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.

中文翻译：

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布维肽与富马酸替诺福韦二吡呋酯联合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

背景

Bulevirtide 是一流的肽进入抑制剂，用于治疗乙型肝炎病毒 (HBV) 和丁型肝炎病毒感染。2020年7月，bulevirtide 2 mg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。我们研究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人（18-65 岁），包括肝硬化患者和对 PegIFNα 治疗有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) 布维肽皮下注射，每天一次，富马酸替诺福韦酯 (TDF) ; 245 mg 每天一次口服）或单独使用 TDF（245 mg 每天一次口服；n=30），持续 24 周。随机化是使用具有分层的数字块方案完成的，由分成 30 个块的 480 个随机化数字组成。_{第 24 周时丁型肝炎病毒 RNA 下降10} IU/mL 或更高，这是在改良的意向治疗人群中进行分析的，包括在随机分组后至少接受过一次研究药物治疗的患者。监测丁型肝炎病毒 RNA 浓度直至第 48 周。对接受至少一剂布维肽或 TDF 的所有患者的安全性进行了评估。

发现

2016年2月16日至12月8日，筛查了171名慢性丁型肝炎病毒感染者；根据排除标准，51 名患者不合格，120 名患者（59 名患有肝硬化）被纳入。在第 24 周，28 名患者中有 15 名（54%，95% CI 34–73）检测不到丁型肝炎病毒 RNA 或丁型肝炎病毒 RNA下降2 log _{10 IU/mL 或更多（p<0·0001} vs单独使用 TDF ） ) 服用 2 mg 布维肽，32 人中有 16 人 (50%, 32–68) 服用 5 mg 布来韦肽 (p<0·0001)，30 人中有 23 (77%, 58–90) 人服用 10 mg 布来韦肽 (p<0· 0001)，而仅使用 TDF 的 28 个中有一个 (4%, 0·1–18)。到第 48 周（布列韦肽停药后 24 周），丁型肝炎病毒 RNA 浓度出现反弹，从第 24 周到第 48 周的中位变化为 1·923 log ₁₀IU/mL (IQR 0·566–2·485) 2 mg 布维肽，1·732 log ₁₀ (0·469–2·568) 5 mg 布维肽，2·030 log ₁₀ (1·262–2· 903) 和 10 毫克布维肽。没有与治疗相关的死亡。bulevirtide 5 mg 组中的三名 (9%) 患者、bulevirtide 10 mg 组中的两名 (7%) 患者和 TDF 组中的一名 (4%) 患者出现了严重的不良事件。常见的治疗中出现的不良事件包括无症状的胆汁盐升高以及谷丙转氨酶和天冬氨酸转氨酶升高。

解释

Bulevirtide 在 24 周内导致丁型肝炎病毒 RNA 显着下降。布列韦肽停用后，丁型肝炎病毒 RNA 浓度反弹。应研究更长的治疗持续时间和联合疗法。

资金

Hepatera LLC、MYR GmbH 和德国感染研究中心 TTU Hepatitis。