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    Home > Active Ingredient News > Infection > Looking at the infinite potential of RNAi from the functional cure of hepatitis B

    Looking at the infinite potential of RNAi from the functional cure of hepatitis B

    • Last Update: 2022-01-10
    • Source: Internet
    • Author: User
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    Vir hepatitis B therapy has clinical potential, RNAi is expected to beat hepatitis B On December 9, the emerging Biotech company Vir announced that a phase 2 clinical trial of its research pipeline VIR-2218 has completed the first patient administration
    .

    VIR-2218 is an RNAi therapy product used to treat patients with chronic hepatitis B virus (HBV) infection
    .

    Vir is collaborating with Gilead to evaluate the efficacy of VIR-2218 in combination with TLR-8 agonists Selgantolimod and PD-1 Nivolumab in the treatment of newly-treated or treated hepatitis B patients, with the goal of achieving a functional cure
    .

    Data source: Vir R&D day, Caitong Securities Research Institute VIR-2218 was jointly developed by Vir and the leading RNAi company Alnylam.
    From the design point of view, VIR-2218 targets the highly conserved DR2 region in the X gene of HBV, and its use SiRNA can inhibit integrated viral DNA (intDNA) and covalently closed circular DNA (cccDNA) at the same time, can degrade a variety of HBV RNA, and inhibit the production of all HBV proteins, including HBV surface antigens (small, medium and large S antigens), Core related protein, X protein and polymerase
    .

    At the same time, VIR-2218 uses Alnylam's ESC modification technology, which increases the stability of siRNA while increasing the stability of siRNA
    .

    On the carrier, VIR-2218 uses GalNAc delivery technology
    .

    Prior to this, VIR-2218 has shown great therapeutic potential
    .

    First, in June of this year's EASL meeting, Vir announced VIR-2218 monotherapy hepatitis B clinical I / Phase II trial results
    .

    The VIR-2218 test group recruited 24 patients with chronic hepatitis B without severe liver fibrosis or cirrhosis.
    Among them, 18 were HBeAg negative and 6 were HBeAg positive.
    They were divided into four dose groups: 20 mg, 50 mg, 100 mg, and 200 mg.
    A corresponding dose of VIR-2218 was injected subcutaneously on the 1st and 29th days
    .

    In terms of safety, there were 1 case of adverse reactions above grade 3 and 5 cases of treatment-related adverse reactions.
    The overall safety was good
    .

    The 48-week follow-up results showed that the patients' HBsAg level decreased in a dose-dependent manner, and 71% of the patients' HBsAg level decreased by more than 1 log10
    .

    Although no patient achieved complete HBsAg clearance, 4 of the 12 patients in the 100mg and 200mg groups had HBsAg levels lower than 100 IU/mL for 48 weeks
    .

    Then, at the November AASLD, Vir announced the preliminary results of the Phase II clinical trial of the combination of VIR-2218 and PEG-IFN-α
    .

    Data show that when receiving VIR-2218 subcutaneous injection alone or in combination with PEG-IFN-α (PEG-IFN-α) for 24 weeks, 64 adult patients with chronic HBV infection all showed significant HBsAg reduction (Average>2 log10 IU/mL)
    .

    The VIR-2218/PEG-IFN-α combination treatment regimen resulted in an earlier treatment response and a greater reduction in HBsAg
    .

    Among patients receiving combination therapy, 95% (n=21/22) HBsAg level <100 IU/mL, and 55% (n=12/22) HBsAg level <10 IU/mL
    .

    Vir RNAi therapeutics, cure hepatitis B seems to function lit the road
    .

    Why is the treatment of hepatitis B so difficult? Hepatitis B affects nearly 250 million people around the world, and about 650,000 people die from HBV-related end-stage liver disease every year.
    There are about 80 million hepatitis B virus carriers in China, and the clinical unmet demand is huge
    .

    Hepatitis B is mostly asymptomatic in the early stage, and hepatitis, liver fibrosis and even liver cancer will gradually appear as the disease progresses
    .

    Commonly used nucleoside drugs (entecavir, tenofovir, etc.
    ) need to be taken for life and can only inhibit hepatitis B virus replication and delay the disease process, and cannot achieve clinical cure, that is, functional cure, and cannot achieve liver inflammation and histopathological improvement.
    The goal of reducing the incidence of end-stage liver disease, including liver cancer
    .

    From the point of view of the virus structure, the hepatitis B HBV virus is composed of a nucleocapsid (HBcAg in serology) with an envelope containing 3 kinds of outer membrane proteins (HBsAg in serology)
    .

    The viral genome contained in the nucleocapsid is a partially double-stranded loose circular DNA, namely RC-DNA
    .

    After the HBV virus enters the cell in the form of endocytosis, the nucleocapsid enters the nucleus under the action of the core protein nuclear localization signal, and releases RC-DNA, and finally forms cccDNA
    .

