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.
Highlights
Treatment-naïve patients were randomized to placebo (n = 6), bepirovirsen 150 mg (n = 6) or 300 mg (n = 12) and on-nucleos(t)ide analogue (NA) patients to placebo (n = 2) or bepirovirsen 300 mg (n = 5) (Supplementary Fig. 2)
No sequence alterations were found in any of the samples assessed at baseline (n = 25), day 29 (n = 17) and day 113 (n = 7). This is the first study in which bepirovirsen has been administered to patients with chronic hepatitis B (CHB)
Based on the findings of the current study, we suggest that the observed hepatitis B surface antigen (HBsAg) reduction is related to bepirovirsen treatment, with the reduction in HBsAg leading to ALT increase, which is possibly due to immune clearance of infected hepatocytes
Summary
Objectives and endpointsThe primary objective of the study was to examine the safety and tolerability of bepirovirsen administration in treatment-naïve participants with CHB infection (primary endpoints were AEs, clinical laboratory tests, vital signs and body weight, physical examination, electrocardiogram and concomitant medication usage).Secondary objectives and endpoints were to: examine the effects of bepirovirsen administration on plasma HBV DNA concentration (change from baseline to day 29 and week 31); examine the effects of bepirovirsen administration on serum HBsAg concentration (change from baseline to day 29 and week 31, proportion of participants with HBsAg loss at day 29 and at week 31); examine the effect of bepirovirsen administration on serum HBeAg concentration in patients who were HBeAg positive at baseline (change from baseline to day 29 and week 31, proportion of participants with HBeAg loss at day 29 and at week 31); assess plasma pharmacokinetics of bepirovirsen in patients with chronic HBV infection (to be published separately); and describe the safety and tolerability of tenofovir disoproxil fumarate (TDF) (and entecavir (ETV) if administered) therapy following conclusion of bepirovirsen administration (AEs after day 29; as the safety profile of TDF and ETV is well established we have not reported this endpoint here).Exploratory endpoints and objectives included describing the rate of seroconversion to anti-HBs or anti-HBe antibody-positive during treatment with bepirovirsen and during subsequent treatment with TDF, or ETV if administered (proportion of patients with antibody positivity at day 29 and at week 31).Key eligibility criteria. The primary objective of the study was to examine the safety and tolerability of bepirovirsen administration in treatment-naïve participants with CHB infection (primary endpoints were AEs, clinical laboratory tests, vital signs and body weight, physical examination, electrocardiogram and concomitant medication usage). Inclusion criteria were chronic HBV infection ≥6 months and serum HBsAg ≥50 IU ml−1; both HBeAg-positive and HBeAg-negative patients could participate. On-NA patients had HBV DNA adequately suppressed (plasma or serum HBV DNA below LLOQ (20 IU ml−1)), were taking stable TDF or ETV for ≥12 months and expected to continue taking stable TDF or ETV without change through to the end of their participation in this study
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