--- title: "Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Pharmacodynamics" description: "Formulary evidence on Hibsago (bepirovirsen, GSK3228836) in Chronic hepatitis B virus infection in adults without cirrhosis: Pharmacodynamics. Topics: Exposure-response relationship in B-Well 1 and B-Well 2, Immunostimulant activity: nonclinical studies in the prescribing information, Immune markers in clinical studies: prescribing information, TLR8 reporter cell lines and hTLR8 transgenic mice, and 17 further topics. 21 evidence topics quoted from 9 sources." canonical: "https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description/pharmacodynamics" published: "2026-10-21T22:39:04-04:00" modified: "2026-10-22T19:07:03-04:00" --- # Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Pharmacodynamics ## 2.1.2.6.2 Pharmacodynamics ### Exposure-response relationship in B-Well 1 and B-Well 2 > “Within the range of bepirovirsen exposures achieved at the dosing regimen in B-Well 1 and B-Well 2 trials, variability in bepirovirsen plasma exposure was not identified as a determinant of treatment response at Week 72.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### Immunostimulant activity: nonclinical studies in the prescribing information > “In nonclinical studies, bepirovirsen exhibited innate immune activity in a sequence-specific, human toll-like receptor 8 (hTLR8)-dependent manner, with no activity observed at other pattern recognition receptors tested.” > “Compared to wild-type mice, hTLR8 knock-in mice showed increased proinflammatory cytokine expression upon bepirovirsen treatment. This immunostimulatory activity was predominantly localized to hepatic macrophages and Kupffer cells, with induction of cytokines including TNF-α, IL-12p40, and CXCL10.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### Immune markers in clinical studies: prescribing information > “In clinical studies, administration of HIBSAGO was associated with increases in innate immune markers of activation and trafficking, which included cytokines and chemokines (e.g., interleukin12, tumor necrosis factor, interferon gamma and CXC motif chemokine ligand 9 and 10). Treatment with HIBSAGO also increased total IgM.” > “The contribution of immunostimulatory activity to antiviral activity at therapeutic concentrations in humans has not been fully determined.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### TLR8 reporter cell lines and hTLR8 transgenic mice > “Analysis of innate immune activation in PRR-overexpressing cells revealed a weak but statistically significant (p = 0.00085) induction only in the presence of human Toll-like receptor 8 (TLR8). In hTLR8 transgenic mice – but not wild-type mice – bepirovirsen treatment induced pro-inflammatory cytokines, similar to the TLR8 agonist selgantolimod. Kupffer cells and macrophages were identified as the primary responders to bepirovirsen in the livers of hTLR8 mice.” > “Notably, induction of type I IFN (IFN-α or IFN-β) did not occur with bepirovirsen in hTLR8 mice.” Source: [Ermler et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13482607/) ### Cytokine induction in the phase 2a study > “At 24 h following bepirovirsen treatment (Fig. 1B), key cytokines known to regulate pro-inflammatory and antiviral processes, such as IFN-γ and TNF, as well as others that induce macrophage and neutrophil (CCL2, CCL4, CSF1, CSF3) or T cell (IL-12B, CCL19) recruitment and activation, were among the upregulated analytes in bepirovirsen-treated individuals.” > “Compared with the non-responder group, the responder group showed trends towards increased activity in the IFN-γ signaling and T-cell response pathways.” Source: [Ermler et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13482607/) ### Innate immune proteins in healthy volunteers and participants with chronic HBV infection > “Bepirovirsen induced significant, transient protein differential expression in the hours after dosing, while there were relatively minor changes in placebo. There were many similarities in protein biomarkers induced in CS3 participants with chronic HBV infection and in the two healthy volunteer studies. Additionally, bepirovirsen treatment increased abundance of many proteins to a higher degree with increasing dose.” > “These findings strengthen the association between bepirovirsen treatment and changes in innate immune-related proteins and indicate that this effect does not require the presence of HBV.” Source: [Delahaye et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13676563/) ### Serum proteomics and transcriptomics in B-Together > “Increases from baseline in mean expression of serum proteins with immune effector and apoptotic functions (Week 3) and transcripts associated with immune cell proliferation and activation (Week 5) were observed regardless of arm or