Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator

• Published in: Viruses 2021-01, Vol.13 (1), p.114
• Main Authors: Hurwitz, Selwyn J, McBrearty, Noreen, Arzumanyan, Alla, Bichenkov, Eugene, Tao, Sijia, Bassit, Leda, Chen, Zhe, Kohler, James J, Amblard, Franck, Feitelson, Mark A, Schinazi, Raymond F
• Format: Article
• Language: English
• Subjects: Animals; Bioavailability; Capsid - drug effects; Capsid - metabolism; capsid effector; Cardiomyocytes; Cardiotoxicity; Cardiotoxins - pharmacokinetics; Chromatography; Circular DNA; cynomolgus monkeys; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA biosynthesis; Dose-Response Relationship, Drug; Drug dosages; Drug resistance; Experiments; GLP-26; Hepatitis; Hepatitis B; Hepatitis B - drug therapy; Hepatitis B - virology; hepatitis B virus; Hepatitis B virus - drug effects; Hepatitis B virus - physiology; Humans; Laboratories; Macaca fascicularis; Male; Mice; Molecular weight; Myocytes, Cardiac - drug effects; Nucleoside analogs; Pharmacokinetics; Placebos; Plasma; Polyethylene glycol; Protein folding; Software; Sulfonylurea Compounds - adverse effects; Sulfonylurea Compounds - chemistry; Sulfonylurea Compounds - pharmacokinetics; Tumors; Viral Load; Virus Assembly - drug effects; Xenografts; α-Interferon
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v13010114

While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3-3 log versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold > in vitro EC corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng·hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection.