Hepatoselective Dihydroquinolizinone (HS-DHQ) Molecules for Treatment and Prevention of Hepatitis A Virus (HAV) Infection

Hepatoselective Dihydroquinolizinone (HS-HS-DHQ) Molecules for Treatment and Prevention of Hepatitis A Virus Infection ABSTRACT This is a Phase I proposal to develop Harlingene’s hepatoselective dihydroquinolizinones (HS- DHQs) for treatment and prevention of hepatitis A virus (HAV) infection. This will be the first antiviral therapy to treat HAV infection, which, despite vaccines to prevent disease, causes thousands of hospitalizations and many deaths each year in the U.S. DHQs, exemplified by the Roche compound, RG7834, have been shown to be effective antivirals for hepatitis B virus (HBV) and have been under development for HBV by a number of small and major pharmaceutical companies. We are pioneering development of DHQs for treatment and prevention of hepatitis A. We have shown DHQs are highly active against HAV in cell culture and in mice. DHQs inhibit the nucleotidyltransferases TENT4A/B, also called PAPD7/5, which play a role in cellular mRNA “quality control” and noncoding transcript metabolism and are necessary for efficient HBV and HAV RNA functions. However, their mechanism of action against HBV and HAV are distinct: while DHQs promote degradation of HBV mRNAs, they do not affect HAV RNA stability. Instead DHQs suppress HAV RNA synthesis. The selective sensitivity of viral over host transcripts to DHQs offered a new strategy of antiviral therapy with low risk for resistance. However, DHQ development has been slowed and even suspended because of neurotoxicity concerns in long- term animal studies. We therefore produced a family of hepatoselective HS-DHQs that use receptors enriched on hepatocytes to achieve a liver-selective distribution. Our lead HS-DHQs 2 and 3 have been shown to have nano-molar activities against HAV in cell culture and they target hepatocytes in culture and are enriched in the liver in mice. We have now synthesized a family of HS-DHQs to optimize their PK profiles. Our mouse studies suggest effective therapy for hepatitis A will require only brief antiviral therapy, and we propose that our HS-DHQs with less plasma and other tissue exposure will carry a low risk of neurotoxicity when used in this context. In this STTR Phase I application, we will perform lead optimization to advance HS-DHQs based not only on anti-HAV efficacy in tissue culture and PK study results, but also a neurotoxicity screen using an in vitro assay with primary rat neurons and in vivo distribution to neuronal tissues. The best HS- DHQs will be further studied for their efficacy in treating and preventing HAV infection in mice. HS-DHQs with the best antiviral, PK, and PD performance in murine models of HAV will then be advanced through preclinical studies in Phase II necessary to support a human clinical study.