response subgroup. By Week 8, serum liver and apoptosis-specific proteins were increased; this was more pronounced in responders than non-responders, with the difference more marked in Arm 1 versus Arm 2. Increased abundance of these proteins was highly correlated with ALT levels, which were often associated with transient hepatitis B virus (HBV) DNA elevations and HBsAg decreases.” Source: [Joshi et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12923464/) ### HBsAg and HBV DNA reduction after 4 weeks of treatment: phase 2a study > “For treatment-naïve patients, the mean (s.d.) HBsAg reduction from baseline to day 29 was 0.50 (0.57) log10 IU ml−1 (P = 0.245 versus placebo) and 1.56 (1.38) log10 IU ml−1 (P = 0.001 versus placebo) in the bepirovirsen 150 mg and 300 mg arms, respectively (Table 3). For on-NA patients, the mean (s.d.) HBsAg reduction to day 29 was 1.99 (1.80) log10 IU ml−1 (Table 3). By contrast, no placebo-treated patient had a reduction in HBsAg of >0.07 log10 IU ml−1 by day 29.” > “The mean (s.d.) HBV DNA reduction from baseline to day 29 was 0.38 (0.42) log10 IU ml−1 (P = 0.116 versus placebo) and 1.66 (1.48) log10 IU ml−1 (P < 0.001 versus placebo) in the bepirovirsen 150 mg and 300 mg arms, respectively (Table 3).” Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/) ### HBsAg decline during 24 weeks of treatment: B-Clear > “In group 1, 43 participants (63%) receiving NA therapy and 41 (59%) not receiving NA therapy had an HBsAg level of less than 100 IU per milliliter by the end of treatment; the values were 26 (38%) and 20 (29%), respectively, at 24 weeks after the end of treatment (Figure 2). By the end of treatment in group 1, a total of 18 participants (26%) receiving NA therapy and 20 (29%) not receiving NA therapy had an HBsAg level below the lower limit of detection; at 24 weeks after the end of treatment, the values were 8 (12%) and 10 (14%), respectively (Figure 2 and Fig. S10).” > “Decreases in HBsAg and HBV DNA levels were dependent on the duration of bepirovirsen treatment (Figs. S5 and S6).” Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027) ### Week 12 HBsAg below 1 IU/mL as an early on-treatment marker > “An early on-treatment response defined as HBsAg <1 IU/mL at Treatment Week 12 was identified as a predictor of achieving the primary efficacy endpoint with HIBSAGO treatment [see Dosage and Administration (2.3)].” > “Among participants with baseline HBsAg ≤3,000 IU/mL who met this criterion, 34% (203/601) had sustained suppression of HBV DNA and HBsAg not detected at 24 weeks after cessation of all chronic HBV treatment.” > “Participants who did not meet this criterion (who had HBsAg ≥1 IU/mL at Week 12) had a 2% (9/498) probability of having sustained suppression of HBV DNA and HBsAg not detected at 24 weeks after cessation of all chronic HBV treatment.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### ALT flares temporally associated with HBsAg decline > “HIBSAGO may cause on-treatment hepatic flares with increases in ALT of >20-40x ULN associated with decline in HBsAg.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) > “Reductions in HBsAg either preceded the ALT increases or occurred concomitantly with ALT flares (Fig. 3a–d and Supplementary Fig. 4). Generally, larger ALT increases (based on peak ALT) were associated with greater HBsAg reductions (Fig. 3e and Supplementary Fig. 6).” > “By contrast, no ALT flares were observed in patients without a HBsAg reduction (<0.2 log10) or in patients receiving placebo.” Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/) ### ALT increases to at least 3 times the upper limit of normal: B-Clear > “Overall, 39 of 225 participants receiving NA therapy (17%) and 93 of 227 not receiving NA therapy (41%) had a transient increase in the ALT level to at least 3 times the upper limit of the normal range between randomization and the end of follow-up (Table S6).” > “In patients with HBV, ALT flares can be a result of disease activity, immune clearance of HBV-infected hepatocytes, or drug-induced liver injury.” Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027) ### C-reactive protein increases after the first dose > “Six (50%) bepirovirsen‐treated participants in the single‐dose cohorts and 9 (100%) in the multiple‐dose cohorts had transient increases in C‐reactive protein (CRP) (single‐dose, Figure S11A; multiple‐dose, Figure 3A–D).” > “Peak CRP levels ranged from 4.2 to 53.3 mg/L; those with peak CRP levels >10 mg/L (n = 5 for single‐dose; n = 6 for multiple‐dose) were reported as treatment‐emergent AEs. These increases were not associated with symptoms, and no participants had chronic CRP elevation.” Source: [Han et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9804925/) > “An increase in C-reactive protein (CRP) levels following the first dose of bepirovirsen was observed in patients with CHB.” > “CRP elevations were dose-related in patients and were consistent with those observed in healthy volunteers (Supplementary Fig. 3b and unpublished data).” Source: [Yuen et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8516644/) ### Cardiac electrophysiology at supratherapeutic doses > “At supratherapeutic doses of 450 or 600 mg (1.5 and 2 times the recommended dosage) of HIBSAGO, clinically significant QTc interval prolongation was not observed.