.5 mg, 1.5
mg, 3 mg or 5 mg). Serum and peripheral blood mononuclear
cells (PBMC) samples were collected at baseline and at
various times after GS-9688 dosing. Serum levels of 89
different proteins were analyzed by high sensitivity ELISA
and multiplexed Luminex panels. PBMCs were analyzed by
flow cytometry. Results: Oral GS-9688 induced a statistically
significant and dose-dependent increase in serum levels of
immunomodulatory (e.g. IL-12p70) and antiviral (e.g. IFN-g
and TNF-a) cytokines, as well as a variety of chemokines
and acute phase proteins (Table 1). Cytokine and chemokine
levels peaked 2–4 hours post-dose, and returned to near
baseline by 24 hours post-dose. Induction of acute phase
proteins C-reactive protein (CRP) and serum amyloid A (SAA)
displayed slower kinetics, with highest levels measured 24
hours post-dose. In addition to these soluble factors, oral GS-
9688 increased the frequency of NK and mucosal associated
invariant T (MAIT) cells expressing the early activation marker
CD69. Conclusion: Oral GS-9688 induced serum levels of
immunomodulatory and antiviral cytokines, and activated NK
and MAIT cells in the periphery. GS-9688 also induced acute
phase proteins, consistent with activation of intrahepatic
cells, as well as chemokines (e.g. CXCL9, CXCL10) with
the potential to induce trafficking of activated T cells and NK
cells into the liver. Together, these data support further clinical
development of GS-9688 in CHB patients.

StephenW

456
对口服的药效学反应
管理选择性Toll样
受体8激动剂GS-9688健康
志愿者
Ethan Grant1，Adarsh Joshi2，Natarajan Ayithan3，Stephane
Daffis4，Jacky Woo5，Tina Lam6，Richard L Mackman7，Simon
Fletcher4，Anuj Gaggar8，Audrey H. Lau9，Shyamasundaran
Kottilil10和Bhawna Poonia11，（1）生物标记科学，吉利德
Sciences，Inc.，（2）Biostatistics，Gilead Sciences，Inc。，（3）
人体研究所临床护理与研究处
马里兰大学医学院病毒学，（4）
病毒学，Gilead Sciences，Inc。，（5）Gilead Sciences，Inc。，（6）
Biomarker Operations，Gilead Sciences，Inc。，（7）Medicinal
化学，Gilead Sciences，Inc。，（8）Gilead Sciences，Inc，
美国加利福尼亚州福斯特城，（9）临床研究，吉利德
Sciences，Inc。，（10）临床护理和研究部，
马里兰大学人类病毒学研究所
医学，巴尔的摩，MD 21201，（11）临床分部
中国人类病毒研究所护理研究所
马里兰大学医学院人类病毒学，
巴尔的摩，MD 21201
背景：GS-9688是一种口服选择性小分子
Toll样受体激动剂8（TLR8）目前处于临床阶段
开发治疗慢性乙型肝炎（CHB）。
单次递增剂量1a期研究（GS-US-389-2021）
在健康志愿者中证明口服GS-9688
诱导剂量依赖性增加血清IL-12p40和
IL-1RA。在这里，我们描述了一个广泛的评估
本研究中的药效学（PD）反应。方法：
健康志愿者（n = 11安慰剂;每个GS-9688组n = 12）
接受单次口服剂量的GS-9688（安慰剂，0.5mg，1.5
mg，3mg或5mg）。血清和外周血单核细胞
在基线和50℃收集细胞（PBMC）样品
GS-9688给药后不同时间。血清水平89
通过高灵敏度ELISA分析不同的蛋白质
和多路复用的Luminex面板。通过分析PBMC
流式细胞术。结果：口服GS-9688诱导了统计学意义
血清水平显着和剂量依赖性增加
免疫调节剂（例如IL-12p70）和抗病毒剂（例如IFN-g
和TNF-α）细胞因子，以及各种趋化因子
和急性期蛋白质（表1）。细胞因子和趋化因子
剂量在给药后2-4小时达到峰值，并回到附近
给药后24小时的基线。诱导急性期
蛋白C反应蛋白（CRP）和血清淀粉样蛋白A（SAA）
显示较慢的动力学，测量最高水平24
给药后数小时。除了这些可溶性因子，口服GS-
9688增加了NK和粘膜相关的频率
表达早期活化标记的不变T（MAIT）细胞
CD69。结论：口服GS-9688可诱导血清白蛋白水平升高
免疫调节和抗病毒细胞因子，和激活NK
和周围的MAIT细胞。 GS-9688也诱发急性
相蛋白，与肝内激活一致
细胞，以及趋化因子（如CXCL9，CXCL10）
诱导活化T细胞和NK的运输的可能性
细胞进入肝脏。这些数据共同支持进一步的临床
在CHB患者中开发GS-9688。