ABSTRACT
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
Keywords: chronic hepatitis B, efficacy, HBsAg inhibitor, Phase II clinical trial, safety
Key Points
GST‐HG131 is a first‐in‐class oral HBsAg inhibitor targeting PAPD5/7, key host factors involved in HBV mRNA stabilization and HBsAg production.
In a randomized, placebo‐controlled Phase IIa study, GST‐HG131 significantly reduced HBsAg levels in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue therapy.
In the 30 mg twice‐daily, 12‐week group, the mean change in HBsAg from baseline was −0.89 log10 IU/mL, and 76.5% (13/17) of evaluable patients achieved HBsAg levels < 100 IU/mL at the end of treatment.
GST‐HG131 was generally well tolerated, supporting further evaluation of PAPD5/7 inhibition as an oral therapeutic strategy for CHB.
Lay Summary
Chronic hepatitis B (CHB) remains a major global health challenge because current antiviral therapies rarely achieve a functional cure, mainly due to the persistence of hepatitis B surface antigen (HBsAg) and stable viral templates in infected liver cells. This study evaluated GST‐HG131, an oral PAPD5/7 inhibitor, in patients with CHB receiving stable nucleos(t)ide analogue therapy. Treatment with GST‐HG131 resulted in significant reductions in HBsAg levels, with the greatest effect observed after 12 weeks of treatment. The treatment was safe and generally well tolerated. These findings suggest that GST‐HG131 may represent a promising therapeutic approach to enhance functional cure rates for patients with CHB.
1. Introduction
Chronic hepatitis B (CHB) affects over 250 million people globally and remains a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC) [1, 2, 3]. Despite advances in prevention and treatment, HBV continues to impose a substantial public health and economic burden, particularly in high‐prevalence regions such as China and Southeast Asia [4, 5, 6, 7]. Current first‐line therapies, including interferons and nucleos(t)ide analogues (NUCs), effectively suppress HBV replication but rarely achieve functional cure. Interferons exert antiviral and immunomodulatory effects but have limited efficacy and significant tolerability issues, whereas NUCs (e.g., entecavir, tenofovir disoproxil fumarate [TDF], tenofovir alafenamide [TAF] and tenofovir amibufenamide [TMF]) potently inhibit HBV DNA replication without targeting covalently closed circular DNA (cccDNA) or reducing HBsAg levels [8, 9, 10, 11]. As a result, most patients require lifelong therapy and remain at risk of viral rebound and disease progression, with < 3% achieving a functional cure [12, 13, 14].
GST‐HG131 is a first‐in‐class, orally bioavailable small‐molecule inhibitor of HBsAg synthesis that acts by selectively binding to and inhibiting the host enzymes PAPD5/7—which are hijacked by the virus and are responsible for HBV mRNA poly(A) tail elongation and stabilization—thereby promoting degradation of cccDNA‐derived transcripts and reducing HBsAg production [15]. This novel mechanism directly targets a key driver of immune tolerance in CHB and represents a promising therapeutic strategy for achieving a functional cure.
This Phase IIa proof‐of‐concept study was designed to investigate the preliminary safety, efficacy and pharmacokinetics (PK) of oral GST‐HG131 in reducing HBsAg levels in a double‐blind, randomized, placebo‐controlled trial of patients with CHB receiving prior NUC therapy.
2. Materials and Methods
2.1. Study Design and Participants
This was a randomized, double‐blind, placebo‐controlled exploratory Phase IIa trial designed to evaluate the safety, tolerability, PK, and preliminary pharmacodynamic (PD) characteristics of GST‐HG131 in patients with CHB. A total of 45 participants were enrolled from four centers in China. All patients were on stable nucleos(t)ide analogue (NUC) therapy, which continued throughout the study. The protocol was approved by the Ethics Committee of The Fifth Medical Center of Chinese PLA General Hospital (no. 22Y250) and registered in ClinicalTrials.gov. Written informed consent was obtained from all participants. GST‐HG131 was manufactured by Fujian Cosunter Pharmaceutical Co. Ltd. (lot# H23001Y(2023.04.26)/H23002Y(2023.07.04)/H23003Y(2023.07.05)); the authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).
Individual participant data that underlie the results reported in this article (after de‐identification) will be made available upon reasonable request to the corresponding author. The study protocol and statistical analysis plan are also available upon request. Data will be shared for academic, non‐commercial purposes, beginning 6 months and ending 36 months following article publication. Proposals for data use will be reviewed by the study team to ensure scientific merit and compliance with participant confidentiality.
2.2. Eligibility Criteria
The key inclusion criteria were as follows: adults aged 35–65 years, HBeAg‐negative CHB, stable NUC monotherapy for ≥ 6 months, HBV DNA below the lower limit of quantitation, HBsAg level of 100–1500 IU/mL, and ALT within the normal range. The HBsAg level was restricted to 100–1500 IU/mL to enroll a relatively homogeneous population with a greater potential for achieving functional cure and to facilitate the evaluation of the antiviral activity of GST‐HG131 in this Phase IIa proof‐of‐concept study. This criterion was not intended to exclude patients with higher HBsAg levels from future clinical development.
In addition, HBeAg‐positive patients were excluded to minimize biological heterogeneity and to facilitate a clearer assessment of GST‐HG131 activity in this Phase IIa proof‐of‐concept study. This criterion was intended to support the initial clinical evaluation and did not preclude future investigation of GST‐HG131 in broader patient populations, including HBeAg‐positive patients.
The major exclusion criteria included cirrhosis, advanced fibrosis, decompensated liver disease, significant comorbidities or use of non‐NUC anti‐HBV or immunomodulatory agents within 6 months.
2.3. Randomization and Blinding
Participants were randomized into three GST‐HG131 dose groups and corresponding placebo controls: GST‐HG131 30 mg BID 28‐day (8 active: 2 placebo), GST‐HG131 60 mg BID 28‐day (8 active: 2 placebo), and GST‐HG131 30 mg BID 12‐week (20 active: 5 placebo). The randomization was computer‐generated and centrally managed. The study was double‐blinded, with patients, investigators, monitors and analysts blinded to treatment assignment. Placebo tablets were identical in appearance and packaging to the active drug.
2.4. Analysis Populations
The Following Analysis Populations Were Pre‐Specified: Full Analysis Set (FAS), the FAS consisted of all randomized patients. This analysis population was used for analyses of subject disposition, demographic data and baseline characteristics. Safety Analysis Set (SAS), the SAS consisted of all randomized patients who received at least one administration of the investigational product. This analysis population was used for safety analyses. Pharmacodynamic Analysis Set (PDS), the PDS consisted of all randomized patients who received at least one administration of the investigational product and had at least one evaluable pharmacodynamic assessment. This analysis population was used for pharmacodynamic analyses.
2.5. Sample Size
This was an exploratory, proof‐of‐concept Phase IIa study. The sample size was not based on a formal power calculation for hypothesis testing but was considered adequate to provide preliminary evidence of biological activity (HBsAg reduction), characterization of pharmacokinetics and evaluation of safety and tolerability within each cohort, consistent with the exploratory proof‐of‐concept objectives of the study.
2.6. Treatment and Dosing
Patients received GST‐HG131 orally in three different regimens: GST‐HG131 30 mg BID 28‐day (G1), GST‐HG131 60 mg BID 28‐day (G2), or GST‐HG131 30 mg BID 12‐week (G3). All doses were administered in addition to stable background nucleos(t)ide analog therapy. Adherence was monitored by using diary cards and drug accountability.
2.7. Follow Up and Assessments
The participants attended scheduled visits for safety and efficacy monitoring throughout the study period. The visit schedules were tailored to the treatment duration of each cohort: GST‐HG131 30 mg BID 28‐day and GST‐HG131 60 mg BID 28‐day (28‐day treatment) were assessed at baseline and on Days 8, 15, 22, 28 (End of Treatment, EOT), 42, and 56; GST‐HG131 30 mg BID 12‐week (12‐week treatment) was assessed at baseline and on Days 15, 29, 57, 85 (EOT), 99, and 113. At each visit, data and samples were collected for a comprehensive evaluation, including virological markers (HBsAg, HBsAb, HBeAg, HBeAb, HBV DNA and pgRNA), routine biochemical and haematological parameters, pharmacokinetic sampling and standard systematical safety assessments (adverse events, vital signs, ECGs and physical examinations).
2.8. Virological and Clinical Assessments
Virological markers, including serum HBsAg, HBsAb, HBeAg, HBeAb, HBV DNA and HBV pgRNA, were quantified using commercially available assays. Specifically, HBsAg, HBsAb, HBeAg and HBeAb levels were measured using electrochemiluminescence immunoassay (Roche Elecsys series). HBV DNA and pgRNA were quantified using qPCR. Safety assessments included recording of adverse events (AEs), laboratory tests, vital signs, electrocardiograms (ECGs) and physical examinations.
2.9. Endpoints
The primary endpoint was the change in HBsAg from baseline at scheduled visits. Secondary endpoints included the changes in HBV pgRNA, the proportion of patients with pgRNA below LLOQ, and the proportions of HBsAb‐positive and HBeAb‐positive patients. Safety endpoints included monitoring of AEs and SAEs. PK endpoints included Tmax, Cmax, AUC0–t , t 1/2, Vz/F, CL/F, Tss,max, Css,max, Css,min, AUCss and Rac.
2.10. Statistical Analysis
Efficacy analyses were conducted in two predefined analysis populations according to the endpoint type. Analysis of HBsAg change from baseline was performed in the PDS, as defined in Section 2.4. Patients who discontinued treatment early were included using all available post‐baseline data. HBsAg response rates at the end of treatment were analysed in the end‐of‐treatment (EOT) evaluable population, defined as patients who completed the assigned treatment and had an available HBsAg measurement at the EOT visit. Continuous variables are presented as mean ± standard deviation (SD) or median (range), as appropriate. Categorical variables were summarized as counts and percentages (%). For the analysis of changes in HBsAg from baseline, a mixed‐effects model for repeated measures (MMRM) was applied, with the treatment group, visit, and treatment‐by‐visit interaction as fixed effects and baseline HBsAg as a covariate. Between‐group comparisons at each time point were performed using this model. HBsAg response rates were summarized descriptively and compared between treatment groups using appropriate categorical methods. All statistical tests were two‐sided, and a p‐value < 0.05 was considered statistically significant. No adjustment for multiple comparisons was made, owing to the exploratory nature of the study. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) or WinNonlin version 8.3.5 (Certara, Princeton, NJ, USA).
3. Results
3.1. Baseline Characteristics
Baseline characteristics were analysed in the FAS, as specified in the statistical analysis plan. The flow diagram of the study is shown in Figure 1. Of the 61 screened patients, 45 eligible patients were randomized. Among them, 8 were assigned to GST‐HG131 30 mg BID 28‐day, 8 to GST‐HG131 60 mg BID 28‐day, 20 to GST‐HG131 30 mg BID 12‐week, and 9 to placebo. A total of 41 patients (91.1%) completed the main study, while four patients withdrew: one from the GST‐HG131 60 mg BID 28‐day group and three from the GST‐HG131 30 mg BID 12‐week group. Of these, three subjects withdrew voluntarily for non‐treatment‐emergent personal reasons and one discontinued due to an adverse event that was judged by the investigator as unrelated to treatment but rendered the patient unsuitable for continued participation.
FIGURE 1.
Study flow chart. Sixty‐one participants were screened, 16 excluded, and 45 randomized into four groups: GST‐HG131 30 mg BID 28‐day (n = 8), GST‐HG131 60 mg BID 28‐day (n = 8), GST‐HG131 30 mg BID 12‐week (n = 20), and placebo (n = 9). Three participants withdrew from the GST‐HG131 60 mg BID 28‐day group and one from the GST‐HG131 30 mg BID 12‐week group; all others completed treatment. In the GST‐HG131 60 mg BID 28‐day group, 1 subject withdrew due to ‘an adverse event that occurred in the subject and was judged by the investigator as rendering the subject unsuitable for continued trial participation’. In the GST‐HG131 30 mg BID 12‐week group, three subjects withdrew due to ‘voluntary withdrawal by the subject during the trial’. (Not due to adverse events or intolerability. No safety signals prompted withdrawal.)
Treatment adherence was high across all groups (excluding three withdrawals), with mean compliance rates of 93.9%–99.8%. Of the 45 participants, 43 patients (95.6%) were of Han ethnicity, 33 (73.3%) were male, and 12 (26.7%) were female. The mean (range) age was 47.6 years (35–63); mean body weight, 70.38 ± 11.63 kg; and mean BMI, 25.05 ± 2.94 kg/m2. There were no significant differences in the demographic characteristics between the experimental and placebo groups.
At baseline, the mean (SD) HBsAg level was 2.63 (0.297) log10 IU/mL, and the mean (SD) pgRNA level was 2.20 (0.59) log10 copies/mL. Ten subjects (22.2%) were HBeAb‐negative, and 35 (77.8%) were HBeAb‐positive. All subjects had received prior nucleos(t)ide analog (NUC) therapy, including entecavir (36 patients, 80.0%), tenofovir disoproxil fumarate (3 patients, 6.7%), and tenofovir alafenamide (8 patients, 17.8%). Some subjects had received more than one NUC prior to study enrollment; therefore, the treatment categories were not mutually exclusive.
Overall, the demographic and baseline disease characteristics were well balanced across the treatment groups (Table 1).
TABLE 1.
Summary of demographic and baseline characteristics (Full Analysis Set [FAS]).
| Index (unit) | Total (N = 45) | GST‐HG131 30 mg BID 28‐day (N = 8) | GST‐HG131 60 mg BID 28‐day (N = 8) | GST‐HG131 30 mg BID 12‐week (N = 20) | Placebo (N = 9) |
|---|---|---|---|---|---|
| Age (years) | 47.6 ± 7.92 | 44.4 ± 8.33 | 51.6 ± 7.42 | 47.9 ± 7.79 | 46.6 ± 8.00 |
| Gender, n (%) | |||||
| Female | 12 (26.7%) | 3 (37.5%) | 2 (25.0%) | 3 (15.0%) | 4 (44.4%) |
| Male | 33 (73.3%) | 5 (62.5%) | 6 (75.0%) | 17 (85.0%) | 5 (55.6%) |
| Body mass index (kg/m2) | 25.05 ± 2.942 | 25.14 ± 4.088 | 25.40 ± 2.499 | 24.43 ± 2.862 | 26.04 ± 2.416 |
| Baseline HBsAg (log10 IU/mL) | 2.63 ± 0.297 | 2.69 ± 0.402 | 2.56 ± 0.365 | 2.62 ± 0.218 | 2.66 ± 0.325 |
| Stratification by baseline | |||||
| Characteristics of HBsAg level | N | N | N | N | N |
| < 200 (N = 6) | 6 | 1 | 3 | 1 | 1 |
| 200–1000 (N = 34) | 34 | 5 | 4 | 18 | 7 |
| > 1000 (N = 5) | 5 | 2 | 1 | 1 | 1 |
| Baseline HBeAb | |||||
| Negative | 10 (22.2%) | 3 (37.5%) | 3 (37.5%) | 3 (15.0%) | 1 (11.1%) |
| Positive | 35 (77.8%) | 5 (62.5%) | 5 (62.5%) | 17 (85.0%) | 8 (88.9%) |
| Baseline ALT | 24.4 ± 9.40 | 18.6 ± 8.28 | 25.6 ± 11.62 | 27.3 ± 8.75 | 21.8 ± 7.87 |
| Baseline pgRNA (log10 Copies/mL) | 2.2 ± 0.59 | 2.1 ± 0.42 | 2.4 ± 0.55 | 2.3 ± 0.69 | 2.0 ± 0.45 |
| NUC type, n (%) | |||||
| Entecavir | 36 (80.0%) | 8 (100.0%) | 7 (87.5%) | 13 (65.0%) | 8 (88.9%) |
| Tenofovir disoproxil fumarate | 3 (6.7%) | 1 (12.5%) | 0 | 1 (5.0%) | 1 (11.1%) |
| Tenofovir alafenamide | 8 (17.8%) | 0 | 1 (12.5%) | 6 (30.0%) | 1 (11.1%) |
Note: N = Number of subjects in each group of the Full Analysis Set (FAS). Percentages are calculated based on the FAS population. Some subjects had received more than one NUC prior to study enrollment; therefore, the treatment categories are not mutually exclusive and the percentages may sum to more than 100%.
