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Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection
Man-Fung Yuen1, Seng-Gee Lim1, Robert Plesniak1
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 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.).
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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