Small molecule HBV RNA destabilizing drugs: Drugs of the future or compounds from the past?

Small-molecule HBV RNA destabilizing agents, such as the dihydroquinolizinones (DHQs), were first disclosed in a patent filing in 2015 and in peer reviewed literature in 2018. These compounds inhibit Poly-adenylating Polymerases 5 and 7 (PAPD5/7) and represent a novel antiviral strategy and their ability to degrade hepatitis B surface antigen (HBsAg) in cell culture and animal models generated considerable excitement and commercial interest. However, extrahepatic toxicity observed in preclinical and Phase I studies led to the discontinuation of several development programs. The subsequent emergence of liver-targeted PAPD5/7 inhibitors with improved safety profiles has rekindled interest in this therapeutic approach. Yet, with the apparent success of other investigational antivirals in reducing HBsAg levels, such as siRNAs, antisense oligonucleotides, and in at least one example, capsid assembly modulators (CAMs), questions remain as to whether RNA destabilizers still have a role in managing chronic hepatitis B (CHB). This review describes the current status of PAPD5/7 inhibitor development, evaluates the advantages and limitations of the approach, and considers potential strategies for integrating this class of molecules with other HBV therapies.