AASLD2019[697]口服TLR8激动剂GS-9688的功效和安全性 慢性抑制病毒

StephenW

EFFICACY AND SAFETY OF ORAL TLR8 AGONIST GS-9688
IN VIRALLY-SUPPRESSED ADULT PATIENTS WITH CHRONIC
HEPATITIS B: A PHASE 2, RANDOMIZED, DOUBLE-BLIND
PLACEBO-CONTROLLED, MULTI-CENTER STUDY
Edward J. Gane1, Yang Zhao2, Susanna Tan2, Audrey H Lau2,
Anuj Gaggar2, Mani Subramanian2, Shyam Kottilil3 and Lydia
Tang4, (1)University of Auckland, (2)Gilead Sciences, Inc,
Foster City, California, USA, (3)Division of Clinical Care and
Research, Institute of Human Virology, University of Maryland
School of Medicine, Baltimore, MD, USA, (4)Division of
Clinical Care and Research, Institute of Human Virology,
University of Maryland School of Medicine
Background: GS-9688 is an oral selective small molecule
agonist of Toll-like receptor 8 (TLR8) in clinical development for
the treatment of chronic hepatitis B (CHB) Here we evaluate
the safety and efficacy of GS-9688 in CHB patients who were
virally suppressed on an oral antiviral (OAV). Methods: In this
multicenter, randomized, double-blind, phase 2 study of GS-
9688 in virally suppressed CHB patients on OAV, 48 patients
were enrolled in two cohorts (HBeAg-positive and HBeAgnegative)
evaluating 3.0 mg, 1.5 mg, and placebo (2:2:1) of
GS-9688 once a week (QW) for 24 weeks in combination with
OAV. Safety assessments included monitoring of adverse
events (AE) and laboratory abnormalities. The primary efficacy
endpoint was the proportion of patients with ≥ 1 log10 IU/mL
decline in HBsAg levels from baseline at week 24 Secondary
endpoints include the proportion of patients with HBsAg and
HBeAg loss and changes in pharmacodynamic (PD) markers,
IL-1RA and IL-12p40 Results: Baseline characteristics of
the 48 patients were similar across groups (table) Safety
and pharmacodynamic parameters are also summarized
in the table. Grade ≥ 3 AE were observed in 0%, 10%, and
0% of patients treated with 3 0 mg, 1 5 mg, and placebo,
respectively One patient in the study (HBeAg-negative,
1.5mg group) achieved the primary endpoint of ≥ 1 log10 IU/
mL decline in HBsAg levels at week 24 One patient in the
study (HBeAg-negative, 3 mg group) achieved HBsAg loss
and another patient (HBeAg-positive, 1 5 mg group) achieved
HBeAg loss at week 24 Dose-dependent increases in serum
IL-1RA and IL-12p40 in the GS-9688 treatment groups were
observed Conclusion: Oral GS-9688 is safe, well-tolerated,
and induced dose-dependent PD changes in CHB patients
5% of patients experienced either ≥ 1 log10 IU/mL decline in
HBsAg levels or HBsAg loss at week 24 Further evaluation
of immunologic, antiviral, and pharmacodynamics markers
through week 48 are underway.

StephenW

口服TLR8激动剂GS-9688的功效和安全性
慢性抑制病毒感染的成人患者
乙型肝炎：第2阶段，随机，双盲
场所控制的多中心研究
Edward J. Gane1，Yang Zhao，Susanna Tan2，Audrey H Lau2，
Anuj Gaggar2，Mani Subramanian2，Shyam Kottilil3和Lydia
Tang4，（1）奥克兰大学，（2）Gilead Sciences，Inc，
美国加利福尼亚州福斯特市（3）临床护理和
马里兰大学人类病毒学研究所研究
美国马里兰州巴尔的摩医学院，（4）
人类病毒研究所，临床护理和研究，
马里兰大学医学院
背景：GS-9688是一种口服选择性小分子
Toll样受体8（TLR8）激动剂在临床开发中的应用
慢性乙型肝炎（CHB）的治疗
GS-9688在CHB患者中的安全性和有效性
被口服抗病毒药物（OAV）抑制。方法：在此
GS-的多中心，随机，双盲，2期研究
接受OAV病毒抑制的CHB患者中9688例，48例
被纳入两个队列（HBeAg阳性和HBeAgnegative）
评估3.0毫克，1.5毫克和安慰剂（2：2：1）的
GS-9688每周一次（QW），连续24周，与
OAV。安全评估包括监测不良事件
事件（AE）和实验室异常。主要功效
终点是≥1 log10 IU / mL的患者比例
第24周时HBsAg水平较基线水平下降
终点包括HBsAg和
HBeAg丢失和药效学（PD）标记的变化，
IL-1RA和IL-12p40结果：基线特征
各组的48例患者相似（表）
并总结了药效学参数
在桌子上。 AE≥3级的发生率分别为0％，10％和
0％的患者接受3 0 mg，1 5 mg和安慰剂治疗，
分别是研究中的一名患者（HBeAg阴性，
1.5mg组）的主要终点≥1 log10 IU /
第24周时HBsAg水平下降100 mL
研究（HBeAg阴性，3 mg组）达到HBsAg丢失
另一名患者（HBeAg阳性，1 5 mg组）达到
第24周HBeAg丢失血清剂量依赖性增加
GS-9688治疗组的IL-1RA和IL-12p40为
观察到的结论：口服GS-9688安全，耐受性好，
慢性乙型肝炎患者的剂量变化和诱导的剂量依赖性PD
5％的患者出现≥1 log10 IU / mL的下降
第24周时HBsAg水平或HBsAg丢失进一步评估
，抗病毒和药效学标记的比较
到第48周为止。