Pharmacodynamics

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“The contribution of immunostimulatory activity to antiviral activity at therapeutic concentrations in humans has not been fully determined.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Notably, induction of type I IFN (IFN-α or IFN-β) did not occur with bepirovirsen in hTLR8 mice.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Compared with the non-responder group, the responder group showed trends towards increased activity in the IFN-γ signaling and T-cell response pathways.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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).” (opens the source at this quote in a new tab)CopyFlag

“Decreases in HBsAg and HBV DNA levels were dependent on the duration of bepirovirsen treatment (Figs. S5 and S6).” (opens the source at this quote in a new tab)CopyFlag

“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)].” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“HIBSAGO may cause on-treatment hepatic flares with increases in ALT of >20-40x ULN associated with decline in HBsAg.” (opens the prescribing information at this quote)CopyFlag

“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).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“By contrast, no ALT flares were observed in patients without a HBsAg reduction (<0.2 log10) or in patients receiving placebo.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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).” (opens the source at this quote in a new tab)CopyFlag

“In patients with HBV, ALT flares can be a result of disease activity, immune clearance of HBV-infected hepatocytes, or drug-induced liver injury.” (opens the source at this quote in a new tab)CopyFlag

“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).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“An increase in C-reactive protein (CRP) levels following the first dose of bepirovirsen was observed in patients with CHB.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“CRP elevations were dose-related in patients and were consistent with those observed in healthy volunteers (Supplementary Fig. 3b and unpublished data).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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.” (opens the source at this quote in a new tab)CopyFlag

“Of 16 post-baseline SNPs, eight were treatment-emergent.” (opens the source at this quote in a new tab)CopyFlag

“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.” (opens the source at this quote in a new tab)CopyFlag

“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.” (opens the source at this quote in a new tab)CopyFlag

“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.” (opens the prescribing information at this quote)CopyFlag

“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).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Maximal reduction of serum HBsAg was ≈99% (2 logs).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“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.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag