Bepirovirsen (Hibsago)

• HIBSAGO therapy should be prescribed only when appropriate laboratory monitoring can be performed to manage the treatment regimen. Close laboratory monitoring is required to assess for toxicities that may necessitate dose modification, treatment interruption, or permanent discontinuation of HIBSAGO [see Dosage and Administration (2.4), Warnings and Precautions (5.1, 5.2, 5.3)].
• HIBSAGO must be administered under the guidance and supervision of a healthcare provider for the initial dose to ensure proper injection technique.
• Patients or caregivers may administer HIBSAGO after their healthcare provider determines that it is appropriate and with medical follow-up, including laboratory testing. Healthcare providers must provide proper training in subcutaneous injection technique before the patient or caregivers can administer HIBSAGO [see Dosage and Administration (2.5)].

The maximum recommended duration of HIBSAGO treatment is 24 weeks [see Dosage and Administration (2.5, 2.7)].

Prior to initiation of HIBSAGO for treatment of chronic HBV infection, test all patients to quantify HBsAg levels in serum or plasma to identify patients with baseline HBsAg levels less than or equal to 3,000 IU/mL [see Indications and Usage (1)]. In addition, test patients for HBV DNA, ALT, AST, bilirubin, platelet count, urine albumin-creatinine ratio (uACR), and estimated glomerular filtration rate (eGFR) prior to initiation of treatment and as directed while on treatment and following treatment completion [see Indications and Usage (1), Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1, 5.2, 5.3)].

Information on FDA-authorized tests for the quantification of HBsAg levels is available at: http://www.fda.gov/CompanionDiagnostics.

HIBSAGO is for subcutaneous use only [see Dosage and Administration (2.5)]. The maximum recommended duration of HIBSAGO treatment is 24 weeks [see Dosage and Administration (2.7)].

HIBSAGO must be used in combination with NrtI therapy. Refer to the NrtI prescribing information for additional information.

Weeks 1 and 2

The recommended dosage of HIBSAGO is 300 mg (administered as two 150 mg subcutaneous injections) twice a week allowing 3 or 4 days between each dose.

Weeks 3 to 24

The recommended dosage of HIBSAGO is 300 mg (administered as two 150 mg subcutaneous injections) once a week on the same day each week.

Early cessation of HIBSAGO may be considered in patients who have not achieved HBsAg <1 IU/mL by Treatment Week 12 [see Clinical Studies (14)].

During treatment with HIBSAGO, laboratory test monitoring is required to detect and manage adverse reactions. Based on laboratory test values, adjustments to HIBSAGO dosage, treatment interruption, and increased frequency of laboratory test monitoring may be required as described in Tables 1, 2, and 3.

Dosage Modifications Based on ALT and Total Bilirubin Values

Table 1 displays the recommended ALT and total bilirubin monitoring and HIBSAGO dosage modifications due to ALT and total bilirubin value changes.

Dosage Modifications Based on Platelet Count

Table 2 displays the recommended platelet count monitoring while on HIBSAGO treatment and HIBSAGO dosage modifications due to platelet count changes.

Dosage Modifications Due to Renal Impairment

Table 3 displays the recommended renal test monitoring while on HIBSAGO treatment and HIBSAGO dosage modifications due to renal impairment.

Refer to the Instructions for Use for additional detailed instruction on preparation and administration of the prefilled syringe. HIBSAGO therapy should be prescribed only when appropriate laboratory monitoring can be performed to manage the treatment regimen.

HIBSAGO must be administered under the guidance and supervision of a healthcare provider for the initial dose.

Patients or caregivers may administer HIBSAGO after their healthcare provider determines that it is appropriate and with medical follow-up, including laboratory testing. Healthcare providers must provide proper training in subcutaneous injection technique before the patient or caregivers can administer HIBSAGO [see Warnings and Precautions (5.5)].

• Ensure HIBSAGO has been at room temperature (below 86°F [30°C]) for a minimum of 30 minutes prior to injection [see How Supplied/Storage and Handling (16)].
• Prior to administration, visually inspect the window of the prefilled syringes for particulate matter or discoloration. HIBSAGO injection should be clear and colorless to yellow and free of visible particulate matter. Do not use HIBSAGO injection if the product exhibits discoloration, cloudiness, or particulate matter. Do not shake the HIBSAGO syringe. Do not use the syringes if they have been dropped or damaged.
• Inject into the thigh or abdomen, avoiding the 2 inches (5 cm) around the navel. The outer area of the upper arm can also be used if a caregiver administers the subcutaneous injections.

• For a 300 mg dose, administer 2 x 150 mg pre-filled syringes, inject one right after the other. Choose a different injection site for each injection, at least 2 inches (5 cm) from the other injection sites [see Warnings and Precautions (5.5)].
• For a 150 mg dose administer 1 x 150 mg pre-filled syringe injection.
• Never give injections into areas where the skin is tender, bruised, red, or hard. Rotate injection sites to reduce the risk of injection site reactions [see Warnings and Precautions (5.5)].

