SBIR PHS 2020-1, TOPIC 084 ENTITLED ANTIVIRAL DRUGS TO CURE CHRONIC HEPATITIS B VIRUS INFECTION

Hepatitis B virus (HBV) is a major global public health threat with over 257 million people worldwide chronically infected; around 1 million deaths are caused by the virus every year. Chronic HBV infection causes almost 40% of cases of hepatocellular carcinoma. All small molecule drugs used in the current standard-of-care for treating chronic HBV are nucleoside/nucleotide analogs (NUC) and target the same single HBV protein, the polymerase (reverse transcriptase). Blocking active HBV replication through NUC treatment conceptually prevents the cycling of new genomes back to the nucleus to amplify or replenish cccDNA levels. However, existing pools of cccDNA have a sufficiently long half-life to maintain chronic infection despite years of potent antiviral suppression. Therefore, current NUC therapy significantly reduces serum HBV DNA levels but HBV continues to replicate in the liver, thereby enabling the infection to persist and progress. For this reason, the nucleoside/nucleotide analogs are not curative drugs. Their lifelong use is needed for sustained suppression of HBV, which furthermore causes adverse effects and resistance problems. Zymeron develops small-molecule protein degraders to induce targeted degradation of a critical HBV protein for functional cure of chronic hepatitis B and overcoming antiviral drug resistance problem.