3.2. Reduction in Serum HBsAg Levels
HBsAg levels in the placebo group remained largely unchanged from baseline throughout the study period. In contrast, there were clear reductions in serum HBsAg levels, which were the primary pharmacodynamic endpoint of the study, in all GST‐HG131 treatment regimens compared with the corresponding placebo groups. Further analysis of HBsAg change from baseline in the PDS population (Figure 2A: log10‐transformed HBsAg change from baseline; Figure 2B: absolute HBsAg change from baseline) revealed significant reductions in all treatment groups, particularly in the GST‐HG131 30 mg BID 12‐week group, while the placebo group showed minimal change relative to baseline. These findings indicate that GST‐HG131‐mediated HBsAg suppression was treatment‐duration‐dependent with the greatest reductions observed following 12 weeks of therapy. As shown in the time course of HBsAg concentration (Figure 2C: log10 HBsAg concentration–time curve; Figure 2D: mean HBsAg concentration–time curve), HBsAg levels gradually declined over time in all GST‐HG131 dose groups (GST‐HG131 30 mg BID 28‐day, GST‐HG131 60 mg BID 28‐day, and GST‐HG131 30 mg BID 12‐week), with the most pronounced and sustained reduction observed in the GST‐HG131 30 mg BID 12‐week group. In the PDS population, mean HBsAg reductions from baseline after 28 days of dosing were −0.65 ± 0.45 log10 IU/mL and −0.53 ± 0.54 log10 IU/mL in the 30 mg BID (G1) and 60 mg BID (G2) groups, respectively. Extending treatment duration to 12 weeks (30 mg BID; G3) resulted in a greater mean decline of −0.89 ± 0.30 log10 IU/mL in the PDS population. In contrast, minimal changes were observed in the placebo groups (P1: 0.00 ± 0.08; P2: −0.04 ± 0.09 log10 IU/mL; P3: 0.01 ± 0.03 log10 IU/mL), indicating negligible HBsAg reductions in the absence of active treatment (Figure 3A).
FIGURE 2.
Different GST‐HG131 treatment regimens versus placebo: Time‐effect curves on HBsAg concentration and HBV pgRNA levels (PDS for HBsAg change analyses). (A) Log10‐Transformed HBsAg Change from Baseline: Depicts the time‐course of mean log10‐transformed changes in HBsAg levels from baseline across all groups, illustrating the relative change in HBsAg logarithmic levels compared to baseline over time. (B) Absolute HBsAg Change from Baseline: Shows the time‐course of absolute changes in HBsAg levels (in IU/mL) from baseline across all groups, reflecting the magnitude of absolute HBsAg concentration changes relative to baseline over time. (C) Log10 HBsAg Concentration‐Time Curve: Displays the time‐course of log10‐transformed HBsAg concentrations across groups receiving GST‐HG131 30 mg BID 28‐day, GST‐HG131 60 mg BID 28‐day, GST‐HG131 30 mg BID 12‐week, and placebo (30 mg BID for 28 days and 12 weeks), reflecting the dynamic changes in HBsAg logarithmic levels over time. (D) Mean HBsAg Concentration‐Time Curve: Presents the time‐course of mean absolute HBsAg concentrations (in IU/mL) across the aforementioned treatment and placebo groups, intuitively showing how absolute HBsAg levels evolve with treatment duration. (E) Log10‐Transformed HBV pgRNA Levels: Displays the time‐course of log10‐transformed HBV pgRNA levels across all groups, characterizing the dynamic changes in HBV pgRNA logarithmic levels during treatment. (F) Absolute HBV pgRNA Levels: Presents the time‐course of absolute HBV pgRNA levels across all groups. Consistent with the manuscript description that “HBV pgRNA levels showed essentially no change across all dose groups and the placebo group”, this subplot illustrates that HBV pgRNA levels had no notable treatment‐related alterations over time. Each treatment group was compared with the corresponding placebo group in the PDS population, *p < 0.05, **p < 0.01, ***p < 0.001.
FIGURE 3.
Effects of different GST‐HG131 treatment regimens versus placebo on changes in HBsAg levels (PDS) and the proportion of patients achieving HBsAg < 100 IU/mL at the end of treatment (EOT‐evaluable population). (A) HBsAg change from baseline (log10 IU/mL) across treatment groups in the PDS population. GST‐HG131 groups (G1: 30 mg BID/28d; G2: 60 mg BID/28d; G3: 30 mg BID/12w) had dose/duration‐dependent reductions (G3: −0.89 ± 0.30; G1: −0.65 ± 0.45; G2: −0.53 ± 0.54), while placebo groups (P1, P2 and P3) had minimal change. (B) Proportions of patients in the EOT‐evaluable population who achieved serum HBsAg levels < 100 IU/mL at the end of treatment. GST‐HG131 treatment groups showed dose/duration‐dependent increases in % of patients with HBsAg below 100 IU/mL (G3: 76.5%; G2: 57.1%; G1: 37.5%), with placebo groups having near‐zero responders.
By contrast, no notable treatment‐related changes of HBV pgRNA levels (Figure 2E: log10‐transformed HBV pgRNA levels; Figure 2F: absolute HBV pgRNA levels) were observed in any treatment groups compared to placebo during the study. HBV pgRNA levels remained close to baseline across all groups, indicating that, within the dose ranges and treatment durations evaluated in this study, GST‐HG131 selectively reduced HBsAg levels.
Consistent with the quantitative decrease in HBsAg, the proportion of patients achieving serum HBsAg levels < 100 IU/mL increased with both dose and duration of GST‐HG131 exposure (Figure 3B). At the end of treatment, the proportions of patients achieving serum HBsAg levels < 100 IU/mL in the end of treatment‐evaluable population were 37.5% (3/8), 57.1% (4/7), and 76.5% (13/17) in the 30 mg BID 28‐day, 60 mg BID 28‐day, and 30 mg BID 12‐week groups, respectively. None of the subjects in the placebo group achieved an HBsAg level < 100 IU/mL.
