Release date: 2017-08-22 Editor's note: There are approximately 257 million hepatitis B (HBV) patients worldwide, and nearly 50% are concentrated in 11 countries, including China. Corresponding to the huge and growing burden of hepatitis B disease, the currently approved standard of care (SOC) for hepatitis B is limited to nucleosides or nucleoside analogues (inhibiting viral polymerase), as well as interferon injections. α (stimulates the immune system's response to infection). These standard therapies only inhibit the virus and are incurable, leading to long-term medication and potential side effects. Therefore, the need for innovative hepatitis B therapy will improve the quality of life of patients as soon as possible. On July 28th of this year, "World Hepatitis Day", we sent you the current research and development pipeline of new hepatitis B drugs. The data show that some early results of HBV monotherapy have confirmed the potential of combination therapy. However, scientists need to explore how many combinations are needed and which components can actually eliminate hepatitis B virus residues after standard therapy. This article is a more detailed review of the progress of hepatitis B research in new drugs, analysis of the world's major companies engaged in hepatitis B drug research companies Arbutus, Johnson & Johnson (Resono) and Replico and Assembly Biosciences research and development pipelines and strategies. It is hoped that within the next 18 months, these companies will soon release potential monotherapy data, and we are expected to see trial data for the addition of a single mechanism of action (MOA) to standard therapies. At the same time, these new drugs with different mechanisms may contribute to more complex combination therapies (cocktail therapy). Let us hope that human beings can make new breakthroughs in this disease field as soon as possible. Mechanism of action of anti-hepatitis B virus drugs The HBV virus consists of a capsid composed of a core protein that contains relaxed viral DNA. Once the virus enters the liver cells, the capsid protein directs the virus to the host cell nucleus. The capsid drives off the loose viral DNA, which is converted by the host cell's enzyme into cccDNA (the active form of viral DNA, which can be transcribed). Transcribed viral mRNA enters the cytoplasm and is converted to viral proteins, including capsid protein (HBcAg), HBsAg and HBV reverse transcriptase. HBsAg is secreted in large quantities from infected cells, causing the host's immune system to collapse. HBV virus structure (Source: Antimicrobe.org) The nucleoside analogue consists of siRNA (silencing RNA), which directly interferes with and destroys the viral RNA, thus providing therapeutic effects. SOC nucleoside analogues, such as Gilead Sciences' Viread (tenofovir), reduce the DNA of hepatitis B virus in the blood, but do not eradicate the storage of circulating DNA (cccDNA) in liver cells; nor against HBV surface antigens ( Systemic immunosuppression caused by HBsAg). Therefore, once treatment is stopped or interrupted, the virus will re-emerge. The shortcoming of existing hepatitis B antiviral therapy is that HBV surface antigen (HBsAg) persists in the body, causing systemic systemic immunosuppression (Source: Replicor official website) Therefore, curing hepatitis B needs to start from four aspects: inhibiting HBV virus replication; inhibiting the secretion of HBV surface antigen into the patient's blood to down-regulate the immune response; and also need to re-awake/activate the host's immune response to make T cells and B Cells can recognize infected hepatocytes; form inhibition and eliminate cccDNA. Arbutus: full attack Dr. Michael Sofia, CSO of Arbutus, was formerly Senior Vice President of Pharmasset, Inc., which was acquired by Gilead for $11 billion in 2012. He discovered and led the drug development of Sovaldi (sofosbuvir), which went on sale in 2013 and completely changed the history of treatment of hepatitis C. (Read in detail: How was one of the most important achievements in public health born?) Dr. Michael Sofia contributed to the development of the heavyweight hepatitis C drug Sovaldi (Source: iupac.org) Now, Arbutus is applying the same innovative thinking to successfully develop a Hepatitis C virus treatment and developing innovative therapies to cure hepatitis B. Arbutus has established a comprehensive research and development pipeline covering