Therapeutic: bepirovirsen for chronic hepatitis B

15-Jul-2022

The hepatitis B virus causes both acute and chronic disease. Chronic hepatitis B can progress to complications including cirrhosis and liver cancer

Current therapy focuses on viral suppression with interferon or nucleoside/nucleotide analogues, but the functional cure rate is low and the virus may start to replicate again once treatment ceases.

As such, lifelong treatment is required to prevent viral rebound. A functional cure would eliminate the virus from circulating in the blood and prevent further liver disease.

One such potential treatment is being developed by GSK, having been in-licensed from Ionis. Bepirovirsen is an antisense oligonucleotide that’s designed to recognise the RNA used by the virus to replicate within infected hepatocytes, and also to make antigens that help the virus to avoid clearance.

The drug recruits liver enzymes to eliminate this RNA and its subsequent reduction gives a decrease in virus levels and the production of viral antigen by the hepatocytes. It also stimulates immune responses, including Toll-like receptor 8, which may help the immune system to achieve durable viral clearance.

In a double-blind, randomised, placebo-controlled Phase II trial, patients who had had the disease for at least 6 months were randomised to receive subcutaneous injections of 150 or 300 mg of bepirovirsen or a placebo twice a week for 2 weeks, then once a week for a further 2 weeks.1

Of the 31 subjects, 24 were treatment naïve and the rest were stable on nucleoside/nucleotide therapy. Treatment-emergent adverse events were mostly mild or moderate … and predominantly injection site reactions.

Significant reductions in antigen levels compared with the placebo were seen with the higher dose in treatment naïve patients, but not in the other cohorts. Two in each of the 300 mg dose groups achieved antigen levels below the lower limit of quantitation by day 36 of a 26-week observation period.

Interim results of a Phase IIb study have been released.2 In the trial, patients were given loading doses plus 300 mg weekly doses of the drug for 24 weeks, 300 mg for 12 weeks then 150 mg or a placebo for 12 weeks, or a placebo without a loading dose.

The incidence of adverse events was low and similar across all treatment arms.

Of those 227 patients who were stable on nucleoside or nucleotide analogue treatment, 300 mg doses for 24 weeks gave reductions of both viral load and antigen levels to below the lower limit of quantification for 28% of patients.

The proportion for the 230 patients not on nucleoside/nucleotide treatment was 29%. The durability of these responses is now being assessed.

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References

  1. M-F. Yuen, et al., Nat. Med. 27, 1725 (2021).
  2. S.G. Lim, et al., EASL Intl Liver Conf. (London, UK, 22–26 June 2022): Abstr. LB004.
  3. Companies