Abstract
REP 2139 is a nucleic acid polymer (NAP) currently under clinical development for chronic hepatitis B (HBV) therapy. This preclinical study investigated different REP 2139 analogs that would display reduced accumulation in the serum and tissues, while retaining an antiviral effect against HBV infection. REP 2139 analogs were evaluated in human plasma, CD-1 mice, cynomolgus monkeys, and Pekin ducks. Discrete ribose transformation to 2′OH in selected riboadenosines resulted in a slow degradation in acidified human plasma that plateaued after 48 hr. REP 2165, a REP 2139 analog containing three unmodified riboadenosines equally spaced throughout the polymer, showed similar plasma clearance and tissue distribution as REP 2139 in mice and cynomolgus monkeys after a single dose. Interestingly, after repeated administration, accumulation of REP 2165 in plasma and organs was reduced, indicating a dramatically faster rate of clearance from organs after therapy was ended in both species. Both REP 2139 and REP 2165 were well tolerated at clinically relevant doses, with no alterations in liver, kidney, or hematological function. In chronic duck HBV (DHBV) infection, REP 2165 displayed significantly reduced liver accumulation after repeated dosing but retained antiviral activity similar to REP 2139. These results indicate the therapeutic potential of REP 2165 against chronic HBV infection in patients is similar to REP 2139, but with significantly reduced drug accumulation and improved tissue clearance.
Highlights
Nucleic acid polymers (NAPs) are oligonucleotide-based, broadspectrum antiviral agents
Evaluation of NAP Pharmacokinetics and Tissue Biodistribution in the Pekin Duck The concentration profile of NAPs in Pekin ducks was assessed by examining REP 2139 concentrations in serum, liver, and kidney following a single 9 mg/kg dose given by bolus intraperitoneal (i.p.) injection (Figure 6A)
Accumulation of various NAPs was consistent with relative stabilities observed in human plasma; REP 2139 and REP 2163 had the highest concentrations in the liver, whereas REP 2055 and REP 2165 had significantly lower liver concentrations
Summary
Nucleic acid polymers (NAPs) are oligonucleotide-based, broadspectrum antiviral agents Their activity is driven by interactions with large amphipathic protein domains important for viral replication and relies only on the length of the oligonucleotide (optimally 40-mer) and the presence of phosphorothioation.[1] The NAP REP 2139 is currently in clinical development for the treatment of chronic hepatitis B (HBV) infection and HBV/hepatitis delta (HDV) co-infection and has shown a unique ability to clear the HBV surface antigen (HBsAg) from the blood in clinical trials.[2,3,4] This activity is driven by the ability of NAPs to block the release of HBsAg from infected hepatocytes, likely by interfering with the assembly of HBV subviral particles[5] by an as yet undefined mechanism. The clearance of HBsAg from the circulation by the NAPs REP 2055 and REP 2139 is associated with a drastic clearance of intrahepatic hepadnaviral infection from the liver (HBsAg, HBcAg, total and covalently closed circular DNA [cccDNA]) that persists after NAP therapy cessation, indicating a functional control of infection has been established.[5,6] The elimination of serum HBsAg improves the efficacy of immunotherapy in human patients,[2,3,4] which may facilitate the achievement of a functional cure (restoration of host immune control of HBV infection) in the absence of treatment
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