GS-4774 作为病毒抑制慢性乙型肝炎患者治疗性疫苗的随机 II 期研究,Journal of Hepatology

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GS-4774 作为病毒抑制慢性乙型肝炎患者治疗性疫苗的随机 II 期研究
Journal of Hepatology ( IF 26.8 ) Pub Date : 2016-09-01 , DOI: 10.1016/j.jhep.2016.05.016
Anna S Lok ₁ , Calvin Q Pan ₂ , Steven-Huy B Han ₃ , Huy N Trinh ₄ , W Jeffrey Fessel ₅ , Timothy Rodell ₆ , Benedetta Massetto ₇ , Lanjia Lin ₇ , Anuj Gaggar ₇ , G Mani Subramanian ₇ , John G McHutchison ₇ , Carlo Ferrari ₈ , Hannah Lee ₉ , Stuart C Gordon ₁₀ , Edward J Gane ₁₁

Affiliation

背景和目的 GS-4774 是一种热灭活、基于酵母的 T 细胞疫苗，旨在引发乙型肝炎病毒 (HBV) 特异性 T 细胞反应。我们评估了 GS-4774 在慢性 HBV 感染患者中的安全性、耐受性和有效性。方法在这项 II 期研究中，178 名慢性 HBV 感染且无肝硬化且口服抗病毒药物 (OAV) 被病毒抑制 ⩾1 年的患者被随机分配 (1:2:2:2) 继续单独使用 OAV 或接受 OAV 加 GS -4774 每 4 周皮下注射 2、10 或 40 个酵母单位 (YU)，直到第 20 周。在研究的其余部分继续 OAV。通过从基线到第 24 周血清乙型肝炎表面抗原 (HBsAg) 的下降来衡量疗效。结果各组之间的基线特征相似（平均年龄 45-50 岁；男性，62-74%；亚洲人，68-80%；乙型肝炎e抗原（HBeAg）阳性，24-26%；平均 HBsAg，2.5-3.1log10IU/ml）。从基线到第 24 周或第 48 周，各组之间的平均 HBsAg 下降没有显着差异。五名接受 GS-4774 的 HBeAg 阳性患者经历了 HBeAg 消失，而对照组则没有。三名接受 GS-4774 40 YU 治疗的患者 HBsAg 下降⩾0.5log10IU/ml，但没有患者出现血清 HBsAg 下降。没有发生病毒学突破。注射部位反应是最常见的不良事件 (AE)，并且没有中断治疗。结论 GS-4774 具有良好的耐受性，但并未显着降低病毒抑制的慢性乙型肝炎患者的血清 HBsAg。GS-4774 在未接受治疗的患者中的疗效仍有待确定。概述 GS-4774 是一种治疗性疫苗，旨在改善已经慢性感染 HBV 的患者对乙型肝炎病毒 (HBV) 的免疫反应。在这项研究中，GS-4774 在接受口服抗病毒治疗的慢性 HBV 感染患者中是安全且耐受良好的，但没有带来临床益处。与其他药物的联合方法以及在其他 HBV 患者人群中的评估正在进行中，以确定 GS-4774 是否可能具有治疗益处。临床试验注册号 NCT01943799。与其他药物的联合方法以及在其他 HBV 患者人群中的评估正在进行中，以确定 GS-4774 是否可能具有治疗益处。临床试验注册号 NCT01943799。与其他药物的联合方法以及在其他 HBV 患者人群中的评估正在进行中，以确定 GS-4774 是否可能具有治疗益处。临床试验注册号 NCT01943799。

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Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B

BACKGROUND & AIMS GS-4774 is a heat-inactivated, yeast-based, T-cell vaccine designed to elicit hepatitis B virus (HBV)-specific T-cell responses. We evaluated the safety, tolerability and efficacy of GS-4774 in patients with chronic HBV infection. METHODS In this phase II study, 178 patients with chronic HBV infection and no cirrhosis who were virally suppressed on an oral antiviral (OAV) for ⩾1year were randomized (1:2:2:2) to continue OAV alone or receive OAV plus GS-4774 2, 10, or 40 yeast units (YU) subcutaneously every 4weeks until week 20. OAV was continued for the remainder of the study. Efficacy was measured by decline in serum hepatitis B surface antigen (HBsAg) from baseline to week 24. RESULTS Baseline characteristics were similar across groups (mean age, 45-50years; male, 62-74%; Asian, 68-80%; hepatitis B e antigen (HBeAg)-positive, 24-26%; mean HBsAg, 2.5-3.1log10IU/ml). There were no significant differences between groups in mean HBsAg declines from baseline to week 24 or 48. Five HBeAg-positive patients receiving GS-4774 experienced HBeAg loss vs. none in the control group. Three GS-4774 40 YU-treated patients had HBsAg declines ⩾0.5log10IU/ml, but no patient experienced loss of serum HBsAg. No virologic breakthrough occurred. Injection site reactions were the most frequent adverse event (AE), and there were no treatment discontinuations. CONCLUSIONS GS-4774 was well tolerated, but did not provide significant reductions in serum HBsAg in virally suppressed patients with chronic hepatitis B. Efficacy of GS-4774 in treatment-naïve patients remains to be determined. LAY SUMMARY GS-4774 is a therapeutic vaccine designed to improve the immune response against hepatitis B virus (HBV) in patients who already have chronic infection with HBV. In this study, GS-4774 was safe and well tolerated in patients with chronic HBV infection receiving oral antiviral therapy, but did not result in a clinical benefit. Combination approaches with other agents, and evaluation in other populations of patients with HBV are ongoing to determine if GS-4774 might have a therapeutic benefit. CLINICAL TRIAL REGISTRATION NUMBER NCT01943799.

更新日期：2016-09-01

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