ARC-520

There are two main methods for combating chronic hepatitis B virus infection, one is interferon/polyethylene glycol interferon, and the other is oral antiviral drugs. But these two methods have their limitations and cannot be promoted on a large scale like a vaccine. For example, although interferon can regulate immunity and achieve a relatively high seroconversion rate of e antigen and surface antigen, its side effects are large, not suitable for patients with decompensated cirrhosis and pregnant women, and the therapeutic effect varies according to HBV genotype. On the other hand, oral nucleotide analogs can strongly inhibit HBV virus replication, have an excellent effect in preventing the progression of liver cirrhosis and reducing the incidence of liver cancer, but have no direct effect on viral cccDNA, which may result in the excessively long treatment cycle.

In summary, there is an urgent need for a new treatment to address the risks to human health caused by chronic hepatitis B infection. The emergence of RNA interference (RNAi) treatment programs undoubtedly brings a new perspective to chronic hepatitis B antiviral therapy. It should be emphasized that an effective targeted RNAi treatment method relies more on the "targeting" process, that is, the effective delivery of siRNA to target cells and the target cytoplasmic presentation system. ARC-520 is an RNAi therapeutic agent designed to reduce all RNA transcripts derived from cccDNA, thereby reducing viral antigens and HBV DNA. Its Dynamic PolyConjugates (DPCs) delivery system is the key to the advancement of ARC-520 animal experiments and clinical trials.

ARC-520 mechanism of action. Figure 1. ARC-520 mechanism of action.

HBV Virus Replication Process and ARC-520 Target Position

The HBV replication process can be divided into 6 steps:

  • The virus enters the hepatocyte cytoplasm, and its nucleocapsid is cleaved to form relaxed circular DNA (rcDNA), which enters the hepatocyte nucleus and repairs rcDNA into cccDNA under the action of viral DNA polymerase and host enzymes.
  • Using cccDNA as the template, under the action of host cell RNA polymerase, it was transcribed into 4 viral messenger RNA (mRNA) and pregenomic RNA (pgRNA) of different lengths to translate various HBV proteins.
  • Viral polymerase and capsidization signal work together on pgRNA to initiate reverse transcription and nucleocapsid assembly.
  • Reverse transcription to synthesize viral negative-strand DNA, while viral polymerase digests viral RNA template.
  • After the viral negative-strand DNA is synthesized, the remaining RNA is used as a primer to start the positive strand DNA synthesis.
  • Complete positive-strand DNA synthesis to form rcDNA, while the nucleocapsid is coated with the outer membrane and secreted out of the cell as an infectious virion.

It can be seen that if the mRNA can be effectively destroyed so that it cannot express viral proteins, the level of the virus antigen in the body can be greatly reduced, and the body's immunity can be restored with sufficient space. The principle of ARC-520 is based on this. The two kinds of siRNA loaded with it can destroy various transcripts from HBV cccDNA transcription through two different targets, block a series of subsequent protein synthesis, and reduce viral load and virus-related antigen load. Known viral proteins including e antigens and surface antigens are related to the body's immune tolerance status. Therefore, the intervention of ARC-520 may be able to rebuild the body's immunity to HBV and eliminate HBV virus.

ARC-520 Therapy for HBV

In the early animal experiments, the injection of ARC-520 in mice can achieve several log reductions of HBV RNA, HBsAg and viral DNA, and achieve HBeAg below the detection limit. In primate experiments such as chimpanzees, the researchers found that ARC-520 2mg/kg single intravenous injection is well tolerated and can cause HBsAg, HBeAg, and HBV DNA to decline significantly. Intravenous injection once again at a dose of 3 mg/kg can increase the curative effect and reduce the above-mentioned indicators by 81-96%. The degree of decline of these indicators and the duration of the effect are consistent with the previous animal experiment results on mice.

Finally, it should be pointed out that the purpose of ARC-520 is not to eliminate HBsAg directly by single-dose injection, but to reduce HBsAg low enough (such as at least 1 log) to give the body's own immune system enough space to a functional cure. In addition, although ARC-520 has a damaging effect on mRNA transcribed from cccDNA, it has no damaging effect on mRNA transcribed from DNA fragments embedded in the human genome. This mechanism also determines the limited scope of ARC-520.

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For research use only. Not intended for any clinical use.