    The most notable feature of the HBV genome is its compact structure and complete functions
    .

    The open reading frame (ORF) of the HBV genome overlaps.
    Through the use of host cell RNA polymerase for transcription, 3 types of subgenomic RNA can be produced for synthesizing viral proteins, and 2 types of RNA longer than the genome are used for virus replication, Translate the core shell and so on
    .

    It can be seen from the life cycle of HBC infection that cccDNA is the template for HBV to replicate in the liver and is the basis for effective infection
    .

    As viral replication intermediary, which is present in the form of micro-chromosome in the host liver cells, current treatment methods difficult to be completely removed, so as to achieve complete cure of chronic hepatitis B
    .

    And, for lack of cccDNA exist mechanism and research methodology has been plagued by a major obstacle to a functional cure for hepatitis B
    .

    Judging from the current clinical situation, there are patients with long-term decline in cccDNA, and viral rebound due to discontinuation of nucleoside drugs or immunosuppression, indicating that cccDNA can continue to exist for decades
    .

    It is not clear whether the life cycle of cccDNA depends on a single molecule, or is there an update of cccDNA? If there is an update, how did it go? What are its dynamic characteristics? There are forms of cccDNA that are more difficult to decompose, such as methylation and chromosomalization
    .

    The mechanism is still unclear.
    The RNAi method is the best treatment method.
    The steady state of the cccDNA pool in liver cells depends on the rate of growth and decline of cccDNA.
    However, there are still many mechanisms for cccDNA that are not understood, especially in terms of renewal kinetics.
    CccDNA seems to be a more straightforward choice
    .

    In this case, due to the unclearness of the replication pathways involved in cccDNA, the commonly used treatment strategies are roughly divided into two categories: 1.
    Immune-mediated clearance of cccDNA, but this has higher requirements for the patient’s immune level.
    And the use of high-dose interferon-α has certain side effects; 2.
    Regulate cccDNA at the genetic level
    .

    Since there may be HBV viral DNA integrated into the liver cell genome, and the virus may use the DNA repair system to re-replicate, and the proteins involved in the viral replication pathway may have an impact on other human pathways, therefore, clinically "reversible" methods such as RNAi technology regulates cccDNA replication and may be the most suitable treatment option today
    .

    Moreover, RNAi has great potential in combination with other drugs
    .

    Because hepatitis B is actually an immune-mediated infectious disease, its occurrence and development, virus suppression, and HBsAg clearance are closely related to the body's immunity
    .

    Specifically, hepatitis B drugs such as siRNA and neutralizing antibodies can significantly reduce HBsAg levels, and siRNA can effectively reduce cccDNA levels
    .

    Immunotherapy, including PD-L1, long-acting interferon, etc.
    , has a weak ability to reduce HBsAg, but it can help patients with low HBsAg levels (for example, <100 IU/mL) to help patients achieve long-term virus clearance by enhancing their own immunity
    .

    Therefore, the two complement each other and can create a broad market
    .

    It can be seen from this that in the treatment of diseases such as hepatitis B, emerging technologies led by RNAi have significant advantages brought about by new mechanisms, and will not conflict with existing treatments, but can create greater space for joint use.
    Broad market prospects
    .

    RNAi is bound to lead the third revolution in biomedicine together with other new therapies
    .

    In order to analyze the entire industry chain of nucleic acid drugs, promote the integration of industry, university and research, and promote the industrialization of nucleic acid drugs in China, it is under the guidance of the Hangzhou Pharmaceutical Port Management Office, the Institute of Oncology and Basic Medicine of the Chinese Academy of Sciences, sponsored by Haichang Biotechnology, co-organized by Caitong Securities, and Baiao The 2022 Nucleic Acid Drug Industry Summit (Hangzhou) Forum (NAMI) hosted by Gu will be held in Hangzhou on March 25-26, 2022.
    The information of the conference is as follows: About the organizer-Haichang Biotech Zhejiang Haichang Biomedical Technology Co.
    , Ltd.
    is located Hangzhou Pharmaceutical Harbor Town is a national high-tech enterprise dedicated to the research and development of innovative biomedical technology, founded by Dr.
    Xiaobin Zhao, a former senior FDA review expert
    .

    Focusing on the core values ​​of "sharing, enterprising, seeking truth and being pragmatic", the company focuses on the development of products in the fields of mRNA vaccines, RNA drug delivery, liposome nanomedicine, and products covering anti-tumor, anti-infection and analgesic fields , The product pipeline is extremely competitive
    .

    Based on China and facing the world, the company strives to become an international pharmaceutical company integrating R&D, production and sales
    .

    The company's newly established Nucleic Acid Innovation Institute (NAMIC), headed by Dr.
    Yongsheng Yang, focuses on the research and development and clinical transformation of nucleic acid drugs such as ASO, siRNA, miRNA and mRNA
    .

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