布列维肽联合富马酸替诺福韦酯治疗乙型肝炎病毒和丁型肝

StephenW

布列维肽联合富马酸替诺福韦酯治疗乙型肝炎病毒和丁型肝炎病毒合并感染患者的安全性和有效性 (MYR202)：一项多中心、随机、平行组、开放标签、2 期试验

    Heiner Wedemeyer 教授，医学博士
    卡特琳·舍内维斯博士
    帕维尔·博戈莫洛夫，医学博士
    安杰·布兰克，医学博士
    娜塔莉亚沃龙科娃博士
    医学博士 Tatiana Stepanova
    等。
    显示所有作者

发布时间：2022年9月13日DOI：https://doi.org/10.1016/S1473-3099(22)00318-8
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概括
背景
Bulevirtide 是一流的用于乙型肝炎病毒（HBV）和丁型肝炎病毒感染的肽进入抑制剂。 2020年7月，布列韦肽2mg获得欧洲医疗机构有条件上市许可，用于治疗慢性丁型肝炎病毒感染。我们调查了布列韦肽在慢性感染 HBV 和丁型肝炎病毒的患者中的抗病毒活性。
方法
MYR202（ClinicalTrials.gov，NCT03546621；EudraCT，2016-000395-13）是一项多中心、平行组、随机、开放标签的 2 期试验。患有慢性丁型肝炎病毒感染的成年人（18-65 岁），包括肝硬化患者和有 PegIFNα 治疗禁忌症或治疗无效的患者，符合条件并从德国的四家医院和俄罗斯的 12 家医院入组.患者被随机分配 (1:1:1:1) 接受 2 mg (n=28)、5 mg (n=32) 或 10 mg (n=30) 皮下注射布列维肽，每天一次和富马酸替诺福韦二吡呋酯 (TDF) ; 245 mg 每天口服一次）或单独的 TDF（245 mg 每天口服一次；n=30）持续 24 周。随机化是使用分层的数字块方案完成的，由 480 个随机数字组成，分成 30 个块。主要终点是在第 24 周无法检测到丁型肝炎病毒 RNA 或丁型肝炎病毒 RNA 下降 2 log10 IU/mL 或更高，在改良的意向治疗人群中进行了分析，包括接受研究药物治疗后至少一次的患者随机化。监测 D 型肝炎病毒 RNA 浓度直至第 48 周。对接受至少一剂布列韦肽或 TDF 的所有患者进行安全性评估。
发现
2016年2月16日至2016年12月8日，共筛查慢性丁型肝炎病毒感染患者171例；根据排除标准，51 名不符合条件，120 名患者（59 名肝硬化）入组。在第 24 周，28 名患者中有 15 名（54%，95% CI 34-73）实现了无法检测到的丁型肝炎病毒 RNA 或丁型肝炎病毒 RNA 下降 2 log10 IU/mL 或更多（p<0·0001 与单独的 TDF）布列维肽 2 mg，32 例中 16 例（50%，32-68）例 5 mg 布列维肽（p<0·0001），30 例中 23 例（77%，58-90）例 10 mg 布列维肽（p<0·0001 )，而仅使用 TDF 的 28 人中有 1 人 (4%, 0·1-18)。到第 48 周（布来维肽停药后 24 周），丁型肝炎病毒 RNA 浓度反弹，使用 2 mg 布列维肽后，从第 24 周到第 48 周的中位变化为 1·923 log10 IU/mL (IQR 0·566–2·485) , 1·732 log10 (0·469–2·568) 与 5 mg 布列维肽，2·030 log10 (1·262–2·903) 与 10 mg 布列维肽。没有与治疗相关的死亡。布列维肽 5 mg 组 3 名 (9%) 患者、布列维肽 10 mg 组 2 名 (7%) 患者和 TDF 组 1 名 (4%) 患者出现严重不良事件。常见的治疗中出现的不良事件包括无症状的胆汁盐增加以及丙氨酸氨基转移酶和天冬氨酸氨基转移酶的升高。
解释
Bulevirtide 在 24 周内诱导丁型肝炎病毒 RNA 显着下降。停止布列韦肽后，丁型肝炎病毒 RNA 浓度反弹。应研究更长的治疗时间和联合治疗。
资金
Hepatera LLC、MYR GmbH 和德国感染研究中心 TTU Hepatitis。

