New hepatitis B drugs: Difference between CpAMs and RNAi targets

New hepatitis B drugs: Difference between CpAMs and RNAi targets. What is the difference between the two targets of hepatitis B global new drug, CpAMs/RNAi, and the mechanism of action.

Although there are currently many new drugs under development in the world of chronic hepatitis B based on core protein allosteric modulators (CpAMs, and also known as capsid assembly modulators in the literature), whether CpAMs can eliminate hepatitis B surface antigen (HBsAg), Hepatitis B e antigen (HBeAg) and or cccDNA still need long-term research.

What is the difference between the two targets of hepatitis B global new drug, CpAMs/RNAi, and the mechanism of action

The new hepatitis B drug ABI-H0731 under study is also based on the CpAMs target. In a double-blind, placebo-controlled study, 38 non-cirrhotic patients were randomly assigned to receive ABI-H0731 or placebo once a day. The administration was continued for 28 days. In the second study, patients with simple hepatitis B e antigen-positive were given Vebicorvir (English translation: VBR, or ABI-H0731) 300 mg daily in combination with entecavir or entecavir and placebo.

When compared with entecavir + placebo treatment, the researchers found that the combination of vebicorvir + ETV had a significant decrease in HBV-DNA and HBV-RNA at the 12th week. In the most recent study data (NCT03576066), 100% of hepatitis B e antigen-negative chronic hepatitis B patients (n=18) received 300 mg of vebicorvir+ETV, TDF or TAF once daily for 48 weeks, HBV- DNA and pgRNA levels are virologically suppressed to less than 20 IU/mL.

Therefore, it seems that the global use of capsid inhibitors, combined with NAs, can lead to a significant reduction in HBV-DNA levels. There is already a phase III study in preparation. Of course, returning to the opening article, whether this new hepatitis B drug based on capsid inhibitors (CpAMs) can eliminate hepatitis B surface antigen, hepatitis B e antigen and or cccDNA requires long-term follow-up research. In addition to the large number of new drugs under research based on CpAMs in the world, RNAi-based interference is also widely used in the research and development of new drugs under research.

How does RNA interference affect HBV?

RNA interference (RNAi), which can directly target HBV transcripts and induce their degradation. RNAi is a highly specific and efficient post-transcriptional gene silencing method. Synthetic small interfering RNA (siRNA) interferes with the expression of specific target genes by degrading mRNA. Unlike RNA therapy, siRNA can inhibit the production of hepatitis B surface antigen, and may rapidly reduce hepatitis B surface antigen and destroy immune tolerance, thereby leading to the recovery of immune response.

A major limitation of this research drug is the reduction of dosing problems and lack of cccDNA. The antisense oligonucleotide is a small nucleic acid complementary to the target transcript, and it functions mainly through steric hindrance of ribonuclease H cleavage and RNA degradation. For example, the previous research drug ARC-520, in two randomized, multi-center studies, was targeted at nucleoside drug (NA) patients who were negative or positive for hepatitis B e antigen.

When compared with the placebo group, the researchers found that the hepatitis B surface antigen level of the high-dose group (2 mg/kg ARC-520+NAs) was significantly reduced, and the hepatitis B surface antigen level of hepatitis B e antigen-negative patients was reduced by an average of 0.38 log IU/mL, while the hepatitis B surface antigen level of hepatitis B e antigen-positive patients decreased by 0.54 log IU/mL on average. This decrease lasted for approximately 85 days. In addition, JNJ-3989 (previously known as) ARO-HBV, it is a modified RNAi that contains 2 types of RNAi, both of which are combined with N-acetylgalactosamine to promote liver uptake.

This new hepatitis B drug JNJ-3989 (ARO-HBV), which is under development, can induce a rapid decline in HBV-DNA and hepatitis B surface antigen in chronic hepatitis B patients. According to recent research data, in 39% (15/38) of chronic hepatitis B patients, injection of entecavir or TDF JNJ-3989 can make the hepatitis B surface antigen continue to decrease by more than or equal to 1 log 10 IU/mL (the above test data From: As of December 28, 2020, a researcher from the Department of Internal Medicine, Yonsei University School of Medicine, Seoul, South Korea, published in the International Journal of Molecular Sciences (International Journal of Molecular Sciences)

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