VIR-2218（elebsiran）联合聚乙二醇干扰素-2a治疗慢性乙型肝炎病毒感染者：2 期研究

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2024-10-08 DOI:10.1016/s2468-1253(24)00237-1

Man-Fung Yuen, Young-Suk Lim, Ki Tae Yoon, Tien-Huey Lim, Jeong Heo, Pisit Tangkijvanich, Won Young Tak, Vaidehi Thanawala, Daniel Cloutier, Shenghua Mao, Andre Arizpe, Andrea L Cathcart, Sneha V Gupta, Carey Hwang, Edward Gane

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Adults (aged 18–65 years) with chronic HBV infection without cirrhosis and with HBsAg more than 50 IU/mL and HBV DNA less than 90 IU/mL who were on continued nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) therapy for 2 months or longer were eligible. Participants were enrolled into one of six cohorts to receive VIR-2218 200 mg subcutaneously every 4 weeks, with or without 180 μg subcutaneous pegylated interferon-alfa-2a once per week. Cohort 1 received six doses of VIR-2218 (total 20 weeks); cohort 2 received six doses of VIR-2218 starting at day 1, plus 12 doses of pegylated interferon-alfa-2a starting at week 12 (total 24 weeks); cohort 3 received six doses of VIR-2218 and 24 doses of pegylated interferon-alfa-2a (total 24 weeks); cohort 4 received six doses of VIR-2218 and up to 48 doses of pegylated interferon-alfa-2a (total 48 weeks); cohort 5 received up to 13 doses of VIR-2218 and up to 44 doses of pegylated interferon-alfa-2a (total 48 weeks); and cohort 6 received three doses of VIR-2218 and 12 doses of pegylated interferon-alfa-2a (total 12 weeks). The primary endpoints were the incidence of adverse events and clinical assessments (including results of laboratory tests). Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. 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Three (20%) participants in cohort 1, four (27%) in cohort 2, eight (44%) in cohort 3, seven (39%) in cohort 4, six (46%) in cohort 5, and two (40%) in cohort 6 reported treatment-emergent adverse events related to VIR-2218. 12 (80%) participants in cohort 2, 12 (67%) in cohort 3, 14 (78%) in cohort 4, 13 (100%) in cohort 5, and three (60%) in cohort 6 reported treatment-emergent adverse events related to pegylated interferon-alfa-2a. Two (13%) participants in cohort 1 had elevations in alanine aminotransferase, compared with 13 (87%) participants in cohort 2, 15 (83%) in cohort 3, 17 (94%) in cohort 4, 11 (85%) in cohort 5, and three (60%) in cohort 6. 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Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. 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引用次数: 0

