Bepirovirsen treatment leads to sustained loss of hepatitis B markers for up to one in five

Up to one in five people with hepatitis B treated with the experimental antiviral bepirovirsen achieved a sustained loss of hepatitis B surface antigen (HBsAg) and HBV DNA, a sign indicating the possibility of long-term functional cure or remission, 24 weeks after stopping treatment with the drug, investigators from the B-CLEAR study reported earlier this month at the AASLD Liver Meeting in Washington DC.

HBsAg loss was associated with lower HBsAg levels before starting bepirovirsen treatment, suggesting that this drug is likely to be suitable for a subset of people with hepatitis B.

Bepirovirsen (GSK-3228836) is an antisense oligonucleotide, a chain of nucleic acid designed to cut hepatitis B RNA, preventing the transcription of viral proteins.

The drug was developed by the biotechnology company Ionis and has been licensed to GlaxoSmithKline (GSK) for development, along with a second antisense oligonucleotide, GSK3389404. GSK aims to develop a functional cure – long-term virus suppression after a fixed course of treatment – using a combination of agents.

A functional cure is judged to have been achieved if hepatitis B surface antigen is cleared from the blood and remains undetectable after stopping all treatment. Although a functional cure doesn’t rid the body of hepatitis B virus, the absence of HBsAg shows that the virus is no longer replicating and causing liver damage. Current treatment suppresses hepatitis B virus for as long as it is taken, but very few people achieve a functional cure after stopping nucleoside or nucleotide analogue (NA) treatment.

Professor Man-Fung Yuen of the Queen Mary Hospital, Hong Kong, presented final endpoint data from the B-CLEAR study, a randomised study of four different doses of bepirovirsen in people with hepatitis B infection controlled by nucleoside or nucleotide antiviral treatment.

Interim results of the B-CLEAR study were presented at the International Liver Congress in June 2022, reporting on outcomes after 24 weeks of treatment.

At The Liver Meeting, Professor Yuen reported on the primary study endpoints, HBsAg levels below the limit of quantitation and an HBV DNA < 20 IU/ml 24 weeks after discontinuing study treatment, in people on stable nucleoside or nucleotide treatment.

People already taking stable NA treatment (tenofovir disoproxil fumarate or entecavir) were eligible to join the study if they had HBV DNA below 90 IU/ml, ALT no more than two times the upper limit of normal and HBsAg above 100 IU/ml.

Participants were randomised to one of four bepirovirsen dosing regimens. Bepirovirsen is administered by injection and participants received loading doses of 300mg at days 4 and 11 followed by weekly doses or placebo injections during the 24-week treatment period.

The study recruited a total of 227 participants. Approximately three-quarters of study participants were male, 52% were Asian, 69% were HBeAg negative and 72% had baseline HBsAg levels above 3log10 IU/ml. The majority had been taking nucleoside or nucleotide treatment for at least three years.

After 24 weeks of bepirovirsen treatment and a further 24 weeks of stable nucleoside or nucleotide treatment, 9% of study participants who received 24 weeks of bepirovirsen had experienced loss of hepatitis B surface antigen and had HBV DNA below 20 IU/ml. Three per cent of those who received bepirovirsen for 12 weeks followed by 12 weeks of placebo injections achieved the primary outcome.

HBsAg loss occurred more frequently in participants with baseline HBsAg levels below 3log10 IU/ml. In the study arms exposed to bepirovirsen for 24 weeks, 16% and 22% achieved HBsAg loss compared to 6% and 2% of those with baseline HBsAg above 3log 10 IU/ml.

Approximately half of participants who achieved HBsAg less after 24 weeks of bepirovirsen treatment maintained this loss 24 weeks after the end of treatment.

Treatment discontinuation due to adverse events was uncommon; 26 participants experienced grade 3 or 4 adverse events and eight discontinued study treatment. Only one serious adverse event was considered to be associated with the study treatment. There was no difference in adverse events between the study arm receiving the greatest bepirovirsen exposure (300mg for 24 weeks) and other study arms.

Yuen MF et al. Bepirovirsen (BPV) in patients with chronic hepatitis B virus (HBV) infection controlled by nucleos(t)ide analogue therapy: HBV DNA and HBsAg loss 6 months after end of BPV treatment (B-CLEAR study). AASLD Liver Meeting, Washington DC, late breaker abstract session 3, 2022.