Article
作者: Morozov, Vyacheslav ; Voloshina, Natalya ; McGonagle, Grant ; Youssef, Amir ; Coffin, Carla S ; Sheng, Guoping ; Kendrick, Stuart ; Janczewska, Ewa ; Greene, Thomas ; Theodore, Dickens ; Andreone, Pietro ; Youssef, Amir S ; Plesniak, Robert ; Fujiwara, Kei ; Lakshminarayanan, Divya ; Lim, Jessica ; Xie, Qing ; Lampertico, Pietro ; McPherson, Stuart ; Paff, Melanie ; Komori, Atsumasa ; Cabezas, Joaquín ; Lee, Maximilian ; Yim, Hyung Joon ; Gankina, Natalya ; Elston, Rob ; Sagalova, Olga ; Poulin, Sébastien ; Plein, Helene ; Dixon, Susan ; Felton, Leigh ; Heo, Jeong ; Atsukawa, Masanori ; Buti, Maria ; Gordon, Stuart C. ; Coffin, Carla S. ; Tanaka, Yasuhito ; Gordon, Stuart C ; Ryan, Pablo ; Chak, Eric
BACKGROUND & AIMSBepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (METHODSIn this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300 mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180 μg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout. The primary outcome was the proportion of participants with HBsAg <0.05 IU/ml and HBV DNA RESULTSThe intent-to-treat population included 108 participants (Arm 1, n = 55; Arm 2, n = 53). The primary outcome was achieved by 5 (9%) participants in Arm 1 and 8 (15%) in Arm 2. All responders had baseline HBsAg ≤3,000 IU/ml. Indirect comparison with the phase IIb study B-Clear indicates that sequential addition of Peg-IFN may reduce the relapse rates previously observed with bepirovirsen alone. The proportions of participants with adverse events and treatment-related adverse events in both treatment windows were similar between treatment arms.CONCLUSIONSSequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective in participants with chronic HBV infection on stable NA therapy. This proof-of-concept trial demonstrates a potential strategy to extend responses to bepirovirsen by reducing relapse.IMPACT AND IMPLICATIONSThis phase IIb study investigated whether sequential therapy with bepirovirsen followed by Peg-IFN could improve off-treatment response rates to bepirovirsen alone by converting partial bepirovirsen responders to full responders and/or reducing relapse rates in participants with chronic HBV. These data show that sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective; in patients with a bepirovirsen response, sequential treatment with Peg-IFN may help to reduce off-treatment relapses in participants on stable NA. Participants had a similar response during bepirovirsen treatment as seen in B-Clear, with increased response rates in participants with lower baseline HBsAg; all responders to the sequential regimen had baseline HBsAg <3000 IU/mL. As the first study of antisense oligonucleotide-mediated RNA silencing followed by interferon immunomodulation in patients with chronic HBV infection, this study is an important proof-of-concept for sequential therapy, shedding light on the therapeutic potential of utilising immunomodulators following suppression of HBV antigens.CLINICAL TRIAL NUMBERNCT04676724.