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Abstract Details |
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Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection |
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N Engl J Med. 2022 Nov 24;387(21):1957-1968. doi: 10.1056/NEJMoa2210027.Epub 2022 Nov 8.
Man-Fung Yuen 1, Seng-Gee Lim 1, Robert Plesniak 1, Keiji Tsuji 1, Harry L A Janssen 1, Cristina Pojoga 1, Adrian Gadano 1, Corneliu P Popescu 1, Tatyana Stepanova 1, Tarik Asselah 1, Gheorghe Diaconescu 1, Hyung Joon Yim 1, Jeong Heo 1, Ewa Janczewska 1, Alexander Wong 1, Nevin Idriz 1, Michio Imamura 1, Giuliano Rizzardini 1, Koichi Takaguchi 1, Pietro Andreone 1, Manuela Arbune 1, Jinlin Hou 1, Sung Jae Park 1, Andrei Vata 1, Jennifer Cremer 1, Robert Elston 1, Tamara Lukic 1, Geoff Quinn 1, Lauren Maynard 1, Stuart Kendrick 1, Helene Plein 1, Fiona Campbell 1, Melanie Paff 1, Dickens Theodore 1, B-Clear Study Group
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Author information
Collaborators
Luis Colombato, Adrian Gadano, Jordan Genov, Dimitar Pavlov, Diana Petrova, Konstantin Tchernev, Carla Coffin, Wayne Ghesquiere, Harry Janssen, Paul Marotta, Sebastien Poulin, Marie-Louise Vachon, Alexander Wong, Xiaoguang Dou, Jinlin Hou, Jidong Jia, Qin Ning, Hong Ren, Guiqiang Wang, Qing Xie, Wen Xie, Tarik Asselah, Vincent Leroy, Véronique Loustaud-Ratti, Lawrence Serfaty, Albert Tran, Fabien Zoulim, Jukka Hartikainen, Andreas Kremer, Thomas Lutz, Michael Sabranski, Kathrin Sprinzl, Man Fung Yuen, Pietro Andreone, Pietro Lampertico, Massimo Memoli, Giuliano Rizzardini, Tomofumi Atarashi, Masanori Atsukawa, Shigetoshi Fujiyama, Michio Imamura, Jun Inoue, Kouji Joko, Kaheita Kakinoki, Atsumasa Komori, Takuya Komura, Masayuki Kurosaki, Koichi Takaguchi, Tetsuo Takehara, Yasuhito Tanaka, Keiji Tsuji, Muhammad Firdaus Md Salleh, Rosmawati Mohamed, Felix Domingo Jr, Madalinee Eternity Labio, Jan Gietka, Ewa Janczewska, Robert Plesniak, Krzysztof Tomasiewicz, Jeong Heo, Hyung Joon Kim, Ju Hyun Kim, Yoon Jun Kim, YoungOh Kweon, Young-Suk Lim, Neung Hwa Park, Sung-Jae Park, Hyung Joon Yim, Manuela Arbune, Dana Crisan, Gheorghe Diaconescu, Iosif Marincu, Adrian Moraru, Cristina Pojoga, Corneliu Popescu, Andrei Vata, Pavel Bogomolov, Natalya Gankina, Denis Gusev, Vyacheslav Morozov, Marina Osipenko, Vladimir Rafalsky, Svetlana Romanova, Olga Sagalova, Tatyana Stepanova, Natalya Voloshina, Sergey Zotov, Rajneesh Kumar, Seng-Gee Lim, Jessica Tan, Primrose Mabale, Rosie Mngqibisa, Naeem Moosa, Zelda Punt, Agatha Wilhase, Sabelo Xaba, Javier Ampuero Herrojo, Raul Andrade Bellido, Maria Buti, José Luís Calleja Panero, Javier Crespo, Xavier Forns Bernhardt, Javier Garcia Samaniego, Pablo Ryan Murua, Raymond Chung, Michael Fuchs, Binu John, James Park, Mordechai Rabinovitz, David Rausher, Eugene Schiff, Norah Terrault
Affiliation
- 1From 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 Babes-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.).
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.).
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