Abstract
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.
Highlights
Hepatitis B virus (HBV) causes significant morbidity and mortality globally [1,2]
Among some HBV carriers, this is associated with the development of chronic hepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [3]
Most mice in group II treated with GLP-26 alone (55 mg/kg on Mondays, Wednesdays and Fridays via feeding tube) had reduced tumor volume (T/V) ratios, but only partially, and T/V ratios increased over time to near pre-treatment levels (Figure 1B)
Summary
Hepatitis B virus (HBV) causes significant morbidity and mortality globally [1,2]. Among some HBV carriers, this is associated with the development of chronic hepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [3]. But they are ineffective in individuals with established infections. Current antiviral nucleoside analogs (NUCs) and interferon therapies rarely clear covalently closed circular DNA (cccDNA), requiring lifelong treatment [4]. HBV persists in the majority of chronically infected individuals due to the formation of cccDNA in the nucleus of hepatocytes. Current therapies require long-term administration to maintain suppression, which may result in reduced compliance and the emergence of resistant virus [3]
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