Among the three dose groups, a total of 11 subjects had a HBsAg level decrease of ≥ 1 log10 IU/mL, with three cases in the GST‐HG131 30 mg BID 28‐day group, two cases in the GST‐HG131 60 mg BID 28‐day group and six cases in the GST‐HG131 30 mg BID 12‐week group. The maximum decrease in HBsAg level was 1.64 log10 IU/mL (≥ 1.0 log10), which occurred in the GST‐HG131 30 mg BID 12‐week group. A total of 29 subjects had more than 50% HBsAg decrease from the baseline level, including seven cases in the GST‐HG131 30 mg BID 28‐day group, four cases in the GST‐HG131 60 mg BID 28‐day group, and 18 cases in the GST‐HG131 30 mg BID 12‐week group. The HBsAg levels decreased rapidly after initiation of the treatment: the fastest patient achieved a decrease of 0.8 log10 IU/mL within 7 days.
3.3. Pharmacokinetic (PK) Characteristics
The plasma pharmacokinetic (PK) characteristics of GST‐HG131 in CHB patients receiving repeated BID dosing (Figure 4A, linear scale) and Figure 4B (semi‐log scale) depict the observed plasma concentration–time profiles following GST‐HG131 30 mg BID 28‐day (pink), GST‐HG131 60 mg BID 28‐day (green), or 30 mg BID for 12 weeks (blue). The corresponding insets expand on the Day 1 (D1), Day 28 (D28), and Day 85 (D85) sampling windows.
FIGURE 4.
Pharmacokinetic Profiles of GST‐HG131 and Pharmacokinetic‐Pharmacodynamic Relationships with HBsAg Reduction across Dose groups. (A and B) Time‐course of plasma GST‐HG131 concentrations in groups receiving GST‐HG131 30 mg BID for 28 days (pink), GST‐HG131 60 mg BID for 28 days (green), or 30 mg BID for 12 weeks (blue) at Day 1, Day 28, and Day 85.
On Day 1, concentrations increased rapidly after dosing and then declined within the first dosing interval, consistent with prompt systemic absorption and a multiphasic distribution/elimination profile (visible more clearly on the semi‐log plot). By Day 28, pre‐dose troughs and within‐interval concentrations were higher than on Day 1, indicating accumulation to near–steady state with repeated BID dosing. Across both days, the GST‐HG131 60 mg BID 28‐day group showed systematically higher concentrations than the GST‐HG131 30 mg BID 28‐day group, suggesting an approximately dose‐proportional exposure over this range, although with moderate inter‐individual variability (scatter at both Cmax and Ctrough).
After extended dosing (GST‐HG131 30 mg BID 12‐week), quantifiable concentrations were still observed on Day 85 (blue), demonstrating a prolonged terminal phase and slow elimination. The near‐linear decline in the terminal portion of the semi‐log plot implies first‐order kinetics in the terminal phase. No obvious time‐dependent clearance or saturation was observed during the study period.
Overall, GST‐HG131 exhibited rapid absorption and accumulation with repeated BID dosing to near–steady state by ~4 weeks, approximately dose‐proportional exposure between 30 and 60 mg, and a long terminal half‐life sufficient to maintain measurable levels several weeks after the last dose.
3.4. Safety Profile
Safety analyses were based on the safety analyses set (SAS) population. A total of 45 subjects were included in the safety analysis. Adverse events (AEs) were monitored during the study period. During the treatment period, three subjects (6.7%) reported grade ≥ 3 adverse events (gastric tumour, infectious pneumonia and joint dislocation), two of which were serious adverse events (SAEs). All were deemed unrelated to the study drug by the investigators and resolved after appropriate management. A total of 32 subjects (71.1%) experienced treatment‐emergent adverse events (TEAEs) considered related to the study drug. Most TEAEs were mild to moderate (Grade 1 or 2) in severity. The most common drug‐related TEAEs were hypoalbuminemia, dizziness and asthenia. Notably, hypoalbuminemia resolved spontaneously without intervention within 2–4 weeks after treatment discontinuation, with no adverse outcomes observed. All reported TEAEs were self‐limiting or manageable, and no clinically meaningful changes were observed in the laboratory parameters, vital signs or ECGs. In summary, GST‐HG131 was generally safe and well‐tolerated across all treatment groups, with no new or unexpected safety concerns identified (Table 2).
TABLE 2.
Summary of investigational drug‐related TEAEs by SOC and PT (safety analysis population).
