vebicorvir 与恩替卡韦在初治慢性乙型肝炎病毒感染患者中的安

StephenW

vebicorvir 与恩替卡韦在初治慢性乙型肝炎病毒感染患者中的安全性和有效性

    马克·S·苏科夫斯基
    科什·阿加瓦尔
    马晓丽
    雅各布·P·拉莱扎里
    斯科特·K·冯
    袁文峰
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开放存取发布时间：2022 年 6 月 10 日DOI：https://doi.org/10.1016/j.jhep.2022.05.027

强调

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    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) 是一种用于治疗慢性 HBV 的 HBV 核心蛋白抑制剂
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    VBR 干扰 HBV 复制中的两个额外步骤，因此补充了 NrtIs
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    与单独使用 ETV 相比，VBR+ETV 导致 HBV DNA 和前基因组 RNA 显着降低
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    在 24 周的治疗期间，VBR+ETV 与良好的安全性和耐受性相关

背景与目标
核苷（酸）类逆转录酶抑制剂不能完全抑制慢性 HBV 感染 (cHBV) 中的 HBV DNA。 Vebicorvir (VBR) 是一种在研核心抑制剂，可干扰 HBV 复制的多个方面。这项 II 期试验评估了 VBR 与恩替卡韦 (ETV) 联合治疗初治 cHBV 患者的安全性和有效性。
方法
HBeAg 阳性、未接受过治疗的无肝硬化患者以双盲方式 1:1 随机分配至每日一次 VBR 300 mg+ETV 0.5 mg 或安慰剂 (PBO)+ETV 0.5 mg 治疗 24 周。主要终点是从基线到第 12 周和第 24 周平均 log10 HBV DNA 的变化。
结果
两个治疗组（PBO+ETV：12/12；VBR+ETV：13/13）的所有患者都完成了研究。在第 12 周，与 PBO+ETV（–3.30 [1.18]；p = 0.0077）相比，VBR+ETV 导致 log10 IU/ml HBV DNA（–4.45 [1.03]）较基线的平均 (SD) 降低更大。在第 24 周，VBR+ETV 导致 log10 IU/ml HBV DNA (–5.33 [1.59]) 与 PBO+ETV (–4.20 [0.98]; p = 0.0084) 相比有更大的降低。在第 12 周和第 24 周，接受 VBR+ETV 与 PBO+ETV 的患者相比，观察到前基因组 RNA 的平均减少幅度更大（p <0.0001 和 p <0.0001）。两组病毒抗原的变化相似。未观察到 VBR 和 ETV 之间的药物相互作用。两名患者在治疗期间经历了 HBV DNA 反弹，未检测到耐药性突破。 VBR+ETV 的安全性与 PBO+ETV 相似。所有治疗出现的不良事件和实验室异常均为 1/2 级。没有死亡、严重的不良事件或药物性肝损伤的证据。
结论
在这项为期 24 周的研究中，VBR+ETV 在未接受过治疗的 cHBV 患者中提供了优于 PBO+ETV 的额外抗病毒活性，具有良好的安全性和耐受性。
临床试验编号
NCT03577171
总结
乙型肝炎是肝脏的长期病毒感染。目前的治疗可以抑制乙型肝炎病毒，但不能提供治愈的机会，因此需要新的治疗方法。在此，我们表明新型核心抑制剂 vebicorvir 与现有抗病毒药物（恩替卡韦）的组合在慢性感染乙型肝炎病毒的初治患者中显示出比单独使用恩替卡韦更强的抗病毒活性。此外，vebicorvir 是安全且耐受性良好的。因此，需要进一步研究评估其在慢性乙型肝炎治疗中的潜在作用。

StephenW

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection

    Mark S. Sulkowski
    Kosh Agarwal
    Xiaoli Ma
    Jacob P. Lalezari
    Scott K. Fung
    Man-Fung Yuen
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Open AccessPublished:June 10, 2022DOI:https://doi.org/10.1016/j.jhep.2022.05.027

Highlights

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    Complete suppression of HBV replication is essential for finite treatment regimens
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    Vebicorvir (VBR) is an HBV core protein inhibitor developed to treat chronic HBV
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    VBR interferes with 2 additional steps in HBV replication and thus complements NrtIs
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    VBR+ETV led to a significantly deeper reduction in HBV DNA and pregenomic RNA than ETV alone
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    VBR+ETV was associated with favorable safety and tolerability during 24 weeks of treatment

Background & Aims
Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV.
Methods
HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24.
Results
All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (–4.45 [1.03]) vs. PBO+ETV (–3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (–5.33 [1.59]) vs. PBO+ETV (–4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury.
Conclusions
In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile.
Clinical trial number
NCT03577171
Lay summary
Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

StephenW

http://www.journal-of-hepatology.eu/article/S0168827822003488/pdf