摘要

背景慢性乙型肝炎病毒（HBV）仍然是一个全球关注的问题，目前的治疗方法仅能达到较低的 HBsAg 血清清除率。VIR-2218（elebsiran）是一种针对HBV转录本的小干扰RNA制剂，可降低HBsAg浓度。我们旨在评估VIR-2218与聚乙二醇干扰素-α-2a治疗或不与聚乙二醇干扰素-α-2a治疗对慢性HBV患者的安全性和抗病毒活性。年龄在 18-65 岁之间、无肝硬化、HBsAg 超过 50 IU/mL、HBV DNA 低于 90 IU/mL、持续接受核苷酸或核苷酸逆转录酶抑制剂 (NRTI) 治疗 2 个月或更长时间的慢性 HBV 感染成人均符合条件。参试者被纳入6个队列中的一个，每4周皮下注射200毫克VIR-2218，同时或不注射180微克皮下聚乙二醇干扰素-2a，每周一次。第 1 组接受 6 次 VIR-2218 治疗（共 20 周）；第 2 组从第 1 天开始接受 6 次 VIR-2218 治疗，并从第 12 周开始接受 12 次聚乙二醇化干扰素-2a 治疗（共 24 周）；第 3 组接受 6 次 VIR-2218 治疗和 24 次聚乙二醇化干扰素-2a 治疗（共 24 周）；第4组接受6剂VIR-2218和最多48剂聚乙二醇化干扰素-2a（共48周）；第5组接受最多13剂VIR-2218和最多44剂聚乙二醇化干扰素-2a（共48周）；第6组接受3剂VIR-2218和12剂聚乙二醇化干扰素-2a（共12周）。主要终点为不良事件发生率和临床评估（包括实验室检测结果）。次要终点为任何时间点血清 HBsAg 平均最大降幅；任何时间点及治疗结束后 6 个月以上血清 HBsAg 清除的参与者比例；任何时间点抗 HBs 血清转换的参与者比例。对于 HBeAg 阳性患者，我们还评估了在任何时间点 HBeAg 血清清除或抗-HBe 血清转换的比例。该研究已在 ClinicalTrials.gov 注册，编号为 NCT03672188，目前仍在进行中。研究结果在 2020 年 7 月 2 日至 2021 年 11 月 2 日期间，共筛选出 124 名符合条件的患者，其中 84 人被纳入研究（队列 1 15 人、队列 2 15 人、队列 3 18 人、队列 4 18 人、队列 5 13 人、队列 6 5 人）。参与者主要为 HBeAg 阴性、亚洲人和男性（66 名[79%]参与者为男性，18 名[21%]参与者为女性）。大多数治疗突发不良事件为 1-2 级。队列 1 中有 3 人（20%）、队列 2 中有 4 人（27%）、队列 3 中有 8 人（44%）、队列 4 中有 7 人（39%）、队列 5 中有 6 人（46%）、队列 6 中有 2 人（40%）报告了与 VIR-2218 相关的治疗突发不良事件。队列2中有12人（80%）、队列3中有12人（67%）、队列4中有14人（78%）、队列5中有13人（100%）、队列6中有3人（60%）报告了与聚乙二醇干扰素-2a相关的治疗突发不良事件。队列 1 中有 2 人（13%）出现丙氨酸氨基转移酶升高，而队列 2 中有 13 人（87%）、队列 3 中有 15 人（83%）、队列 4 中有 17 人（94%）、队列 5 中有 11 人（85%）、队列 6 中有 3 人（60%）出现这种情况。在任何时间点，HBsAg 浓度与基线相比的平均最大变化为：队列 1 -2-0 log10 IU/mL（95% CI -2-1~-1-8），队列 2 -2-2 log10 IU/mL（-2-5~-1-8）、队列 3 中为 -2-5 log10 IU/mL（-2-8 至 -2-1），队列 4 中为 -2-4 log10 IU/mL（-3-1 至 -1-8），队列 5 中为 -3-0 log10 IU/mL（-3-7 至 -2-3），队列 6 中为 -1-7 log10 IU/mL（-2-1 至 -1-4）。11名接受VIR-2218联合聚乙二醇干扰素-2a治疗的患者（队列2中1人，队列3中1人，队列4中5人，队列5中4人）在任何时间点均出现HBsAg血清清除。其中，10 人（91%；1 人在队列 2 中，5 人在队列 4 中，4 人在队列 5 中）抗 HBs 血清阳性。6名参与者（组群2中1名，组群4中3名，组群5中2名）在治疗结束后24周内持续清除HBsAg血清。接受VIR-2218单药治疗（队列1）或VIR-2218加聚乙二醇干扰素-2a 12周治疗方案（队列6）的患者均未出现HBsAg血清清除。基线时HBeAg阳性的26名参与者中，有12人（42%）（队列1的4人中有1人，队列2的6人中有2人，队列3的7人中有4人，队列4的6人中有4人，队列5的3人中有1人）HBeAg血清清除或抗-HBe血清转换。VIR-2218联合或不联合聚乙二醇干扰素-1-2a与HBsAg靶向单克隆抗体的其他临床试验正在进行中。

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VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study

Background

Chronic hepatitis B virus (HBV) remains a global concern, with current treatments achieving low rates of HBsAg seroclearance. VIR-2218 (elebsiran), a small interfering RNA agent against HBV transcripts, reduces HBsAg concentrations. We aimed to evaluate the safety and antiviral activity of VIR-2218 with and without pegylated interferon-alpha-2a treatment in participants with chronic HBV.

