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Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection
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Download the PDF here
Download the PDF here
November 8, 2022
Although this is a relatively low percentage of participants overall, it indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both.
The B-Clear data suggest that the HBsAg level at baseline may predict response. Participants with a low HBsAg level at baseline were more likely to have a primary-outcome event than those with a high level at baseline, findings that are consistent with previous observations and that highlight the importance of baseline HBsAg levels in predicting response as seen with other HBV therapies.12,24 We found substantial decreases in HBsAg levels in participants with a high HBsAg level at baseline, but the reductions were often not enough to result in HBsAg loss. A receiver-operating-characteristic analysis suggested that an HBsAg level of 3000 IU per milliliter at baseline may be an appropriate cutoff point as a predictor of response.
To put the results of the B-Clear trial in context, in group 1, a total of 9% of the participants receiving NA therapy and 10% of those not receiving NA therapy had both HBsAg and HBV DNA loss maintained for 24 weeks after the end of bepirovirsen treatment. The immunostimulatory activity of bepirovirsen may be mediated through TLR813; this mode of action may explain differences seen as compared with other new HBV therapies.
These findings may represent progress in the search for achieving a functional cure. Optimization of response will most likely require combination therapy to target multiple steps of the HBV life cycle, stimulate the immune system, or both.18,19 Studies are ongoing that combine bepirovirsen with other therapies (e.g., an inhibitor of PAPD5 and PAPD7 [ClinicalTrials.gov number, NCT05330455. opens in new tab], pegylated interferon therapy [NCT04676724. opens in new tab], and ASO-HBV vaccine [NCT03866187. opens in new tab]) to enable more patients to have a response.
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. opens in new tab.)
Chronic hepatitis B virus (HBV) infection is a major worldwide health problem, with an estimated 1.5 million new infections and 820,000 deaths each year (predominantly from cirrhosis and hepatocellular carcinoma).1,2 The goal of therapy is to achieve functional cure - that is, long-term hepatitis B surface antigen (HBsAg) loss, with or without HBsAg seroconversion (positive for antibodies against HBsAg [anti-HBs]), and sustained undetectable HBV DNA after cessation of therapy.3-5 Despite prolonged treatment with nucleoside or nucleotide analogue (NA) therapy (first-line treatment for HBV infection),6 fewer than 5% of patients have HBsAg loss after 12 months of treatment,5,7-11 which underscores the need for therapies capable of achieving functional cure.
Bepirovirsen (GSK3228836), a 2'-O-methoxyethyl modified antisense oligonucleotide, targets all HBV RNAs, including HBV messenger RNA and pregenomic RNA.10 In a phase 2a trial, 4 weeks of bepirovirsen elicited a rapid and dose-dependent reduction in HBsAg levels and, in some participants, transient HBsAg loss.12 Immunostimulatory activity of bepirovirsen through toll-like receptor 8 (TLR8) may be correlated with HBsAg reduction.13
We conducted a phase 2b trial (B-Clear) to investigate the efficacy and safety of 12- and 24-week bepirovirsen treatment in participants with chronic HBV infection either receiving stable NA therapy or not receiving NA therapy. To assess durability of response, the primary efficacy outcome was HBsAg and HBV DNA loss for 24 weeks after the discontinuation of bepirovirsen treatment in the absence of newly initiated antiviral treatment.
Discussion
In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks (group 1) resulted in 9 to 10% of participants having HBsAg and HBV DNA loss for 24 weeks after the end of bepirovirsen treatment. Results were similar in participants receiving NA therapy and those not receiving NA therapy.
Results for the modified primary outcome, which permitted "blips" in response, were consistent with the primary analysis, with 10 to 14% of the participants having an outcome event. HBV DNA "blips" after HBV DNA loss are a known phenomenon when stopping NA therapy and are suggested to represent spontaneous fluctuations due to a release of virions from hepatic reservoirs.16,17 The "blips" in HBsAg seen in the B-Clear trial may have a similar cause.
