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Abstract Details
ATI-2173, A Novel Liver-Targeted Non-Chain Terminating Nucleotide for HBV Cure Regimens
Antimicrob Agents Chemother. 2020 Jun 15;AAC.00836-20. doi: 10.1128/AAC.00836-20.Online ahead of print.
Katherine E Squires1, Douglas L Mayers1, Gregory R Bluemling2, Alexander A Kolykhalov2, David B Guthrie2, Prabhakar Reddy2, Debbie G Mitchell2, Manohar T Saindane2, Zachary M Sticher2, Vindhya Edpuganti2, Abel De La Rosa1
Author information
1Antios Therapeutics, Inc.
2Emory Institute for Drug Development (EIDD) and/or Drug Innovation Ventures at Emory (DRIVE), Atlanta, GA.
Abstract
ATI-2173 is a novel liver-targeted molecule designed to deliver the 5'-monophosphate of clevudine for the treatment of chronic hepatitis B. Unlike other nucleos(t)ides, the active clevudine-5'-triphosphate is a noncompetitive, non-chain terminating inhibitor of HBV polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans up to six months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5' phosphoramidate to deliver the 5'-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5'-monophosphate is converted to the active 5'-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV EC50 of 1.31nM in primary human hepatocytes with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5'-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5'-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5'-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.