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### Placebo-corrected QTcF change at Cmax: thorough QT study | Arm | Participants analyzed | Placebo-corrected change from baseline in QTcF, geometric mean (90% CI), milliseconds | | --- | --- | --- | | Bepirovirsen, four subcutaneous injections | “5” | “2.360” “(-0.249 to 4.970)” | | Bepirovirsen, three subcutaneous injections | “18” | “2.024” “(-0.541 to 4.589)” | Source: [ClinicalTrials.gov NCT06422767](https://clinicaltrials.gov/study/NCT06422767?tab=results) ### Response by HBV genotype and baseline HBsAg in B-Well 1 and B-Well 2 > “Overall response rates were 28% for genotype A, 21% for genotype B, 20% for genotype D, and 15% for genotype C. Response rates declined with increasing baseline HBsAg levels and fell below 10% for genotypes B and C at baseline HBsAg levels exceeding 1,000 IU/mL.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### Resistance: binding-site polymorphisms in B-Well 1 and B-Well 2 | Trial and baseline HBsAg stratum | Baseline nucleotide polymorphisms, % (n/N) | Treatment-emergent nucleotide mutations, % (n/N) | | --- | --- | --- | | B-Well 1, baseline HBsAg ≤3,000 IU/mL | “6 (7/123)” | “5 (2/42)” | | B-Well 2, baseline HBsAg ≤3,000 IU/mL | “7 (7/104)” | “6 (2/31)” | | B-Well 1, baseline HBsAg ≤1,000 IU/mL | “3 (2/69)” | “5 (1/22)” | | B-Well 2, baseline HBsAg ≤1,000 IU/mL | “12 (6/50)” | “0 (0/10)” | Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### Resistance: phenotypic susceptibility of binding-site variants > “Cell culture based phenotypic testing of baseline and treatment emergent variants identified in HIBSAGO clinical trials indicated 1.2- to 4.1-fold reductions in susceptibility relative to wild-type based on HBsAg inhibition in primary human hepatocytes.” > “Approximate EC50 fold-changes for individual variants relative to wild-type were: G1588A (2.8-fold), C1589A (4.1-fold), T1590A (1.8-fold), T1590G (3.0-fold), C1595T (2.3-fold), and C1600T (1.2-fold). The clinical impact of reduced susceptibility to HIBSAGO in these variants is unknown.” > “Deep mutational scanning identified resistance-conferring mutations predominantly within the central DNA gap region of the bepirovirsen target sequence; mutations in the 2’-MOE-modified wing regions had minimal effect on susceptibility.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### Resistance: binding-site polymorphisms and response in B-Clear > “Baseline SNPs were identified in 7% (22/309) of participants. These participants showed numerically smaller HBsAg reductions than those without SNPs, but 18% (4/22) achieved transient HBsAg loss.” > “Of 16 post-baseline SNPs, eight were treatment-emergent.” > “Findings from this phase IIb clinical study demonstrate that the vast majority (92%) of non-responders, partial responders, or relapsers did not harbor bepirovirsen binding site SNPs.” > “These results suggest that routine testing for specific HBV variants prior to bepirovirsen administration is not currently warranted, and that resistance due to altered sequence complementarity is likely minimal and multifactorial.” Source: [Bouquet et al. (2026)](https://doi.org/10.1016/j.jhep.2025.12.025) ### Cross-resistance with nucleos(t)ide analogue reverse transcriptase inhibitors > “Cross-resistance between bepirovirsen and NrtIs including entecavir and tenofovir is not expected. The bepirovirsen target site (encoding polymerase amino acid residues 832–839) is located in a region distinct from the reverse transcriptase domain associated with NrtI resistance substitutions (polymerase amino acid residues 385–605). The bepirovirsen target site does not overlap with HBV vaccine epitope coding sequences.” Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF) ### Preclinical pharmacology: HBV-transgenic mice and human dose prediction > “Bepirovirsen dose‐dependently reduced hepatic expression of HBV RNA in HBV transgenic mice, with a maximal reduction >90% achieved following a dose of 50 mg/kg/week (Figure S4A).” > “Maximal reduction of serum HBsAg was ≈99% (2 logs).” > “The preclinical transgenic mouse model showed that the 90% effective dose for HBsAg reduction was ≈20 mg/kg, which corresponds to a plasma PK exposure equivalent dose of 280 mg (4 mg/kg) of bepirovirsen in humans.” Source: [Han et al. 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