Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator
Selwyn J. Hurwitz,
Noreen McBrearty,
Alla Arzumanyan,
Eugene Bichenkov,
Sijia Tao,
Leda Bassit,
Zhe Chen,
James J. Kohler,
Franck Amblard,
Mark A. Feitelson,
Raymond F. Schinazi
Affiliations
Selwyn J. Hurwitz
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Noreen McBrearty
Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
Alla Arzumanyan
Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
Eugene Bichenkov
Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
Sijia Tao
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Leda Bassit
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Zhe Chen
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
James J. Kohler
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Franck Amblard
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Mark A. Feitelson
Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
Raymond F. Schinazi
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
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 log10 versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log10 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 EC90 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.
