Discovery of XT1061, a HBV Capsid Assembly Modulator, as a Promising Therapeutic Candidate for Clinical Treatment of HBV Infection

Abstract Hepatitis B virus (HBV) persists as a major unresolved infectious disease. Patients typically require lifelong administration of nucleos(t)ide analogs (NAs) or interferons but seldom achieve functional cure. Recent studies indicate that HBV core assembly modulators (CAMs), when combined with NAs and interferons, can more effectively reduce HBsAg in plasma, thereby facilitating functional cure. In this research, we discovered compound 39 (designated XT1061) through structural optimization of previously reported GLP-26, which exhibited potent anti-HBV activity in vitro (EC50 = 1.0 ± 0.1 nM). In the murine AAV/HBV model, XT1061 induced rapid reduction of HBV DNA and sustained viral DNA clearance throughout treatment. Notably, Combination therapy of XT1061 with pradefovir mesylate (PDV) exhibited significantly enhanced efficacy compared with monotherapy. Further preclinical evaluation and Phase I clinical trials (NCT06280534) confirmed that XT1061 possesses favorable drug-like properties and low safety risks. Collectively, XT1061 represents a promising anti-HBV therapeutic candidate, providing a viable strategy for the clinical management of chronic HBV infection.