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 log 10 IU/mL in the 30 mg BID 28‐day group and −0.53 log 10 IU/mL in the 60 mg BID 28‐day group. The 30 mg BID 12‐week group showed a greater reduction of −0.89 log 10 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 log 10 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