four mechanisms for the treatment of hepatitis B virus, including anti-HBV viral replication, immune reactivation and elimination of cccDNA. ARB-1467 is Arbutus's fastest-growing drug in research, an RNAi therapy formulated with lipid nanoparticles (LNP) targeting a conserved region of the three HBV viral genomes. Early data confirmed that it can inhibit HBsAg levels. At the April meeting of the European Association for the Study of the Liver (EASL), Arbutus published data on 18 patients in the 2a dose escalation trial of ARB-1467. In 13 patients, HBsAg decreased by more than 0.5 log, and 6 of them decreased by more than 1 log. The company is evaluating the fourth group of patients in ARB-1467, which is maintained for one year on a biweekly dosing schedule. Arbutus has established a comprehensive research and development pipeline to treat the mechanism of action of hepatitis B virus (Source: Arbutus official website) AB-423 is a capsid inhibitor (1.0) and is undergoing Phase 1 clinical trials. Phase 2 clinical trials are expected to begin this year. In November last year, preclinical data submitted by Arbutus at the American Association for the Study of Liver Diseases (AASLD) showed that AB-423 inhibited the formation of HBV RNA in the outer coat of the virus and converted RNA into The ability of cccDNA. If the virus is equipped with an incorrect shell, you can delay virus replication. AB-506 (capsid inhibitor 2.0) is designed as a capsid inhibitor with better pharmacodynamics and pharmacokinetics than AB-423, and is expected to enter the clinic this year. AB-452 is a small molecule RNA destabilizer and is scheduled to enter clinical trials next year. This molecule has been shown to reduce the effects of HBV proteins, including HBsAg, in preclinical trials. This is a small molecule, but it can stop the virus from producing proteins like RNAi. Arbutus has not yet decided whether to use AB-452 to replace or supplement siRNA therapy. Arbutus is also testing a variety of methods to stimulate the immune response. In December, the company announced a collaboration with Spring Bank Pharmaceuticals to conduct a preclinical study of the combination of AB-423 and SB 9200, a small molecule nucleic acid mixture targeting RIG-I (DDX58) and NOD2 (CARD15). The SB 9200 can increase RIG-I activation. Activated RIG-I binds to viral reverse transcriptase and prevents it from binding to viral RNA to transcribe DNA. In addition, activation of RIG-I and NOD2 triggers an innate immune response and subsequent release of interferon. Arbutus' internal research pipeline also includes checkpoint inhibitors and projects that directly target cccDNA. This year, Arbutus began Phase 2 clinical trials of ARB-1467 in combination with nucleoside analogues and interferon therapy with the goal of achieving undetectable levels of HBV DNA and surface antigens after 12 months of treatment. If the Phase 2 result of AB-423 is positive, Arbutus will also open a new combination of ARB-1467 plus AB-423. Phase 2 AB-423 single-agent clinical trials will begin in the next quarter. Next year, we will be able to see the effects of these tests. Dr. Michael Sofia believes: "In the next four to five years, we may see new hepatitis B drugs that can improve the cure rate, reduce the duration of treatment, and have a major impact on patients." Johnson & Johnson: Cooperative development Johnson & Johnson established the HBV R&D pipeline through internal R&D and external cooperation. There are currently two compounds in preclinical trials and the other in phase 1 clinical trials. In 2015, Johnson & Johnson acquired Novira Therapeutics to obtain a clinical Phase 1 capsid assembly modulator (CAM) NVR 3-778. Johnson & Johnson also has an in-house developed CAM drug JNJ-56136379 (JNJ-379) in Phase 1 clinical. At the AASLD meeting in November last year, Johnson & Johnson released the safety and tolerability data of JNJ-379, showing that the adverse events were mild to moderate. At the same time, in vitro experiments also showed that JNJ-379 reduced HBV RNA levels. Johnson & Johnson believes that HBV RNA is a template for cccDNA, which is an important part of the healing of MOA. It is also indicated that JNJ-379 is more effective in both capsid inhibitors. The mechanism of action of Johnson & Johnson's hepatitis B in the research of new drug capsid assembly regulator JNJ-379 (Source: AASLD) Johnson & Johnson and Arcturus Therapeutics jointly