比匹韦林治疗慢性乙型肝炎感染的疗效和安全性
Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection.
作者信息
Yuen Man-Fung, Lim Seng-Gee, Plesniak Robert, Tsuji Keiji, Janssen Harry L A, Pojoga Cristina, Gadano Adrian, Popescu Corneliu P, Stepanova Tatyana, Asselah Tarik, Diaconescu Gheorghe, Yim Hyung Joon, Heo Jeong, Janczewska Ewa, Wong Alexander, Idriz Nevin, Imamura Michio, Rizzardini Giuliano, Takaguchi Koichi, Andreone Pietro, Arbune Manuela, Hou Jinlin, Park Sung Jae, Vata Andrei, Cremer Jennifer, Elston Robert, Lukić Tamara, Quinn Geoff, Maynard Lauren, Kendrick Stuart, Plein Helene, Campbell Fiona, Paff Melanie, Theodore Dickens
机构信息
From the Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, and the State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong (M.-F.Y.), and Nanfang Hospital, Southern Medical University, Guangzhou (J. Hou) - all in China; National University Health System, Singapore (S.-G.L.); the University of Rzeszow, College of Medical Sciences, Centrum Medyczne w Lancucie, Lancut (R.P.), and the Faculty of Health Sciences in Bytom, Medical University of Silesia, Katowice (E.J.) - both in Poland; the Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital (K. Tsuji), and Hiroshima University Hospital (M.I.), Hiroshima, and Kagawa Prefectural Central Hospital, Takamatsu (K. Takaguchi) - all in Japan; Toronto General Hospital, Toronto (H.L.A.J.), and the Department of Medicine, University of Saskatchewan, Regina (A.W.) - both in Canada; Erasmus Medical Center, Rotterdam, the Netherlands (H.L.A.J.); Regional Institute of Gastroenterology and Hepatology and Babeş-Bolyai University, Department of Clinical Psychology and Psychotherapy, International Institute for Advanced Study of Psychotherapy and Applied Mental Health, Cluj-Napoca (C.P.), Dr. Victor Babes Clinical Hospital of Infectious and Tropical Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest (C.P.P.), Spitalul Clinic de Boli Infectioase si Pneumoftiziologie, Craiova (G.D.), Sfanta Cuvioasa Parascheva Infectious Diseases Clinical Hospital, Galati (M.A.), and "Grigore T. Popa" University of Medicine and Pharmacy, Iasi (A.V.) - all in Romania; Hospital Italiano de Buenos Aires, Buenos Aires (A.G.); Modern Medicine Clinic, Moscow (T.S.); Université de Paris-Cité and INSERM Unité Mixte de Recherche 1149, Department of Hepatology, Assistance Publique-Hôpitaux de Paris Hôpital Beaujon, Clichy, France (T.A.); Korea University Ansan Hospital, Ansan (H.J.Y.), and the College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital (J. Heo), and Inje University Busan Paik Hospital (S.-J.P.), Busan - all in South Korea; the University of Medicine and Hospital for Active Treatment Sofiamed, Sofia, Bulgaria (N.I.); Luigi Sacco Hospital, Milan (G.R.), and Azienda Ospedaliero-Universitaria di Modena, Baggiovara Hospital, Modena (P.A.) - both in Italy; GSK, Durham, NC (J.C., D.T.); GSK, Stevenage (R.E., G.Q., L.M., S.K., F.C.), and GSK, Brentford (H.P.) - both in the United Kingdom; GSK, Dubai, United Arab Emirates (T.L.); and GSK, Collegeville, PA (M.P.).
出版信息
N Engl J Med. 2022 Nov 24;387(21):1957-1968. doi: 10.1056/NEJMoa2210027. Epub 2022 Nov 8.
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.).
背景
比匹罗韦森是一种反义寡核苷酸，可靶向所有乙型肝炎病毒（HBV）信使核糖核酸，并降低病毒蛋白水平。
方法
我们进行了一项2b期、随机、研究者非盲试验，纳入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（按3:3:3:1的比例）接受为期24周的每周一次皮下注射300mg比匹罗韦森（第1组）、300mg比匹罗韦森注射12周然后150mg注射12周（第2组）、300mg比匹罗韦森注射12周然后12周安慰剂（第3组），或12周安慰剂然后300mg比匹罗韦森注射12周（第4组）。第1、2和3组接受比匹罗韦森的负荷剂量。复合主要结局是在比匹罗韦森治疗计划结束后24周，乙肝表面抗原（HBsAg）水平低于检测下限且HBV DNA水平低于定量下限，且未新启动抗病毒药物治疗。
结果
意向性分析人群包括457名参与者（227名接受NA治疗，230名未接受NA治疗）。在接受NA治疗的参与者中，第1组有6名参与者（9%；95%可信区间，0至31）发生主要结局事件，第2组有6名（9%；95%可信区间，0至43），第3组有2名（3%；95%可信区间，0至16），第4组有0名（0%；事后可信区间，0至8）。在未接受NA治疗的参与者中，主要结局事件分别发生在7名参与者（10%；95%可信区间，0至38）、4名（6%；95%可信区间，0至25）、1名（1%；事后可信区间，0至6）和0名（0%；事后可信区间，0至8）。在第1至12周期间，比匹罗韦森组（第1、2和3组）的不良事件，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，比安慰剂组（第4组）更常见。
结论
在这项2b期试验中，每周一次300mg比匹罗韦森治疗24周使9%至10%的慢性HBV感染参与者实现了HBsAg和HBV DNA的持续清除。需要更大规模和更长时间的试验来评估比匹罗韦森的疗效和安全性。（由葛兰素史克公司资助；B-Clear临床试验注册号，NCT04449029。）
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