StephenW

Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial

    Prof Heiner Wedemeyer, MD
    Katrin Schöneweis, PhD
    Pavel Bogomolov, MD
    Antje Blank, MD
    Natalia Voronkova, PhD
    Tatiana Stepanova, MD
    et al.
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Published:September 13, 2022DOI:https://doi.org/10.1016/S1473-3099(22)00318-8
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Summary
Background
Bulevirtide is a first-in-class peptidic entry inhibitor for hepatitis B virus (HBV) and hepatitis D virus infection. In July, 2020, bulevirtide 2 mg received conditional marketing authorisation by the European Medical Agency for treatment of chronic hepatitis D virus infection. We investigated the antiviral activity of bulevirtide in patients chronically infected with HBV and hepatitis D virus.
Methods
MYR202 (ClinicalTrials.gov, NCT03546621; EudraCT, 2016-000395-13) was a multicentre, parallel-group, randomised, open-label, phase 2 trial. Adults (aged 18–65 years) with chronic hepatitis D virus infection, including patients with cirrhosis and patients who had contraindications to PegIFNα treatment or for whom treatment did not work, were eligible and were enrolled from four hospitals in Germany and 12 hospitals in Russia. Patients were randomly assigned (1:1:1:1) to receive 2 mg (n=28), 5 mg (n=32), or 10 mg (n=30) subcutaneous bulevirtide once per day with tenofovir disoproxil fumarate (TDF; 245 mg once per day orally) or TDF alone (245 mg once per day orally; n=30) for 24 weeks. Randomisation was done using a digital block scheme with stratification, consisting of 480 randomisation numbers separated into 30 blocks. The primary endpoint was undetectable hepatitis D virus RNA or 2 log10 IU/mL or higher decline in hepatitis D virus RNA at week 24, which was analysed in the modified intention-to-treat population, including patients who received study medication at least once after randomisation. Hepatitis D virus RNA concentrations were monitored until week 48. Safety was assessed for all patients who received at least one dose of bulevirtide or TDF.
Findings
Between Feb 16, 2016, and Dec 8, 2016, 171 patients with chronic hepatitis D virus infection were screened; 51 were ineligible based on the exclusion criteria and 120 patients (59 with cirrhosis) were enrolled. At week 24, 15 (54%, 95% CI 34–73) of 28 patients achieved undetectable hepatitis D virus RNA or a 2 log10 IU/mL or more decline in hepatitis D virus RNA (p<0·0001 vs TDF alone) with 2 mg bulevirtide, 16 (50%, 32–68) of 32 with 5 mg bulevirtide (p<0·0001), and 23 (77%, 58–90) of 30 with 10 mg bulevirtide (p<0·0001), versus one (4%, 0·1–18) of 28 with TDF alone. By week 48 (24 weeks after bulevirtide cessation), hepatitis D virus RNA concentrations had rebounded, with median changes from week 24 to week 48 of 1·923 log10 IU/mL (IQR 0·566–2·485) with 2 mg bulevirtide, 1·732 log10 (0·469–2·568) with 5 mg bulevirtide, and 2·030 log10 (1·262–2·903) with 10 mg bulevirtide. There were no deaths associated with treatment. Three (9%) patients in the bulevirtide 5 mg group, two (7%) patients in the bulevirtide 10 mg group, and one (4%) patient in the TDF group had serious adverse events. Common treatment-emergent adverse events included asymptomatic bile salt increases and increases in alanine aminotransferase and aspartate aminotransferase.
Interpretation
Bulevirtide induced a significant decline in hepatitis D virus RNA over 24 weeks. After cessation of bulevirtide, hepatitis D virus RNA concentrations rebounded. Longer treatment durations and combination therapies should be investigated.
Funding
Hepatera LLC, MYR GmbH, and the German Centre for Infection Research, TTU Hepatitis.