| Preferred term | GST‐HG131 30 mg BID 28‐day (N = 8), n (%) | GST‐HG131 60 mg BID 28‐day (N = 8), n (%) | GST‐HG131 30 mg BID 12‐week (N = 20), n (%) | Placebo (N = 9), n (%) | Total (N = 45), n (%) |
|---|---|---|---|---|---|
| Subjects with at least one TEAE related to the investigational drug | 8 (100.0%) | 8 (100.0%) | 11 (55.0%) | 5 (55.6%) | 32 (71.1%) |
| Gastrointestinal system disorders | 3 (37.5%) | 7 (87.5%) | 3 (15.0%) | 1 (11.1%) | 14 (31.1%) |
| Hard stool | 0 | 3 (37.5%) | 0 | 0 | 3 (6.7%) |
| Dry mouth | 0 | 2 (25.0%) | 0 | 0 | 2 (4.4%) |
| Nausea | 2 (25.0%) | 1 (12.5%) | 0 | 1 (11.1%) | 4 (8.9%) |
| Constipation | 0 | 1 (12.5%) | 1 (5.0%) | 0 | 2 (4.4%) |
| Vomiting | 2 (25.0%) | 0 | 0 | 0 | 2 (4.4%) |
| Epigastric pain | 1 (12.5%) | 0 | 1 (5.0%) | 0 | 2 (4.4%) |
| Various Examinations | 2 (25.0%) | 2 (25.0%) | 6 (30.0%) | 2 (22.2%) | 12 (26.7%) |
| Alanine aminotransferase increased | 0 | 2 (25.0%) | 0 | 1 (11.1%) | 3 (6.7%) |
| Aspartate aminotransferase increased | 0 | 2 (25.0%) | 1 (5.0%) | 0 | 3 (6.7%) |
| Blood creatinine increased | 1 (12.5%) | 1 (12.5%) | 0 | 0 | 2 (4.4%) |
| Urine red blood cells positive | 0 | 0 | 1 (5.0%) | 1 (11.1%) | 2 (4.4%) |
| Serum luteinizing hormone increased | 0 | 0 | 2 (10.0%) | 0 | 2 (4.4%) |
| Metabolism and nutrition disorders | 7 (87.5%) [14] | 2 (25.0%) [3] | 1 (5.0%) | 0 | 10 (22.2%) |
| Hypoalbuminemia | 5 (62.5%) [6] | 1 (12.5%) | 0 | 0 | 6 (13.3%) |
| Hyperlipidemia | 2 (25.0%) | 1 (12.5%) | 1 (5.0%) | 0 | 4 (8.9%) |
| Hyperglycemia | 2 (25.0%) | 0 | 0 | 0 | 2 (4.4%) |
| Hypophosphatemia | 1 (12.5%) | 0 | 0 | 0 | 1 (2.2%) |
| Hypocalcemia | 1 (12.5%) | 0 | 0 | 0 | 1 (2.2%) |
| Decreased appetite | 0 | 1 (12.5%) | 0 | 0 | 1 (2.2%) |
| Hyperuricemia | 1 (12.5%) | 0 | 0 | 0 | 1 (2.2%) |
| Hypertriglyceridemia | 1 (12.5%) | 0 | 0 | 0 | 1 (2.2%) |
| General disorders and administration site conditions | 4 (50.0%) | 3 (37.5%) | 2 (10.0%) | 1 (11.1%) | 10 (22.2%) |
| Weakness | 4 (50.0%) | 3 (37.5%) | 1 (5.0%) | 1 (11.1%) | 9 (20.0%) |
| Nervous system disorders | 5 (62.5%) | 3 (37.5%) | 1 (5.0%) | 1 (11.1%) | 10 (22.2%) |
| Dizziness | 5 (62.5%) | 2 (25.0%) | 0 | 0 | 7 (15.6%) |
| Headache | 0 | 1 (12.5%) | 0 | 1 (11.1%) | 2 (4.4%) |
| Hypoesthesia | 0 | 0 | 1 (5.0%) | 0 | 1 (2.2%) |
| Musculoskeletal and connective tissue disorders | 0 | 1 (12.5%) | 1 (5.0%) | 1 (11.1%) | 3 (6.7%) |
| Back Pain | 0 | 1 (12.5%) | 0 | 0 | 1 (2.2%) |
| Arthralgia | 0 | 0 | 1 (5.0%) | 0 | 1 (2.2%) |
| Cardiac disorders | 1 (12.5%) | 0 | 1 (5.0%) | 0 | 2 (4.4%) |
| Ventricular extrasystoles | 1 (12.5%) | 0 | 1 (5.0%) | 0 | 2 (4.4%) |
| Reproductive system and breast diseases | 1 (12.5%) | 0 | 1 (5.0%) | 0 | 2 (4.4%) |
| Menstrual disorders | 1 (12.5%) | 0 | 0 | 0 | 1 (2.2%) |
| Sexual dysfunction | 0 | 0 | 1 (5.0%) | 0 | 1 (2.2%) |
| Psychiatric disorders | 0 | 0 | 2 (10.0%) | 0 | 2 (4.4%) |
| Insomnia | 0 | 0 | 1 (5.0%) | 0 | 1 (2.2%) |
| Poor sleep quality | 0 | 0 | 1 (5.0%) | 0 | 1 (2.2%) |
| Endocrine disorders | 0 | 1 (12.5%) | 0 | 0 | 1 (2.2%) |
| Thyroid disorders | 0 | 1 (12.5%) | 0 | 0 | 1 (2.2%) |
4. Discussion
CHB remains a major global health challenge, as functional cure is rarely achieved with current therapies [16, 17, 18]. The persistence of covalently closed circular DNA (cccDNA) and high circulating levels of hepatitis B surface antigen (HBsAg) maintain the viral reservoir and immunotolerant state, preventing sustained viral clearance [19, 20, 21]. Elevated HBsAg suppresses HBV‐specific adaptive immune responses, impairing T‐ and B‐cell activation and limiting viral control [22, 23]. As a result, a functional cure, defined as sustained HBsAg loss, undetectable serum HBV DNA, and normalization of liver function, is achieved in < 10% of patients receiving current treatments [23, 24].
Current therapies for CHB primarily include interferons and nucleos(t)ide analogs (NUCs). Interferons have antiviral and immunomodulatory effects, but are limited by low response rates, systemic adverse effects and parenteral administration. NUCs (e.g., entecavir and tenofovir) effectively suppress HBV DNA replication, but do not eliminate cccDNA or substantially reduce HBsAg levels. Consequently, most patients require lifelong therapy and remain at risk of viral rebound, cirrhosis and hepatocellular carcinoma. These limitations highlight the need for novel therapies to directly reduce HBsAg levels and address immune tolerance.
GST‐HG131 is an orally bioavailable small‐molecule HBsAg inhibitor with a novel mechanism that destabilizes HBV mRNA and suppresses antigen production [15]. It selectively targets the host PAPD5/7 enzymes responsible for the elongation of the HBV RNA poly(A) tail, thereby accelerating transcript degradation. By directly reducing antigen production, this mechanism addresses a central driver of immune tolerance and distinguishes GST‐HG131 from the current standard‐of‐care therapies.
