PRESENTATION TYPE: Poster Only
CURRENT CATEGORY: Viral Hepatitis C
CURRENT DESCRIPTORS: S06. HCV Therapy: Preclinical and Early Clinical Development
TITLE: Discovery and Preclinical Profiling of LG-7501, A Liver-Targeted Hepatitis C Virus (HCV) Nucleotide NS5B Polymerase Inhibitor Designed to Improve Clinical Efficacy and Safety
AUTHORS (FIRST NAME, LAST NAME): Eric G. Vajda1, Keith B. Marschke1, Ian Henderson1, K Raja Reddy1, James M. Fujitaki1, Scott J. Hecker1, Lin Zhi1
INSTITUTIONS (ALL): 1. Ligand Pharmaceuticals Inc., La Jolla, CA, United States.
Background: HepDirect™ technology enables creation of a novel class of cytochrome P450-activated prodrugs capable of targeting certain drugs to the liver, potentially improving the efficacy and safety of the drug. Early lead compound MB11362 (RG7348) demonstrated clinical efficacy in chronic hepatitis C patients in a proof-of-concept study. We now report the discovery and preclinical profiling of LG-7501, a novel, HepDirect™ prodrug of a potent, clinically-validated nucleoside analog, 2′-C-methylguanosine (2'-C MeG), intended to optimize clinical efficacy and safety.
Methods: Activity in the replicon assay and NTP levels in rat and human hepatocytes was evaluated. Pharmacokinetic studies were performed in rats and monkeys to evaluate oral absorption, hepatic extraction, and systemic nucleoside levels. Levels of nucleoside triphosphate (NTP) were measured in the liver and small intestine of rats to compare delivery efficiency and liver targeting.
Results: In hepatocytes, LG-7501 at 10 µM is efficiently converted to NTP levels of 810 ± 460 pmol/106 cells (human) and 560 ± 137 pmol/106 cells (rat), similar to the levels observed with other 2'-C MeG prodrugs in clinical development. LG-7501 is ~99% orally bioavailable in rat liver based on portal vein exposure (AUC) after oral administration. The HepDirect™ prodrug is rapidly cleaved in the rat liver with a hepatic extraction of 89% based on the ratio of portal and jugular vein exposures. The net systemic exposure of the prodrug is consequently low after oral administration (12% bioavailability), however dose normalized systemic levels of 2'-C MeG are comparable by oral (168 ng.h/mL/mg/kg) or i.v. (186 ng.h/mL/mg/kg) administration. In monkeys, LG-7501 prodrug has low systemic bioavailability but 2'-C MeG is orally bioavailable based on the relative i.v. and oral nucleoside exposure. LG-7501 is liver targeted in rats which is demonstrated by superior NTP level (AUC0-24: 79 µg.h/g) in rat liver in comparison to NTP level in rat intestine (8.4 µg.h/g) and plasma 2'-C MeG level (4.5 µg.h/mL).
Conclusions: The HepDirect™ prodrug LG-7501 demonstrates excellent oral bioavailability and efficient hepatic uptake, with enhanced conversion to the potent nucleoside triphosphate in rat liver in vivo and human hepatocytes in vitro. In the clinic, higher intra-hepatic levels of nucleoside triphosphate are expected to improve clinical efficacy, while lower extra-hepatic levels should reduce nucleoside-related side effects.