vebicorvir 在病毒学抑制的慢性乙型肝炎病毒感染患者中的安全

StephenW

vebicorvir 在病毒学抑制的慢性乙型肝炎病毒感染患者中的安全性和有效性

    袁文峰
    科什·阿加瓦尔
    马晓丽
    雅各布·P·拉莱扎里
    斯科特·K·冯
    马克·S·苏科夫斯基
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开放存取发布时间：2022 年 4 月 20 日DOI：https://doi.org/10.1016/j.jhep.2022.04.005


强调

    •
    完全抑制 HBV 复制对于有限的治疗方案至关重要。
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    Vebicorvir (VBR) 是一种新型的 HBV 核心蛋白抑制剂。
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    与 NrtIs 相比，VBR 干扰 HBV 复制的两个额外步骤。
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    添加到 NrtI 后，VBR 在 24 周内没有显着改变平均 HBV 抗原。
    •
    添加到 NrtI 后，VBR 通过高灵敏度 PCR 检测进一步减少了 HBV DNA 和 pgRNA。

背景与目标
HBV 核苷（酸）类逆转录酶抑制剂 (NrtIs) 不能完全抑制 HBV 复制。先前的报告表明，尽管无法检测到 HBV DNA，但在 NrtI 治疗期间仍存在持续的病毒血症。 HBV 核心抑制剂与 NrtIs 联合使用时可增强病毒抑制作用。这项 II 期试验 (NCT03576066) 评估了在研核心抑制剂 vebicorvir (VBR) 在使用 NrtIs 的病毒学抑制患者中的疗效和安全性。
方法
非肝硬化、NrtI 抑制的慢性 HBV 患者被随机分配至 VBR 300 mg 每日一次或匹配安慰剂 (PBO) 治疗 24 周。治疗按乙型肝炎 e 抗原 (HBeAg) 状态分层。主要终点是 24 周后血清 HBeAg 或乙型肝炎表面抗原 (HBsAg) 从基线的变化。
结果
入组的 73 名患者中，47 名 HBeAg 阳性，26 名 HBeAg 阴性。在 HBeAg 阳性和阴性患者中，HBsAg 或 HBeAg 与第 24 周基线相比的变化没有差异。使用一种新的、高灵敏度的检测方法来检测 HBV DNA，在 VBR+NrtI 与 PBO+NrtI 组中，更大比例的基线时可检测到 HBV DNA 的患者在第 24 周达到了不可检测的 HBV DNA。在 HBeAg 阳性患者中，在第 24 周，VBR+NrtI 与 PBO+NrtI 相比，HBV 前基因组 (pg)RNA 的基线变化更大。 VBR+NrtI 患者的治疗中出现的不良事件 (TEAE) 包括上呼吸道感染、恶心和瘙痒。没有报告严重的不良事件、4 级 TEAE 或死亡。
结论
在这项为期 24 周的研究中，VBR+NrtI 表现出良好的安全性和耐受性。虽然病毒抗原水平没有显着变化，但与单独的 NrtI 相比，添加 VBR 后 DNA 和 pgRNA 的更大变化证明了病毒抑制的增强。
临床试验编号
NCT03576066。
总结
核心抑制剂代表了一种治疗慢性乙型肝炎病毒 (HBV) 感染的新方法，其作用机制不同于现有的治疗方法。在这项研究中，与现有治疗相比，添加到现有治疗中的 vebicorvir 在更大程度上减少了 HBV 复制，并且通常安全且耐受性良好。

StephenW

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection

    Man-Fung Yuen
    Kosh Agarwal
    Xiaoli Ma
    Jacob P. Lalezari
    Scott K. Fung
    Mark S. Sulkowski
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Open AccessPublished:April 20, 2022DOI:https://doi.org/10.1016/j.jhep.2022.04.005


Highlights

    •
    Complete suppression of HBV replication is essential for finite treatment regimens.
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    Vebicorvir (VBR) is a novel inhibitor of the HBV core protein.
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    VBR interferes with two additional steps in HBV replication than NrtIs.
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    Added to NrtI, VBR did not significantly change mean HBV antigens over 24 weeks.
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    Added to NrtI, VBR further reduced HBV DNA and pgRNA by high-sensitivity PCR assays.

Background & Aims
HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs.
Methods
Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks.
Results
Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported.
Conclusions
In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone.
Clinical trials number
NCT03576066.
Lay summary
Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

StephenW

https://doi.org/10.1016/j.jhep.2022.04.005

StephenW

对我来说，这是一个非常令人失望的结果.