Safety and efficacy of GST-HG141, a novel HBV capsid assembly modulator, for the treatment of chronic hepatitis B patients with low-level viremia: a randomized, double-blind, placebo-controlled, multicenter phase II study
Chong Wang, Fei Kong, Haibing Gao, Dachuan Cai, Guoqiang Zhang, Qin Ning, Bei Zhong, Zhenguo Liu, Zhijun Su, Guicheng Wu, Jinlin Hou, John Mao, Tianxiang Zhang, Wenqiang Wu, Wenhao Yan, Xiu‐Ping Yan, Guoping Li, Yanhang Gao, George Zhang, Junqi Niu, George Zhang, Junqi Niu
Abstract
Background Chronic hepatitis B (CHB) remains a major global health challenge with no curative therapies. Approximately 15–40% of patients treated with current standard-of-care antiviral therapies such as nucleos(t)ide analogs (NUCs), including entecavir (ETV) and tenofovir (TDF/TAF), fail to fully suppress serum HBV DNA, resulting in persistent low-level viremia (LLV), which is associated with increased risks of cirrhosis, liver failure, and hepatocellular carcinoma. GST-HG141, a novel HBV capsid assembly modulator, previously demonstrated favorable safety and antiviral activity in a Phase Ib study, offering a promising approach for LLV management in CHB patients. Methods This Phase II, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of GST-HG141 in CHB patients with LLV. It is registered at ClinicalTrials.gov (NCT05637541) and Clinical Trial Registry (GST-HG141-II-02). From January 2023 to July 2024, 144 patients were screened across ten research centers in China, and 90 eligible participants were enrolled. All participants had been on NUC therapy for over one year, with serum HBV DNA levels between 20 and 2000 IU/mL and ALT ≤5 × ULN. Patients were randomized 1:1:1 to receive low-dose GST-HG141 (50 mg BID, n = 30), high-dose GST-HG141 (100 mg BID, n = 30), or placebo ( n = 30), administered orally for 24 weeks. The primary endpoint was the proportion of participants achieving serum HBV DNA levels below the lower limit of detection (<20 IU/mL) at Week 24. Secondary endpoints included changes in HBV DNA levels and other virological markers from baseline. A 4-week follow-up phase assessed safety and sustained virologic response. Findings A total of 89 patients who received at least one dose of study medication were enrolled. Among them, eighty patients completed the treatment and were included in the per-protocol analysis: 25 in the low-dose group, 27 in the high-dose group, and 28 in the placebo group. GST-HG141 significantly reduced serum HBV DNA levels in CHB patients with suboptimal responses to prior NUC therapy. By week 24, 84.0% of patients in the low-dose group and 81.5% in the high-dose group achieved HBV DNA <20 IU/mL, compared to 32.1% in the placebo group ( p < 0.05 for both treatment groups vs. placebo). Mean HBV DNA reductions exceeded 1 log 10 IU/mL in both GST-HG141groups. Additionally, pregenomic RNA (pgRNA) levels also declined by an average of 1.7 log 10 copies/mL, with 60% and 55% of participants in the low- and high-dose groups, respectively, achieving undetectable pgRNA, compared to 9.5% in the placebo group. Safety profiles were favorable with good tolerability and comparable for adverse events across all groups. Interpretation GST-HG141, administered orally at 50 and 100 mg BID, was safe, well-tolerated, and highly effective in suppressing residual HBV DNA and pgRNA levels in CHB patients with LLV. These results support the further development of GST-HG141 as a novel therapeutic option for CHB patients inadequately responding to conventional NUC treatment. Funding This work was supported by the Fujian Akeylink Biotechnology Co., Ltd.