中国香港玛丽医院Man-Fung Yuen团队研究了bepirovirsen治疗慢性乙型肝炎的疗效和安全性。2022年11月8日，该研究成果发表在《新英格兰医学杂志》上。

Bepirovirsen是一种反义寡核苷酸，靶向所有乙型肝炎病毒（HBV）信使RNA，可降低病毒蛋白水平。

研究组进行了一项2b期随机、研究者非盲试验，招募接受或未接受核苷或核苷酸类似物（NA）治疗的慢性HBV感染者。参与者被随机分配（以3:3:3:1的比例）分别接受每周皮下注射300mg剂量的bepirovirsen 24周（组1）；300mg剂量bepirovirsen 12周，然后150mg剂量12周（组2）；300mg剂量bepirovirsen持续12周，然后服用安慰剂12周（第3组）；或安慰剂12周，300mg剂量bepirovirsen持续12周（第4组）。

第1、2和3组接受负荷剂量的bepirovirsen。综合主要结局为在未使用新的抗病毒药物的情况下，在计划结束bepirovirsen治疗后24周内，乙型肝炎表面抗原（HBsAg）水平低于检测限，HBV DNA水平低于定量限。

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，第一组有6名（9%）、第二组有6名（9%）、第三组有2名（3%）和第四组有0名（0%）参与者出现主要结局事件。在未接受NA治疗的参与者中，分别有7名（10%）、4名（6%）、1名（1%）和0名参与者（0%）发生主要结局事件。在第1至12周期间，bepirovirsen（第1、2和3组）比安慰剂（第4组）更易发生不良事件，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。

研究结果表明，在这项2b期试验中，每周300mg剂量的bepirovirsen持续24周，可导致9%至10%的慢性HBV感染者持续HBsAg和HBV DNA检测不到。仍需要更大规模、更长时间的试验来评估bepirovirsen的疗效和安全性。

附：英文原文

Title: Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection | NEJM

Author: 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 Luki, 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.

Issue&Volume: 2022-11-08

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.

DOI: 10.1056/NEJMoa2210027

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