In this randomized, placebo‐controlled Phase IIa proof‐of‐concept study, oral GST‐HG131 produced treatment‐duration‐dependent reductions in serum HBsAg levels with a favourable safety profile. HBsAg levels declined rapidly across treatment groups, with the greatest and most durable suppression observed in the 30 mg BID 12‐week regimen. Nearly two‐thirds of the treated patients achieved > 50% HBsAg reduction, and approximately one‐quarter achieved a ≥ 1 log10 decline at the end of treatment. Notably, 76.5% of patients in the 12‐week cohort achieved HBsAg levels below 100 IU/mL, a threshold that has been associated with improved immune control and an increased likelihood of subsequent HBsAg seroclearance in patients with CHB. Previous studies have suggested that lower HBsAg levels may identify patients who are more likely to respond to immune‐based therapies and achieve sustained off‐treatment responses [25, 26]. The magnitude of HBsAg reduction observed with GST‐HG131 appears comparable to or greater than reductions reported for several emerging HBsAg‐lowering approaches. Importantly, GST‐HG131 achieved these effects as an orally administered small molecule, potentially offering practical advantages with respect to treatment convenience and long‐term combination strategies.
The reduction in HBsAg levels reflects the intended mechanism of PAPD5/7 inhibition and destabilization of HBV transcripts encoding surface antigens [27]. This pharmacodynamic effect demonstrates proof of mechanism, but should not be directly equated with long‐term clinical outcomes, as cross‐trial comparisons are confounded by differences in study design and populations. Nevertheless, the observation that more than three‐quarters of patients achieved HBsAg levels below 100 IU/mL after 12 weeks of treatment is particularly encouraging. Although HBsAg loss was not observed in this short‐duration study, achieving low HBsAg levels may represent an important intermediate milestone towards functional cure and may enhance responsiveness to future immunomodulatory interventions.
The dissociation between the marked HBsAg reduction and the absence of a corresponding decline in serum pgRNA may have several non‐mutually exclusive explanations. Integrated HBV DNA, particularly in NUC‐suppressed, HBeAg‐negative patients, can represent an important source of HBsAg transcripts but does not substantially contribute to replication‐competent pgRNA. Thus, the observed HBsAg reduction may include an effect on transcripts derived from integrated HBV DNA. Differential sensitivity of HBV RNA species to PAPD5/7 inhibition may also contribute to this dissociation, as suggested by the preclinical findings described below. However, the present clinical data do not establish the genomic origin of the affected HBsAg transcripts, and further mechanistic studies are warranted to determine the relative contributions of cccDNA‐ and integrated‐HBV‐DNA‐derived transcripts to the observed HBsAg reduction.
Preclinical studies further support the proposed mechanism of GST‐HG131. In HepG2.2.15 cells, GST‐HG131 inhibited HBsAg and HBeAg production, with EC50 values of 4.52 and 8.33 nM, respectively, and also reduced HBV DNA. Mechanistic analyses demonstrated effects on multiple HBV RNA species, including both 3.5‐kb HBV RNA corresponding to pgRNA/precore RNA and the 2.4/2.1‐kb surface‐antigen transcripts, with a greater inhibitory effect on the 2.4/2.1‐kb RNA species. In PHHs, GST‐HG131 similarly inhibited HBsAg and HBeAg, with a smaller effect on HBV DNA. Together, these findings are consistent with PAPD5/7‐mediated destabilization of HBV RNA and suggest differential sensitivity among HBV transcript species, which may contribute to the preferential HBsAg reduction observed clinically.
GST‐HG131 was well tolerated, with most adverse events being mild or moderate and no dose‐related or unexpected safety signals. The lack of a clear dose–response difference between the two 28‐day regimens likely reflects the short treatment duration and small cohort size, a known limitation of exploratory proof‐of‐concept Phase II studies. Larger and longer trials are needed to better characterize dose–response relationships.
A clear treatment‐duration‐dependent effect was observed in this study, with the 12‐week cohort showing the greatest HBsAg reduction. Longer treatment durations (6–12 months) may further enhance efficacy, as HBsAg declines appeared to continue through the end of the treatment period.
The development of other HBsAg‐targeting agents, particularly antisense oligonucleotides (ASOs) and small‐interfering RNAs (siRNAs), has demonstrated the feasibility of profound antigen suppression [28, 29]. Candidates, such as bepirovirsen and elebsiran, showed significant HBsAg reduction and improved but modest functional cure rates. However, their clinical utility may be limited by reduced efficacy in patients with high baseline HBsAg levels, rebound after treatment discontinuation, and the need for parenteral administration.
By contrast, GST‐HG131 offers a complementary and mechanistically distinct approach. As an oral small‐molecule inhibitor of HBsAg biosynthesis, it avoids injections and may facilitate long‐term treatment adherence. Its favourable safety profile and oral administration make it suitable for use in combination regimens. The substantial proportion of patients achieving HBsAg levels < 100 IU/mL suggests that GST‐HG131 may reduce the antigenic burden and help reverse immune tolerance, potentially enhancing the efficacy of co‐administered therapies, which generally are more effective in patients with lower baseline levels of HBsAg. This supports GST‐HG131's role as a priming agent in multi‐targeted regimens, consistent with the growing consensus that combination strategies represent the most viable path toward a functional cure [30, 31, 32, 33, 34].
HBsAg rebound after treatment discontinuation was observed in most patients, which is consistent with the persistence of cccDNA‐driven viral reservoirs and the mechanism of transcript destabilization. Similar rebound patterns have been reported for other HBsAg‐reducing agents such as ASOs and siRNAs. These findings highlight the need for prolonged therapy or rational combination regimens incorporating immunomodulatory agents to achieve sustained viral clearance rather than finite monotherapy. Given its oral bioavailability and good tolerability, GST‐HG131 is well suited for combination with other oral antivirals, such as NUCs and capsid assembly modulators (CAMs). Such a fully oral triple‐combination approach could provide a practical, adherence‐friendly strategy for a functional cure.
