NEJM(IF=176) Welcome another breakthrough! The clinical trial of Yuen Mengfeng's team at the University of Hong Kong has shown that antisense oligonucleotides are effective and safe in the treatment of hepatitis B

Chronic hepatitis B virus (HBV) infection leads to an increased
risk of cirrhosis and death from hepatocellular carcinoma.
Current treatment regimens (nucleotide analogues (nucleos(t)ide analogs (NAs) and peginterferon) have low
functional cure rates.

Bepirovirsen is an antisense oligonucleotide that targets all HBV messenger RNAs
.
In cell culture and animal models, bepirovirsen leads to a decrease in HBV-derived RNA, HBV DNA, and viral
。

On October 12, 2022, Yuen Mengfeng's team from the University of Hong Kong was present at Nature The journal Medicine published a title titled "Safety, tolerability and antiviral activity of the.
" antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a Phase 2 randomized controlled trial", a randomized, double-blind, placebo-controlled phase II clinical trial (NCT02981602) that first evaluated targeted HBV RNA Safety and antiviral activity
of ASO in patients with chronic hepatitis B who have undergone treatment-naive and virally suppressed.
A total of 31 patients (24 untreated and 7 NA) participated in the continuation of 4 weeks of treatment and followed up for 26 weeks
.

The results showed that most of the adverse events during treatment were mild/moderate (most commonly at the injection site).

In terms of antiviral activity, in the high-dose group (300 mg), patients had HBsAg and HBV DNA levels were significantly reduced compared to placebo, whereas those treated with NA did not
.
In short, The safety and tolerability of bepirovirsen is good, and it is necessary to conduct larger clinical trials in patients with chronic hepatitis B to further study its safety and antiviral activity
.

The team of Yuen Mengfeng of the University of Hong Kong continued the clinical trial on November 8, 2022 in New The England Journal of Medicine published an online article titled "Efficacy.
" and Safety of Bepirovirsen in Chronic Hepatitis B Infection", which conducted a Phase 2b randomized, investigator-unblinded trial (NCT04449029) that showed weekly A dose of 300 mg of bepirovirsen, for 24 weeks, was able to cause 9-10% of chronic HBV Infected participants develop persistent hepatitis B surface antigen B surface antigen (HBsAg) and HBV DNA loss
.
Larger and longer trials are needed to assess follow-up Efficacy and safety
of bepirovirse.

In this Phase 2b randomized, investigator-unblinded trial (B-Clear) to investigate chronic HBV in patients receiving stable NA or not receiving NA In infected patients, the effectiveness and safety
of bepirovirsen treatment for 12 and 24 weeks.
Participants were randomly assigned (3:3:3:1 ratio) and each group was randomly assigned (in a 3:3:3:1 ratio).
), the weekly subcutaneous injection dose is 300 mg of bepirovirsen for 24 weeks (group 1) at a dose of 300 mg Bepirovirsen for 12 weeks, then 150 mg of bepirovirsen for 12 weeks (group 2) at a dose of 12 weeks 300 mg of bepirovirsen for 12 weeks, followed by placebo for 12 weeks (group 3), or placebo for 12 weeks, followed by bepirovirsen 300 mg for 12 weeks (group 4)
。 Groups 1, 2 and 3 received a loading dose of bepirovirsen
.
The main outcome is at the end of the program Within 24 weeks after bepirovirsen treatment, hepatitis B surface antigen (HBsAg) levels were below the detection limit and HBV DNA levels were below the quantitative limit, and no new antiviral therapy
has been initiated.

Figure 1 Experimental design (Image from New England Journal of Medicine).

The final intention-to-treat population included 457 participants (227 receiving NA and 230 not receiving NA treatment )
。 Of the patients treated with NA, six of those in group 1 experienced major outcome events (9%; 95% confidence interval, 0 ~ 31), 6 in group 2 (9%; 95% confidence interval, 0 ~ 43), 2 in group 3 (3%; 95% confidence interval, 0 ~ 16), 0 in group 4 (0%; Post-event confidence interval, 0-8).

Among participants who did not receive NA, seven (10%) experienced major outcome events in groups 1 to 4, respectively; 95% confidence interval, 0 ~ 38), 4 (6%; 95% confidence interval, 0 ~ 25), 1 (1%; Ex post confidence intervals, 0 to 6) and 0 (0%; Post-event confidence interval, 0 to 8).

In weeks 1 ~ 12, the bepirovirsen group (1st, 2nd and 3 groups) had a higher incidence of adverse events (including injection site reactions, fever, fatigue, and elevated alanine aminotransferase levels) than placebo Group 4).

Figure 2 The primary outcome (intention-to-treat population) is from the New England Journal of Medicine

In summary, in a phase 2b trial, 300 mg per week of bepirovirsen was treated for 24 weeks ( Group 1) resulted in 9-10% of participants after the end of treatment with Bepirovirsen24 HBsAg and HBV DNA loss
occurred in weeks.
Results were similar
for participants treated with NA and those who did not.
This efficacy was achieved with a single drug (10% of participants; 95% confidence interval, 0 - 38) and combination NA therapy (9%; 95% confidence interval, 0 ~ 31).

While this was a relatively low percentage of participants overall, it suggests that selecting patients based on baseline characteristics (HBsAg levels are low at baseline), in combination with treatment, or both, has the potential to improve efficacy
.
Larger trials and longer follow-up are needed to assess the safety and efficacy
of Bepirovirsen.

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