developed the preclinical siRNA project Lunar-HBV in 2015. In a mouse experiment, a single injection of Lunar-HBV resulted in a 1.7 log reduction in HBsAg and a 1.2 log reduction in HBV DNA. This product contains three unlocked nucleocapsid monomer (UNA) oligomers that target all HBV transcripts and cover all known HBV sequences. Johnson & Johnson plans to advance it to the clinic early next year. In terms of immune stimulation, Johnson & Johnson is developing a TLR7 agonist (a license from Sino in 2016) to trigger an immune activation response against viral nucleic acids. Johnson said that this compound stimulates the release of interferon in the liver, which can alleviate T cell failure, but does not produce side effects associated with systemic administration of interferon. These side effects, including flu-like symptoms, make interferon difficult to treat as a long-term treatment for hepatitis B. Johnson & Johnson plans to publish preclinical data at AASLD and plans to begin Phase 1 clinical trials this year. Johnson & Johnson also has an early preclinical vaccine program that delivers HBV DNA plasmids via electroporation of the skin. It sends the plasmid to the skin cells, which then begin to release the HBV antigen and activate T cells and other immune cells to direct the HBV response. Replicor and Assembly: Less is more Both Replicor and Assembly Biosciences believe that cocktail therapy can include fewer ingredients. Replicor believes that since nucleoside analogues have reduced HBV DNA, the key to curing hepatitis B is HBsAg blockade and the use of interferons to provide immune enhancement. Replicator's REP 2139-Ca interferes with the formation of subviral particles and prevents the release of HBsAg from the cells. The compound is a novel therapeutic nucleic acid polymer (NUCLEIC ACID-BASED POLYMERS, NAP) for the treatment of chronic hepatitis, and has broad-spectrum antiviral activity. It contains a phosphorothioate-bonded nucleic acid polymer that acts like an oligonucleotide; however, it is not sequence-dependent, making it non-resistant. Replicor's hepatitis B is studying the mechanism of action of new drug nucleic acid polymer (NAP) (Source: Replicor official website) Phase 2 clinical data published at the EASL meeting in April showed that among the 30 patients treated, REP 2139 plus Viread and interferon were treated for 12 weeks, and 29 patients achieved a reduction in serum HBsAg by more than 1 log. HBsAg was not detected completely in 14 patients. Replicator expects to report follow-up data at the AASLD meeting in October this year to assess whether patients can maintain these reductions after discontinuation. Assembly Biosciences believes that targeting capsids to SOC may be sufficient because capsid proteins are very common in the HBV life cycle. ABI-H0731 is a core protein assembly regulator (CAM) that is undergoing Phase 1b/2 clinical trials of chronic hepatitis B. The company's hypothesis is that the molecule may destroy the virus long enough for the host to produce an autoimmune response similar to the successful mechanism in HCV. Assembly's hepatitis B product line mainly includes capsid assembly regulator CAM (Source: Assembly official website) Dr. Cri Uri Lopatin of Assembly said that in the mid-1920s, companies investigating HCV were reluctant to give up interferon because it is widely believed that the immune system needs to be stimulated and that hepatitis C can never be cured without immunization. But it turns out that when the right small molecule reaches the liver and breaks the virus long enough, the virus can be completely eliminated. "Now we see the exact same debate in HBV." The Assembly hopes to disclose a large amount of the latest data on ABI-H0731 at the AASLD meeting in October. We wish that these new drugs in the research and development of hepatitis B can achieve positive results in clinical trials, and go public as soon as possible to help humans overcome the ills of hepatitis B! Reference material [1] HOW FAR INDUSTRY IS FROM ASSEMBLING A FUNCTIONAL CURE IN HBV [2] Arbutus, Johnson & Johnson, Replicor and Assembly Biosciences [3] Capsid assembly modulator JNJ-56136379 prevents de novo infection of primary human hepatocytes with hepatitis B virus Source: WuXi PharmaTech (Wei Signal WuXiAppTecChina) Infusion And Syringe Pump,Pet Syringe Pump,Medical Vet Syringe Pump,Vet Pet Syringe Infusion Pump Medton Medical , https://www.medton.cn