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After 12 months of treatment with chronic HBV infection with first-line regimens (nucleosides or nucleotide analogues), only 5% of patients achieve hepatitis B surface antigen (HbsAg) below the detection limit
.
Once the drug is stopped, the patient is at risk of recurrence and even death
.
Therefore, there is an urgent need for a functional cure for HBV infection, i.
e.
, HBVDNA and HbsAg are below the detection limit, and there is no risk of
recurrence after stopping treatment.
The New England Journal of Medicine (NEJM) today has published a Phase 2b randomized trial (published November 8) of the antisense oligonucleotide bepiroversen targeting HBV RNA for hepatitis B virus infection
.
In the trial, patients with hepatitis B received a weekly subcutaneous injection of bepiroversen for 12 or 24 weeks
.
The primary outcome was that both HBV DNA and HbsAg were below the detection limit
for 24 weeks after treatment ended.
The results showed that 300 mg per week of Bepiroversen injections for 24 weeks enabled ~10% of patients to achieve the primary outcome
.
The NEJM editorial at the same time pointed out that new RNA-based therapies such as bepiroversen provide a modern solution to the ancient infectious disease of hepatitis B, but also raise questions
that remain unanswered.
For example, can an HbsAg negative persist after 24 weeks? When can nucleosides or nucleotide analogues be safely discontinued? What factors predict a response? Does HbsAg-negative with RNA therapy actually improve long-term outcomes?
"NEJM Medical Frontiers" specially invited Professor You Hong of the Liver Disease Center of Beijing Friendship Hospital affiliated to Capital Medical University to interpret the research
in depth.
You Hong
Liver Disease Center, Beijing Friendship Hospital, Capital Medical University
Hepatitis B surface antigen (HbsAg) clearance is considered to be one of the most important indicators of sustained remission and clinical prognosis improvement after discontinuation of
hepatitis B.
However, after treatment with existing nucleoside (acid) analogues (NA) or interferon, HBsAg clearance is still unsatisfactory
except for some dominant populations.
This unmet clinical need is the main goal
of new hepatitis B drug development.
In recent years, the research and development of new hepatitis B drugs for the purpose of achieving functional cure (i.
e.
, persistent negative HBsAg after stopping treatment, with or without hepatitis B surface antibodies [anti-HBs], hepatitis B virus (HBV) DNA below the lower limit of detection, normal liver biochemical indexes, and possible covalent closed circular [cccDNA] in the nucleus of hepatocytes
) has become increasingly active.
Up to now, most of them are still in the early/exploratory clinical trial stage, some new drugs have entered phase 3 clinical trials, and China is also actively participating in new drug research and development
.
For different targets in the life cycle of HBV and different links of human immunomodulation, new hepatitis B curative drugs can be divided into two categories
: direct-acting antivirals and immunomodulators.
According to published data, some new drugs have shown good potential in reducing HBsAg levels, among which new RNA-interfering drugs aimed at inhibiting HBV protein synthesis have performed well
.
RNA interference drugs mainly include small interfering RNA (siRNA) and antisense oligonucleotide (ASO).
bepirovirsen is one of the representative drugs of ASO, and data from phase 2 clinical trials published in the previous stage showed that HBsAg could be rapidly and significantly reduced after 4 weeks of administration, and HBsAg clearance was achieved in 4 patients (a total of 31 patients were enrolled) [1].
However, the 4-week treatment period was short, and the HBsAg level rebounded at different times after discontinuation, so the durability of the response needs to be further evaluated
.
The B-Clear study, just presented at the annual meeting of the American Association of Hepatology (AASLD) and published concurrently in the New England Journal of Medicine (NEJM), evaluated the efficacy and safety of bepirovirsen dosing at 12 and 24 weeks in patients with chronic HBV infection treated with and naïve NA [2].
This was a randomized, unblinded Phase 2b clinical trial
.
The investigators enrolled patients with chronic HBV infection with HBsAg> 100 IU/mL in 123 research centers (8 of Chinese mainland) worldwide, and patients were randomly assigned to receive different doses and courses of bepirovirsen or placebo (once weekly subcutaneously, 1,300 mg for 24 weeks; Group 2,300 mg for 12 weeks + 150 mg for 12 weeks; Group 3,300 mg for 12 weeks + placebo for 12 weeks; Group 4, placebo for 12 weeks + 300 mg for 12 weeks), followed up for 24 weeks
after the end of the treatment period.
The primary endpoint was that HBsAg and HBV DNA remained below the lower limit
of detection during the 24-week follow-up period after the end of bepirovirsen's treatment.
In addition, the researchers also evaluated the safety of
the drug.
Figure 1 Design of experiments
A total of 227 treated patients with NA and 230 treatment-naïve patients were included in intention-to-treat analysis (ITT).
