Hepatitis B: New drug GLP-26 under development

Hepatitis B: New drug GLP-26 under development. Preclinical, potential cardiotoxic cynomolgus PK study.

In the special issue “Capsid Targeted Antiviral Drugs and Host Factors” of the scientific journal “Viruses”, a researcher in the Laboratory of Pediatric Biochemical Pharmacology at Emory University School of Medicine and School of Child Health, and the Department of Biology, Temple University School of Science and Technology Introduced, the new hepatitis B drug GLP-26 as a powerful HBV capsid assembly modulator has the efficacy, potential cardiotoxicity and pharmacokinetic data of cynomolgus monkeys (see figure below: from Viruses).

Hepatitis B new drug GLP-26, preclinical, potential cardiotoxic cynomolgus PK study

According to the researchers, we recently discovered GLP-26, which is an oxalamide derivative that regulates the assembly of HBV capsids. Although there are treatment options for patients with hepatitis B virus (HBV) infection, there is currently no cure. Anti-HBV nucleoside analogues and interferon-α-2b rarely remove HBV covalently closed circular DNA (cccDNA) and require life-long treatment. Researchers from Emory University in the United States evaluated the effects of GLP-26 on virus replication and DNA integration in nude mice/AD38 mouse models transfected with HBV.

The results of the study showed that on the 45th day after infection, GLP-26 reduced the HBV titer by 2.3-3 log10 compared with the placebo-treated infected mice. Compared with placebo, the combination therapy of GLP-26+Entecavir (ETV) reduced HBV log10 titer by 4.6 times. Next, the researchers also administered intravenous IV (1 mg/kg) or oral PO (5 mg/kg) via gastric tube, and tested the pharmacokinetics of GLP-26 in cynomolgus monkeys (PK).

The results showed that the oral bioavailability of GLP-26 was 34%, and the average infusion time was 3.17 h. The peak average plasma concentration produced by the oral dose was 380.7 ng/mL, and the terminal elimination half-life was 2.4 h. The binding rate of GLP-26 in monkey plasma was 86.7%. Finally, GLP-26 demonstrated good toxicity in human primary cardiomyocytes. Therefore, researchers such as Emory University believe that GLP-26 can be used as a supplementary treatment for HBV infection, and further preclinical development is needed.

Because this is an early version published by Emory University in the special issue of the scientific journal Viruses on January 15, 2021, it is expected that the complete test data version will be released soon. GLP-26 is based on a capsid inhibitor and is being studied in preclinical studies. In the process of hepatitis B virus replication, there is a very important link, namely the assembly of the capsid. In this capsid assembly process, the hepatitis B virus replication template cccDNA and viral reverse transcriptase are packaged into the capsid protein together to form the entire capsid assembly process and achieve subsequent reverse transcription.

Therefore, many pharmaceutical companies or scientific research institutions around the world have tried to block this step in the life cycle of hepatitis B virus: capsid assembly by blocking capsid protein assembly or accelerating the degradation of capsid protein. The principle of blocking capsid assembly is different from the currently approved entecavir and tenofovir dipivoxil, but they can all affect HBV replication, but the steps that affect the virus life cycle are different. There are also more and more medical scientists who regard capsid assembly inhibitors (or capsid assembly regulators) as new targets for the development of hepatitis B antiviral drugs.

This research refers to the Laboratory of Pediatric Biochemical Pharmacology of Emory University School of Medicine and School of Child Health Care, and the Department of Biology, School of Science and Technology, Temple University. Researchers include Selwyn J. Hurwitz, Noreen McBrearty, Alla Arzumanyan, Eugene Bichenkov , Sijia Tao, Leda Bassit, Zhe Chen, James J. Kohler, Frank Amblard, Mark A. Feitelson, Raymond F. Schinazi, together on January 15, 2021, the special issue of the scientific journal Viruses, “Capsid Targeted Antiviral Published on “Drugs and Host Factors”.

In short, researchers from Emory University School of Medicine in the United States published data on the efficacy, potential cardiotoxicity, and monkey pharmacokinetics of GLP-26 as a powerful modulator of HBV capsid assembly on Viruses. According to the researchers, we have discovered GLP-26, an oxamide derivative that regulates the assembly of HBV capsids. It may be used as a complementary treatment for HBV infection, and further preclinical development is needed in the future

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