The continued decline in HBsAg through Week 12 provides a rationale for evaluating longer treatment durations. Further, in the 30 mg BID cohort, HBsAg levels remained below baseline after treatment discontinuation, suggesting that prolonged treatment may potentially result in further HBsAg reductions. Based on these findings, the subsequent clinical development of GST‐HG131 is focusing on the treatment with a longer duration (6 months) and as a component of combination therapy. A Phase II study of GST‐HG131 alone or in combination with the capsid assembly modulator GST‐HG141 as well as immune modulators has been approved by the National Medical Products Administration (NMPA). The combination is designed to provide complementary antiviral effects, with GST‐HG131 targeting HBV RNA stability and HBsAg production and GST‐HG141 targeting capsid assembly and the HBV replication cycle. The addition of immunomodulators may help reduce post‐treatment rebound of HBsAg and HBV DNA after discontinuation of the treatment. This strategy may provide a more comprehensive approach to HBV suppression and potentially increase the likelihood of achieving functional cure.
This study had several limitations. The sample size was relatively small, treatment duration was limited, and follow‐up after treatment discontinuation was short. In addition, immunologic biomarkers were not systematically evaluated. Larger studies with longer treatment durations and assessment of combination strategies will be required to determine the potential contribution of GST‐HG131 to functional cure regimens.
GST‐HG131 demonstrated favourable safety and meaningful HBsAg reductions in virally suppressed patients with CHB. These findings support further clinical evaluation of PAPD5/7 inhibition and provide proof‐of‐concept for the development of oral HBsAg‐lowering therapies as components of future functional cure strategies.
5. Conclusions
This Phase IIa proof‐of‐concept study provides preliminary evidence that GST‐HG131, an orally bioavailable, first‐in‐class small‐molecule HBsAg inhibitor, is safe and well tolerated across all tested regimens, with no dose‐related safety concerns or new adverse signals identified. GST‐HG131 consistently reduced serum HBsAg levels across active treatment groups, with the most pronounced effect observed in the 12‐week regimen, in which 76.5% of patients achieved HBsAg levels < 100 IU/mL at the end of treatment. HBsAg levels rebounded after treatment discontinuation, underscoring the need for extended treatment duration or combination approaches. Given its favourable safety profile and oral administration, GST‐HG131 may be suitable for combination with other antiviral agents, such as nucleos(t)ide analogs or capsid assembly modulators, as well as host‐directed immunomodulators, to support functional cure strategies. Taken together, these findings support the further clinical development of GST‐HG131 as a potential first‐in‐class oral HBsAg inhibitor for CHB.
Author Contributions
All authors contributed significantly to this work. Fu‐Sheng Wang (F.W.), George Zhang (G.Z.), John Mao (J.M.), and Yuming Guo (Y.G.) conceived the study, designed the experiments, and were responsible for the overall methodology. Zhe Xu, Yuanyuan Li (Y.L.), Yonggang Li, Fanping Meng (F.M.), Junliang Fu (J.F.), Dong Ji (D.J.), Yingjie Ji (Y.J.), Yongqian Cheng (Y.C.), Min Zhang (M.Z.), Xin Zhang (X.Z.), and Ying Sun (Y.S.) contributed to the collection and interpretation of clinical data and patient recruitment at The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, and performed data analysis. Zuxiong Huang (Z.H.), Dachuan Cai (D.C.), and Jinlin Hou (J.H.) contributed to patient recruitment, data collection, and clinical management at their respective medical centers. John Mao (J.M.), Tianxiang Zhang (T.Z.), Wenqiang Wu (W.W.), Wenhao Yan (W.Y.), Xiuping Yan (X.Y.), and Guoping Li (G.L.) contributed to the experimental design and collection and interpretation of clinical data. F.‐S.W., G.Z., J.M., and Y.G. were responsible for manuscript writing and revision and ensuring the accuracy and clarity of the text. F.‐S.W., G.Z., J.M., and Y.G. accessed and verified the underlying data. All the authors contributed to the critical review of the manuscript, provided feedback, and approved the final version for submission.
Funding
This work was financially supported by Fujian Akeylink Biotechnology Co. Ltd.
Ethics Statement
The protocol was approved by the Ethics Committee of The Fifth Medical Center of Chinese PLA General Hospital (No. 22Y250) and registered in ClinicalTrials.gov. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).
Consent
Written informed consent was obtained from all the participants.
Conflicts of Interest
J.H. reports receiving an investigator‐initiated study grant from F. Hoffmann‐La Roche Ltd., and consulting fees from Aligos Therapeutics Inc., Gilead Sciences Inc., and GlaxoSmithKline. J.M., W.W., K.H., G.L., and G.Z. report stock ownership or stock options in Fujian Akeylink Biotechnology Co. Ltd. The other authors declare no conflicts of interest.
Acknowledgements
J.H. reports receiving an investigator‐initiated study grant from F. Hoffmann‐La Roche Ltd., and consulting fees from Aligos Therapeutics Inc., Gilead Sciences Inc., and GlaxoSmithKline, participating in the design, conduct, analysis, and reporting of the trial. This work was supported by the Fujian Akeylink Biotechnology Co. Ltd.
Guo Y., Xu Z., Li Y., et al., “Safety, Tolerability and Antiviral Activity of GST‐HG131 in Chronic Hepatitis B: A Randomized, Double‐Blind Phase IIa Study,” Liver International 46, no. 11 (2026): e70918, 10.1111/liv.70918.
Handling Editor: Luca Valenti
Contributor Information
George Zhang, Email: george.zhang@akeylink.cn.
Fu‐Sheng Wang, Email: fswang302@163.com.
Data Availability Statement
All data were included in the manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data were included in the manuscript.