Among patients treated for NA, 6 (9%), 6 (9%), 2 (3%), and 0 (0%) patients in each group met the primary endpoint
.
Among treatment-naïve patients, 7 (10%), 4 (6%), 1 (1%), and 0 (0%) patients in each group met the primary endpoint
.
Of particular concern is the low baseline HBsAg (<3 log 10) compared with the baseline high HBsAg (>3log10 IU/mL).
IU/mL) patients were more likely to meet the primary endpoint (6% and 16% treated and 7% and 25% treated naïve in Group 1), and the baseline HBsAg cut-off for the predicted primary endpoint was approximately 3000 IU/mL
.
In terms of safety, compared with placebo, Bepirovirsen treatment for 1 to 12 weeks (group 1~3) had a higher incidence of adverse events, such as injection site reactions (erythema, pain, itching), fever, fatigue, etc
.
Figure 2 The proportion of
patients with both HbsAg and HBV DNA below the detection limit.
Figure 3 Adverse events
.
This study brings some thoughts and tips
for our follow-up and interpretation of new drug clinical trials.
First, for new hepatitis B cured drugs, baseline HBsAg levels may remain the most important predictor
of response.
In this study, the lower limit of baseline HBsAg level in the enrolled population was 100 IU/mL, and the proportion of patients with a baseline of 100~3000 IU/mL who met the primary endpoint was significantly higher than that of patients with >3000 IU/mL
.
This suggests that when designing new drug clinical trials, the baseline HBsAg level of the enrolled population should be taken into account to avoid treatment failure due to high HBsAg in the enrolled population or false response rate due to low HBsAg
.
Baseline HBsAg levels should also be taken into account when interpreting the results of new hepatitis B cured drugs
.
In addition, it is also crucial
for how to select dominant groups to improve response rates in the future.
Second, identifying the causes of repeated elevations in ALT levels is critical
to patient safety.
In the development of new hepatitis B curative drugs, the causes of fluctuations in ALT levels include elevated immune-related ALT (i.
e.
, "good elevation"), hepatitis B virus-induced ALT elevation (e.
g.
, insufficient efficacy or drug resistance), and drug-induced elevated ALT (i.
e.
, drug-induced liver injury).
In this study, two patients experienced serious adverse events associated with elevated ALT, one of which was considered to be hepatitis B virus induced and started NA therapy, and the other had elevated ALT levels accompanied by a significant decrease
in HBsAg levels.
Therefore, in the process of clinical trials, it is necessary to consider the comprehensive judgment of drug treatment time, HBV DNA, HBsAg level, bilirubin and alkaline phosphatase level, whether it is accompanied by fatigue, etc.
, and formulate a clear safety monitoring process and rescue treatment measures to fully ensure patient safety
.
The Phase 2b results make us look forward to the follow-up Phase 3 trial, and clinical trials of Bepirovirsen combined with new drugs with different targets are also underway [3.
4].
Key issues such as discontinuation criteria and the length of the consolidation treatment period also need to be further explored
in longer-term, larger-sample clinical studies.
We look forward to more new drugs in the future through scientific, rigorous and standardized clinical trials to bring us more surprises, and will also help to achieve the "goal of eliminating viral hepatitis as a public health hazard by 2030"
proposed by WHO at an early date.
References
1.
Yuen MF, Heo J, Jang JW, et al.
Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial.
Nat Med 2021; 27:1725-1734.
2.
Yuen MF, Lim SG, Plesniak R, et al.
, for the B-Clear Study Group.
Efficacy and safety of Bepirovirsen in chronic hepatitis B infection.
N Engl J Med 2022; 387:1957-1968.
3.
Cornberg M, Lok AS-F, Terrault NA, et al.
Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference.
J Hepatol 2020; 72:539-557.
4.
Wong GLH, Gane E, Lok ASF.
How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development? J Hepatol 2022; 76:1249-1262.
About the author
You Hong, Vice President of Beijing Friendship Hospital Affiliated to Capital Medical University, Professor, Chief Physician, Researcher, and Doctoral Supervisor
of Gastroenterology Center.
He is currently the vice chairman of the Hepatology Branch of the Chinese Medical Association, and the deputy secretary-general and executive member of the Asia-Pacific Association of
Hepatology.
His research interests include digestive liver diseases, especially chronic liver disease liver fibrosis
.
In terms of clinical research on liver fibrosis, he led the national 12th and 13th Five-Year Major Infectious Diseases Special Project "Reverse Hepatitis B fibrosis Cirrhosis and Intercept Disease Progression Optimization Treatment" project
.
He has presided over key projects and general projects of the National Natural Science Foundation of China
.
Won the National Millions of Talents Project and the New Century Excellent Talent Project
of the Ministry of Education.
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.
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.
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