Safety, Tolerability and Antiviral Activity of GST-HG131 in Chronic Hepatitis B: A Randomized, Double-Blind Phase IIa Study

Background and Aims: Chronic hepatitis B (CHB) remains a major global health burden. Current therapies rarely achieve a functional cure due to low rates of HBsAg clearance, the persistence of the viral replication template—covalently closed circular DNA (cccDNA)—and the need for lifelong treatment. GST-HG131 is a first-in-class, orally bioavailable small-molecule inhibitor of PAPD5/7, key host factors involved in HBV mRNA stabilization and HBsAg production. We evaluated the safety, tolerability and antiviral activity of GST-HG131 in patients with CHB receiving nucleos(t)ide analogue (NUC) therapy in a randomized, double-blind, placebo-controlled Phase IIa study. Methods: This double-blind, randomized, placebo-controlled Phase IIa study evaluated the efficacy and safety of GST-HG131 in 45 CHB patients. Cohorts 1 and 2 (n = 10 each; 8 active, 2 placebo) received 30 mg or 60 mg BID for 28 days, respectively. Cohort 3 (n = 25; 20 active, five placebo) received 30 mg BID for 12 weeks. All participants were on nucleos(t)ide analog monotherapy for more than 6 months, with HBsAg between 100 and 1500 IU/mL, and serum ALT below 1× ULN. Results: At Day 28, HBsAg reductions were −0.65 log10 IU/mL in the 30 mg BID 28-day group and −0.53 log10 IU/mL in the 60 mg BID 28-day group. The 30 mg BID 12-week group showed a greater reduction of −0.89 log10 IU/mL at the end of treatment versus placebo (p < 0.001). Two-thirds of treated patients achieved a > 50% reduction in HBsAg with a maximum decrease of 1.64 log10 IU/mL. Notably, 76.5% of patients in the 12-week group achieved HBsAg below 100 IU/mL. Rebounds in HBsAg were observed following treatment discontinuation. GST-HG131 was well tolerated, with no dose-related toxicity or emerging safety concerns across all cohorts. Conclusion: GST-HG131, a first-in-class oral PAPD5/7 inhibitor, demonstrated favourable safety and significant HBsAg reduction in patients with CHB. The greatest antiviral activity was observed after 12 weeks of treatment, supporting further clinical development of GST-HG131 as a component of functional cure strategies for CHB. Trial Registration: ClinicalTrials.gov identifier: NCT06263959. © 2026 The Author(s). Liver International published by John Wiley & Sons Ltd.