If a dose of HIBSAGO is missed at any time during treatment (Weeks 1-24), the missed dose must be administered as soon as possible, unless the next scheduled dose is due in less than three days, in which case the missed dose must be skipped and the next dose administered as scheduled.

HIBSAGO must be stopped upon completion of 24 weeks of treatment, and patients must remain on their NrtI therapy for at least an additional 24 weeks. Following the 24 weeks of further NrtI treatment, stopping NrtI therapy can be considered in those patients who:

• are hepatitis B e-antigen (HBeAg) negative,
• have HBV DNA <LLOQ (lower limit of quantification, defined as <20 IU/mL), HBsAg not detectable (LOD = 0.05 IU/mL), and alanine aminotransferase (ALT) values ≤2x upper limit of normal (ULN), and
• do not need the nucleos(t)ide analog reverse transcriptase inhibitor therapy to treat Human Immunodeficiency Virus (HIV) co-infection [see Warnings and Precautions (5.7)].

If NrtI therapy is stopped, frequent monitoring of HBsAg, HBV DNA, and hepatic function is recommended for at least one year following NrtI therapy cessation, with routine monitoring as clinically indicated afterwards [see Warnings and Precautions (5.6), Clinical Studies (14)].

During treatment with HIBSAGO, increases in ALT ≥3 x ULN to 69 x ULN were observed in clinical trials [see Adverse Reactions (6.1)]. Most ALT increases occurred in the first 12 weeks of treatment (typically between Weeks 5 to 10), started to resolve within 2 weeks, and were not associated with any clinical signs or symptoms of liver dysfunction. The ALT increases were temporally associated with a preceding or concurrent decline in HBsAg suggesting host immune response. Two percent of participants receiving HIBSAGO had ALT increases ≥20 x ULN that resolved when treatment was interrupted or permanently discontinued. There have been isolated cases of ALT increases associated with an increase in total bilirubin up to 4 x ULN that resolved when treatment was permanently discontinued.

ALT and total bilirubin must be measured prior to initiation of treatment. Do not initiate HIBSAGO in patients with evidence of acute hepatic impairment or cirrhosis [see Contraindications (4)].

During and after HIBSAGO treatment, follow the recommended monitoring for ALT and total bilirubin and the treatment recommendations as specified in Table 1 [see Dosage and Administration (2.4)]. In all patients, the minimum recommended on-treatment monitoring of ALT and total bilirubin is weekly through Week 12 and every other week from Weeks 12 through 24, but more frequent monitoring may be necessary. In addition, HIBSAGO dose reduction or temporary or permanent discontinuation of HIBSAGO may be necessary based on the results of liver laboratory testing. In all patients with abnormal values at the time of HIBSAGO discontinuation, obtain ALT and total bilirubin values at 4, 12, and 24 weeks post-treatment to assess recovery of ALT values to within the normal range, as appropriate [see Dosage and Administration (2.4)].

HIBSAGO may cause reductions in platelet count at any time during treatment that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In the HIBSAGO clinical trials, two participants reported serious adverse reactions of thrombocytopenia <50 × 10⁹/L, including one participant with immune thrombocytopenia [see Adverse Reactions (6.1)]. In addition, a gradual, dose-dependent decline in platelet count was observed in most patients that continued to worsen while on HIBSAGO.

Platelet Monitoring and Dosing

Platelet count must be measured prior to initiation of treatment. Do not initiate HIBSAGO in patients with a platelet count below 100 x 10⁹/L [see Contraindications (4)]. In patients with platelet count below the normal range but ≥100 x 10⁹/L, rule out cirrhosis before initiating HIBSAGO [see Contraindications (4)].

During and after HIBSAGO treatment, follow recommended monitoring and treatment recommendations for platelet count as specified in Table 2 [see Dosage and Administration (2.4)]. In all patients, the minimum recommended on-treatment monitoring of platelet counts is weekly through Week 24, but more frequent monitoring may be necessary. In addition, HIBSAGO treatment interruption or permanent discontinuation may be necessary based on the results of platelet testing. If platelet count falls below 50 x 10⁹/L, permanently discontinue treatment with HIBSAGO and consider corticosteroid treatment in consultation with an expert. In all patients with abnormal values at the time of HIBSAGO discontinuation, obtain repeat platelet counts 4 and 12 weeks post-treatment to assess for platelet count recovery, as appropriate.

