贝匹罗韦森在慢性乙型肝炎感染中的疗效和安全性

StephenW

贝匹罗韦森在慢性乙型肝炎感染中的疗效和安全性
作者名单。

    Man-Fung Yuen, M.D., Ph.D., D.Sc., Seng-Gee Lim, M.B., B.S., M.D., Robert Plesniak, M.D., Ph.D., Keiji Tsuji, M.D., Ph.D., Harry L.A. Janssen, M.D., Ph.D., Cristina Pojoga, M.D., Ph.D., Adrian Gadano, M.D., Ph.D., Corneliu P. Popescu, M.D., Ph.D., Tatyana Stepanova, M.Sc., Tarik Asselah, M.D., Ph.D., Gheorghe Diaconescu, M.D., Ph.D., Hyung Joon Yim, M.D., Ph.D., Jeong Heo, M.D., Ph.D., Ewa Janczewska, Ph.D., D. Sc., Alexander Wong, M.D., Nevin Idriz, M.D., Michio Imamura, M.D., Ph.D., Giuliano Rizzardini, M.D., Koichi Takaguchi, M.D., Ph.D., Pietro Andreone, M.D., Manuela Arbune, M.D., Ph.D. D., Jinlin Hou, M.D., Sung Jae Park, Ph.D., Andrei Vata, M.D., Ph.D., Jennifer Cremer, Pharm.D., Robert Elston, Ph.D., Tamara Lukić, M.D., Geoff Quinn , M.Sc., Lauren Maynard, M.Sc., Stuart Kendrick, Ph.D., Helene Plein, Ph.D., Fiona Campbell, B.Sc., Melanie Paff, Ph.D. 和 Dickens Theodore,医学博士、公共卫生硕士

    对于 B-Clear 研究组*

抽象的
背景

Bepirovirsen 是一种反义寡核苷酸，可靶向所有乙型肝炎病毒 (HBV) 信使 RNA，并起到降低病毒蛋白水平的作用。
方法

我们进行了一项 2b 期、随机、研究者非盲法试验，涉及正在接受或未接受核苷或核苷酸类似物 (NA) 治疗的慢性 HBV 感染参与者。参与者被随机分配（以 3:3:3:1 的比例）接受每周皮下注射 300 mg 的贝匹罗韦森 24 周（第 1 组），贝匹罗韦森 300 mg 的剂量 12 周，然后 150 mg 12 周（第 2 组），贝匹罗韦森 300 mg 剂量 12 周，然后安慰剂 12 周（第 3 组），或安慰剂 12 周，然后贝匹罗韦森 300 mg 剂量 12 周（第 4 组）。第 1、2 和 3 组接受负荷剂量的贝匹罗韦森。复合主要结果是乙型肝炎表面抗原 (HBsAg) 水平低于检测限和 HBV DNA 水平低于定量限，在计划结束贝匹罗韦森治疗后维持 24 周，无需新启动抗病毒药物治疗。
结果

意向治疗人群包括 457 名参与者（227 名接受 NA 治疗，230 名未接受 NA 治疗）。在接受 NA 治疗的患者中，第 1 组的 6 名参与者（9%；95% 可信区间，0 到 31）发生了主要结果事件，第 2 组的 6 名参与者（9%；95% 可信区间，0 到 43）发生了主要结果事件，第 3 组中有 2 人（3%；95% 可信区间，0 至 16），第 4 组中有 0 人（0%；事后可信区间，0 至 8）。在未接受 NA 治疗的参与者中，主要结果事件发生在 7 名参与者（10%；95% 可信区间，0 到 38）、4 名（6%；95% 可信区间，0 到 25）、1 名（1%；事后可信区间，0 到 6）和0（0%；事后可信区间，0 到 8）。在第 1 周至第 12 周期间，不良事件，包括注射部位反应、发热、疲劳和丙氨酸氨基转移酶水平升高，使用贝匹罗韦森（第 1、2 和 3 组）比使用安慰剂（第 4 组）更常见。
结论

在这项 2b 期试验中，每周 300 mg 剂量的贝匹罗韦森持续 24 周导致 9% 至 10% 的慢性 HBV 感染参与者持续 HBsAg 和 HBV DNA 丢失。需要更大规模和更长的试验来评估贝匹罗韦森的疗效和安全性。 （由 GSK 资助；B-Clear ClinicalTrials.gov 编号，NCT04449029。在新标签中打开。）

StephenW

Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection
List of authors.

    Man-Fung Yuen, M.D., Ph.D., D.Sc., Seng-Gee Lim, M.B., B.S., M.D., Robert Plesniak, M.D., Ph.D., Keiji Tsuji, M.D., Ph.D., Harry L.A. Janssen, M.D., Ph.D., Cristina Pojoga, M.D., Ph.D., Adrian Gadano, M.D., Ph.D., Corneliu P. Popescu, M.D., Ph.D., Tatyana Stepanova, M.Sc., Tarik Asselah, M.D., Ph.D., Gheorghe Diaconescu, M.D., Ph.D., Hyung Joon Yim, M.D., Ph.D., Jeong Heo, M.D., Ph.D., Ewa Janczewska, Ph.D., D.Sc., Alexander Wong, M.D., Nevin Idriz, M.D., Michio Imamura, M.D., Ph.D., Giuliano Rizzardini, M.D., Koichi Takaguchi, M.D., Ph.D., Pietro Andreone, M.D., Manuela Arbune, M.D., Ph.D., Jinlin Hou, M.D., Sung Jae Park, Ph.D., Andrei Vata, M.D., Ph.D., Jennifer Cremer, Pharm.D., Robert Elston, Ph.D., Tamara Lukić, M.D., Geoff Quinn, M.Sc., Lauren Maynard, M.Sc., Stuart Kendrick, Ph.D., Helene Plein, Ph.D., Fiona Campbell, B.Sc., Melanie Paff, Ph.D., and Dickens Theodore, M.D., M.P.H.

    for the B-Clear Study Group*

Abstract
Background

Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.
Methods

We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Groups 1, 2, and 3 received loading doses of bepirovirsen. The composite primary outcome was a hepatitis B surface antigen (HBsAg) level below the limit of detection and an HBV DNA level below the limit of quantification maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication.
Results

The intention-to-treat population comprised 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Among those receiving NA therapy, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) in group 1, in 6 (9%; 95% credible interval, 0 to 43) in group 2, in 2 (3%; 95% credible interval, 0 to 16) in group 3, and 0 (0%; post hoc credible interval, 0 to 8) in group 4. Among participants not receiving NA therapy, a primary-outcome event occurred in 7 participants (10%; 95% credible interval, 0 to 38), 4 (6%; 95% credible interval, 0 to 25), 1 (1%; post hoc credible interval, 0 to 6), and 0 (0%; post hoc credible interval, 0 to 8), respectively. During weeks 1 through 12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen (groups 1, 2, and 3) than with placebo (group 4).
Conclusions

In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks resulted in sustained HBsAg and HBV DNA loss in 9 to 10% of participants with chronic HBV infection. Larger and longer trials are required to assess the efficacy and safety of bepirovirsen. (Funded by GSK; B-Clear ClinicalTrials.gov number, NCT04449029. opens in new tab.)

StephenW

https://www.nejm.org/doi/full/10.1056/NEJMoa2210027