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An RNA interference therapeutic potentially achieves functional cure of chronic hepatitis B virus infection

Year: 2025

Type: article

Abstract: Current therapeutics for chronic hepatitis B virus (HBV) infection are insufficient due to immune exhaustion caused by high circulating hepatitis B surface antigen (HBsAg) levels. Here, an HBV S region-targeted small interfering RNA (siRNA) is reported, aiming to dramatically suppress HBsAg and provide windows for host immune restoration. This siRNA agent, called KC13-M2G2, exhibits potent antiviral efficacy against all HBV genotypes in vitro. Notably, in multiple mouse models, KC13-M2G2 triggers rapid and sustained loss of HBsAg and HBV DNA accompanied by hepatitis B surface antibody seroconversion, outperforming the clinical drug elebsiran and bepirovirsen. Toxicity studies in Sprague-Dawley rats and cynomolgus monkeys indicate satisfactory biosafety profiles of KC13-M2G2. Given that elebsiran and bepirovirsen have achieved a functional cure rate of no more than 20% in their clinical studies, KC13-M2G2 as a more potent candidate drug is expected to exhibit superior performance in clinical applications. Treatments to cure chronic hepatitis B (HBV) infection are currently lacking. Here, the authors identify an HBV targeting siRNA that exhibits potent and broad-spectrum antiviral activity in preclinical animal models and demonstrates a favorable safety profile and functional cure indicators, promising clinical translation potential.

Source: Nature Communications

DOI: 10.1038/s41467-025-66876-5