Symptoms of Thrombocytopenia

Symptoms of thrombocytopenia can include unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache. Instruct patients to report to their healthcare provider immediately if they experience any symptoms of thrombocytopenia. If a patient develops signs or symptoms of thrombocytopenia, treatment with HIBSAGO must be paused and a platelet count obtained as soon as possible [see Dosage and Administration (2.4)].

Additional Considerations

Consider the risks and benefits of treatment with HIBSAGO when treating patients who may be particularly susceptible to platelet count decreases, e.g., elderly patients, or patients with bleeding diathesis/coagulopathy, history of major bleeding events or patients taking antiplatelets, anticoagulants, or drugs that lower platelet count [see Drug Interactions (7.1)].

In the HIBSAGO clinical trials, mean eGFR declined within 4 weeks of initiation of HIBSAGO and continued to decline during treatment. These changes were generally reversible after treatment discontinuation. The mechanism of the decrease in eGFR is not clear [see Adverse Reactions (6.1)].

Obtain eGFR and uACR in all patients prior to initiation of treatment. The clinical trials excluded participants with moderate or severe renal impairment (eGFR ≤60 mL/min/1.73m²) or uACR >0.3 mg/mg; insufficient data are available on the safety of HIBSAGO in these populations [see Use in Specific Populations (8.6)]. Consider the risks and benefits of HIBSAGO when treating patients who may be more susceptible to renal injury [see Drug Interactions (7.2)].

During and after HIBSAGO treatment, follow the recommended monitoring for eGFR and the treatment recommendations as specified in Table 3 [see Dosage and Administration (2.4)]. In all patients, the minimum recommended on-treatment monitoring of eGFR is every other week through Week 24, but more frequent monitoring may be necessary. In addition, HIBSAGO treatment interruption or permanent discontinuation may be necessary based on the results of renal laboratory testing. In all patients with abnormal values at the time of HIBSAGO discontinuation, obtain repeat eGFR 4 and 12 weeks post-treatment to assess for renal function recovery, as appropriate.

Although no cases of glomerulonephritis were observed with HIBSAGO administration in the clinical trials, glomerulonephritis has been observed after administration of other antisense oligonucleotides. Consider assessing for proteinuria periodically during treatment, as appropriate. If a diagnosis of glomerulonephritis is suspected or confirmed, permanently discontinue HIBSAGO and consider early initiation of immunosuppressive therapy in consultation with an expert.

In trials with HIBSAGO, influenza-like symptoms, laboratory test changes (e.g., decreases in complement factors C3 and C4), purpuric leg rashes, cutaneous leukocytoclastic vasculitis, dermatitis, pruritus/erythematous plaque, and polyarthralgia were observed. In addition, serious inflammatory and immune adverse reactions were reported, including immune thrombocytopenia, autoimmune hemolytic anemia, systemic inflammatory response syndrome, and a cryoglobulinemic flare [see Adverse Reactions (6.1)].

Consider the risks and benefits of HIBSAGO when treating patients that may be more susceptible to inflammatory and/or immune effects, e.g., solid organ transplant recipients, patients with autoimmune hepatitis, or patients with a history of vasculitis or conditions associated with vasculitis (including systemic lupus erythematosus, cryoglobulinemia, or rheumatoid arthritis). The risks and benefits of HIBSAGO must also be considered in patients with a history of, or suspected, extrahepatic disorders related to HBV immune‑mediated effects (including but not limited to nephrotic syndrome or any type of glomerulonephritis).

If signs and symptoms suggestive of vasculitis/immune-associated events occur, and no alternative cause is identified, permanently discontinue treatment with HIBSAGO.

Improper HIBSAGO administration, including not rotating injection sites, has been associated with the serious adverse reaction of omental infarction in one participant. Ensure that injection sites are rotated from one week to the next and that the two injections administered weekly to constitute the recommended dose of HIBSAGO are separated by at least 2 inches (5 cm). Never give injections into areas where the skin is tender, bruised, red, or hard [see Dosage and Administration (2.5), Adverse Reactions ( 6.1 )].

Severe acute exacerbations of HBV infection may occur after discontinuation of anti-HBV therapy. If NrtI therapy is discontinued after completing HIBSAGO treatment, frequent monitoring is recommended. Patients should be closely monitored with both laboratory (HBsAg, HBV DNA, and hepatic function) and clinical follow-up for at least one year following NrtI therapy cessation, with routine monitoring as clinically indicated afterwards, to detect acute exacerbations of HBV infection and the possible need for resumption of HBV treatment.

Patients who are taking nucleos(t)ide analog reverse transcriptase inhibitors as part of antiretroviral therapy for HIV-1 and HBV coinfection must not stop taking their nucleos(t)ide analog reverse transcriptase inhibitor therapy unless an HIV healthcare provider has directed them to do so.

There are no data on the safety and efficacy of HIBSAGO in patients with HBV and hepatitis D virus (HDV) coinfection. HIBSAGO is not recommended in patients with HDV coinfection due to the potential for an exacerbated risk of clinically significant ALT increases.