Methods

This open-label, phase 2 study was conducted at 23 sites in six countries (New Zealand, Australia, Hong Kong, Thailand, South Korea, and Malaysia). Adults (aged 18–65 years) with chronic HBV infection without cirrhosis and with HBsAg more than 50 IU/mL and HBV DNA less than 90 IU/mL who were on continued nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) therapy for 2 months or longer were eligible. Participants were enrolled into one of six cohorts to receive VIR-2218 200 mg subcutaneously every 4 weeks, with or without 180 μg subcutaneous pegylated interferon-alfa-2a once per week. Cohort 1 received six doses of VIR-2218 (total 20 weeks); cohort 2 received six doses of VIR-2218 starting at day 1, plus 12 doses of pegylated interferon-alfa-2a starting at week 12 (total 24 weeks); cohort 3 received six doses of VIR-2218 and 24 doses of pegylated interferon-alfa-2a (total 24 weeks); cohort 4 received six doses of VIR-2218 and up to 48 doses of pegylated interferon-alfa-2a (total 48 weeks); cohort 5 received up to 13 doses of VIR-2218 and up to 44 doses of pegylated interferon-alfa-2a (total 48 weeks); and cohort 6 received three doses of VIR-2218 and 12 doses of pegylated interferon-alfa-2a (total 12 weeks). The primary endpoints were the incidence of adverse events and clinical assessments (including results of laboratory tests). Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. This study is registered with ClinicalTrials.gov, NCT03672188, and is ongoing.

Findings

Between July 2, 2020, and Nov 2, 2021, 124 individuals were screened for eligibility, 84 of whom were enrolled (15 in cohort 1, 15 in cohort 2, 18 in cohort 3, 18 in cohort 4, 13 in cohort 5, and five in cohort 6). Participants were predominantly HBeAg-negative, Asian, and male (66 [79%] participants were male and 18 [21%] were female). Most treatment emergent adverse events were grades 1–2. Three (20%) participants in cohort 1, four (27%) in cohort 2, eight (44%) in cohort 3, seven (39%) in cohort 4, six (46%) in cohort 5, and two (40%) in cohort 6 reported treatment-emergent adverse events related to VIR-2218. 12 (80%) participants in cohort 2, 12 (67%) in cohort 3, 14 (78%) in cohort 4, 13 (100%) in cohort 5, and three (60%) in cohort 6 reported treatment-emergent adverse events related to pegylated interferon-alfa-2a. Two (13%) participants in cohort 1 had elevations in alanine aminotransferase, compared with 13 (87%) participants in cohort 2, 15 (83%) in cohort 3, 17 (94%) in cohort 4, 11 (85%) in cohort 5, and three (60%) in cohort 6. The mean maximum change from baseline at any timepoint in HBsAg concentration was –2·0 log₁₀ IU/mL (95% CI –2·1 to –1·8) in cohort 1, –2·2 log₁₀ IU/mL (–2·5 to –1·8) in cohort 2, –2·5 log₁₀ IU/mL (–2·8 to –2·1) in cohort 3, –2·4 log₁₀ IU/mL (–3·1 to –1·8) in cohort 4, –3·0 log₁₀ IU/mL (–3·7 to –2·3) in cohort 5, and –1·7 log₁₀ IU/mL (–2·1 to –1·4) in cohort 6. 11 participants (one in cohort 2, one in cohort 3, five in cohort 4, and four in cohort 5) receiving VIR-2218 plus pegylated interferon-alfa-2a had HBsAg seroclearance at any timepoint. Of these, ten (91%; one in cohort 2, five in cohort 4, and four in cohort 5) had anti-HBs seropositivity. Six participants (one in cohort 2, three in cohort 4, and two in cohort 5) had sustained HBsAg seroclearance through to 24 weeks after the end of treatment. No participants receiving VIR-2218 monotherapy (cohort 1) or VIR-2218 plus pegylated interferon-alfa-2a 12-week regimen (cohort 6) had HBsAg seroclearance. 12 (42%) of 26 participants (one of four in cohort 1, two of six in cohort 2, four of seven in cohort 3, four of six in cohort 4, and one of three in cohort 5) who were HBeAg positive at baseline had HBeAg seroclearance or anti-HBe seroconversion.

Interpretation

The results of this phase 2 study support further development of VIR-2218 as a potential therapy for patients with chronic HBV infection. Additional clinical trials of VIR-2218 with and without pegylated interferon-alfa-2a in combination with an HBsAg-targeting monoclonal antibody are ongoing.

Funding

Vir Biotechnology.

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来源期刊

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.