Abstract
SAG-524 is a novel, oral HBV RNA destabilizer developed to address the limitations of treatment with nucleos(t)ide analogues (NAs), which are effective against HBV DNA but show limited efficacy in reducing hepatitis B surface antigen (HBsAg) levels. SAG-524 exerts its effect by destabilizing HBV RNA by shortening the poly(A) tail, which leads to a significant reduction of both pgRNA and PreS/S mRNA. This destabilization seems to be specific for HBV RNA molecules. The mechanism involves the recruitment of PAPD5/7 by ZCCHC14 to the HBV RNA, where guanine is incorporated into the poly(A) tail to protect against degradation. SAG-524 disrupts this process by directly targeting PAPD5, thus destabilizing HBV RNA. In preclinical trials, oral administration of SAG-524 reduced serum HBsAg levels in HBV-infected PXB mice. When combined with NAs or capsid assembly modulators (CAMs), significant reductions in HBsAg, HBV DNA, and intrahepatic covalently closed circular DNA were observed. Safety studies conducted over 13 weeks in mice and monkeys revealed no significant toxicity, demonstrating the drug demonstrated a favorable safety profile. In conclusion, the novel mechanism of action, high oral bioavailability, and strong suppression of HBsAg make SAG-524 a promising candidate for future therapeutic use. The potential for combination therapy with NAs or CAMs underscores its capacity to contribute to achieving a functional cure for chronic HBV infection.