Author information

¹Department of Medicine and State Key Laboratory of Liver Research, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China. mfyuen@hkucc.hku.hk.

²College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.

³Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.

⁴Seoul National University Hospital, Seoul, Republic of Korea.

⁵Kyungpook National University Hospital, Daegu, Republic of Korea.

⁶Inje University Busan Paik Hospital, Busan, Republic of Korea.

⁷Ionis Pharmaceuticals Inc, Carlsbad, CA, USA.

⁸GlaxoSmithKline, Collegeville, PA, USA.

⁹GlaxoSmithKline, Stevenage, UK.

¹⁰GlaxoSmithKline, Research Triangle Park, NC, USA.

Abstract

Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml^-1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population.

Annotation:

Jacobson, I. (2021) Yuen MF, Heo J, Jang JW et al. Safety, tolerability and antiviral activity of the antisense olionucleotide bepiroversen in patients with chronic hepatitis B: a phase 2 randomized trial.  Nat Med 2021;27(10):1725-1734

Targeting of HBV mRNA transcripts in an effort to sharply reduce HBsAg expression is thought to have the potential to stimulate immune reconstitution of “exhausted T cells” after a long period of suppression postulated to be induced by years of circulating HBsAg in chronic HBV infection.  Achievement of this goal is being sought actively in programs using novel small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs).  In this phase 2 study, the authors report their results with 4 weeks of treatment with bepiroversen, an ASO, in 24 treatment naïve HBV-infected patients and nine patients on nucleotide analogue therapy.  Significantly greater reductions in HBsAg levels were noted with the higher of the two doses studied (300 mg vs 150 mg), and greater reductions occurred in HBeAg-negative patients and nucleotide treated patients.  Four patients, all HBeAg negative (2 naïve, 2 on nucleotide therapy), cleared HBsAg transiently at weeks 4-5.  ALT flares (over 2 x ULN) were common, but no serious flares were reported.  One of the most interesting aspects of the paper is the discussion about how the data appear to indicate target engagement with transcripts from integrated HBV DNA, from which a preponderance of the HBsAg in HBeAg-negative patients is thought to arise, as opposed to cccDNA from which HBsAg is thought to arise in large part in HBeAg-positive patients.  The recognition of integrated HBV DNA as a source of HBsAg is one of the more important discoveries in HBV biology in recent years, with important implications for ongoing efforts to induce “functional cure” of chronic hepatitis B.