HBsAg loss is rarely achieved with currently available HBV treatments. New therapies are being developed for the treatment of chronic HBV infection, including small interfering RNAs (siRNAs).18,19 Clinical trials with siRNAs have shown HBsAg reduction to less than 100 IU per milliliter in up to 70% of participants, but no, or very few, participants had HBsAg loss.20-23 To put the results of the B-Clear trial in context, in group 1, a total of 9% of the participants receiving NA therapy and 10% of those not receiving NA therapy had both HBsAg and HBV DNA loss maintained for 24 weeks after the end of bepirovirsen treatment. The immunostimulatory activity of bepirovirsen may be mediated through TLR813; this mode of action may explain differences seen as compared with other new HBV therapies. These findings may represent progress in the search for achieving a functional cure.
Optimization of response will most likely require combination therapy to target multiple steps of the HBV life cycle, stimulate the immune system, or both.18,19 Studies are ongoing that combine bepirovirsen with other therapies (e.g., an inhibitor of PAPD5 and PAPD7 [ClinicalTrials.gov number, NCT05330455. opens in new tab], pegylated interferon therapy [NCT04676724. opens in new tab], and ASO-HBV vaccine [NCT03866187. opens in new tab]) to enable more patients to have a response.
The B-Clear data suggest that the HBsAg level at baseline may predict response. Participants with a low HBsAg level at baseline were more likely to have a primary-outcome event than those with a high level at baseline, findings that are consistent with previous observations and that highlight the importance of baseline HBsAg levels in predicting response as seen with other HBV therapies.12,24 We found substantial decreases in HBsAg levels in participants with a high HBsAg level at baseline, but the reductions were often not enough to result in HBsAg loss. A receiver-operating-characteristic analysis suggested that an HBsAg level of 3000 IU per milliliter at baseline may be an appropriate cutoff point as a predictor of response.
Most patients with chronic HBV infection are HBeAg-negative, with the prevalence of this subgroup increasing.25 In HBeAg-negative patients, HBV sequences are potentially integrated (with some HBV sequences deleted) into the host genome, and the integrated HBV DNA is a primary source of HBsAg.26The HBsAg reductions and loss with bepirovirsen that we observed in HBeAg-negative participants suggest that the bepirovirsen target site is preserved in the majority of integrated HBV-derived transcripts. In HBeAg-positive participants, a primary-outcome event occurred only in those receiving NA therapy. Because the primary driver of response seemed to be the HBsAg level at baseline, the apparent lack of response in HBeAg-positive participants who were not receiving NA therapy may be explained by higher HBsAg levels at baseline in this subgroup, with only two HBeAg-positive participants having a low HBsAg level at baseline.
In patients with HBV, ALT flares can be a result of disease activity, immune clearance of HBV-infected hepatocytes, or drug-induced liver injury.12,27,28 There were two serious adverse events related to ALT changes, which are discussed further in the Results section in the Supplementary Appendix, and one case of Gilbert's syndrome. Otherwise, increases in ALT levels were asymptomatic and resolved without increases in bilirubin or alkaline phosphatase levels and without evidence of liver dysfunction.
During the first 12 weeks of the trial when group 4 received placebo, adverse events (primarily those identified as adverse events of special interest, including an increased ALT level) were more common with bepirovirsen than with placebo. Other commonly reported adverse events were pyrexia and fatigue. Eight serious adverse events occurred in the first 12 weeks of bepirovirsen treatment and none with receipt of placebo. Overall, injection-site reactions were the most common adverse events; two participants (one receiving NA therapy and one not receiving NA therapy) withdrew owing to an injection-site reaction. Among participants receiving NA and those not receiving NA therapy, bepirovirsen at a dose of 300 mg weekly for 24 weeks did not show any marked difference in safety or side-effect profile as compared with other regimens.
In this phase 2b trial, 24-week treatment with bepirovirsen at a dose of 300 mg per week induced HBsAg and HBV DNA loss for 24 weeks after the end of treatment. This efficacy was achieved with a single agent (in 10% of participants; 95% credible interval, 0 to 38) and in combination with NA therapy (in 9%; 95% credible interval, 0 to 31). Although this is a relatively low percentage of participants overall, it indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both. Durability of response is being investigated in the B-Sure trial (ClinicalTrials.gov number, NCT04954859. opens in new tab), which will follow participants for an additional 33 months and includes criteria for stopping NA therapy. Larger trials and longer follow-up are needed to assess the safety and efficacy of bepirovirsen.
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