There are no data on the effect of HIBSAGO in preventing transmission of HBV. Patients must be advised to use appropriate precautions to prevent transmission of HBV.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of HIBSAGO in the treatment of chronic HBV infection has been evaluated in two pooled, Phase 3, placebo-controlled randomized trials (B‑Well 1 and B‑Well 2) in which 1,223 participants received at least one dose of HIBSAGO (300 mg subcutaneously, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24) and 611 participants received matching placebo.

The most common adverse reactions (≥10%), excluding laboratory abnormalities, reported with HIBSAGO included injection site reactions, pyrexia, fatigue, and headache. In the pooled B-Well 1 and B-Well 2 trials, 3% of participants receiving HIBSAGO and <1% of participants receiving placebo discontinued due to adverse events.

The incidence of adverse reactions in the pooled safety data set (Weeks 1‑36) with HIBSAGO is shown in Table 4.

Cutaneous Vasculitis

Adverse reactions of biopsy-confirmed vasculitis occurred in two participants treated with HIBSAGO. One participant developed arthralgia, lower limb edema, and purpuric lesions at Treatment Week 2. The second participant developed a pruritic circular lesion on the left lower limb at Treatment Week 14 which progressed to bilateral lower limb pruritic scaly lesions on Treatment Week 17. For both cases, skin biopsy confirmed leukocytoclastic vasculitis, and the events resolved with corticosteroid treatment after permanent discontinuation of HIBSAGO [see Warnings and Precautions (5.4)].

Injection Site Reactions (ISRs)

ISRs were the most common adverse reactions reported with HIBSAGO. The most commonly reported ISRs (all grades) in the pooled safety data set (Weeks 1‑36) are presented in Table 5. The frequency and severity of injection site reactions decreased over time, and 99% of injection site reactions reported in HIBSAGO recipients were mild to moderate in severity.

A serious adverse reaction of omental infarction requiring surgical intervention occurred at Treatment Week 11 in a participant who had four weeks of persistent erythema at the HIBSAGO injection site and in whom injection sites had not been rotated. The infarcted omentum was adherent to the peritoneum directly underlying the area of injection site at which reactive changes, including a granuloma, were seen on CT scan [see Warnings and Precautions (5.5)].

Less Common Adverse Reactions Reported in Clinical Trials:

The following adverse reactions occurred in <3% of participants receiving HIBSAGO and are included because of a potential causal relationship:

Immune system disorders: Hypersensitivity

Skin and soft tissue disorders: Angioedema

Laboratory Abnormalities

ALT Increased

During the first 24 weeks, <1% (n = 1) of HIBSAGO recipients had ALT ≥3x ULN with bilirubin ≥2x ULN (>35% direct bilirubin) and permanently discontinued treatment [see Warnings and Precautions (5.1)]. Three other participants also permanently discontinued treatment because of ALT ≥10 x ULN for 4 or more weeks, and 53 (4%) paused treatment due to ALT increases.

Decreased Platelet Counts

During the first 24 weeks, two participants treated with HIBSAGO had serious adverse reactions of thrombocytopenia, with platelet counts <50 × 10⁹/L. One participant experienced platelet decline from 283 × 10⁹/L at baseline to 161× 10⁹/L at Week 5, 83 × 10⁹/L at Treatment Week 6 and a nadir of 42 × 10⁹/L at Treatment Week 7. The other participant experienced platelet decline from 261 × 10⁹/L at baseline, to 177 × 10⁹/L at Week 6, to 108 × 10⁹/L at Treatment Week 7, with a nadir of 8 × 10⁹/L at Treatment Week 8. This participant was assessed as having immune thrombocytopenia. Both participants recovered with corticosteroid treatment and permanent discontinuation of HIBSAGO [see Warnings and Precautions (5.2)]. In total, 8 (<1%) participants met permanent discontinuation criteria, and 114 (9%) participants paused treatment due to platelet declines.

In the pivotal clinical trials, the maximum change from baseline in platelet count in the HIBSAGO group occurred at Week 24, with a mean (SD) change from baseline of -68 x 10⁹/L (40.7) or -28.1% (13.79), from a baseline of 233 x 10⁹/L. The mean platelet count in the HIBSAGO group recovered to within 5% of baseline values by Week 60 (36 weeks after last dose of HIBSAGO).

Decrease in Neutrophil Counts

During the first 24 weeks, 27 (2%) of participants had neutrophil counts <1,000 cells/mm³ at 2 or more consecutive visits. No participant had a value <500 cells/mm³ at 2 or more consecutive visits. The decline in neutrophil count was not associated with adverse events that indicated increased risk of infection.

In the pivotal clinical trials, the maximum change from baseline in absolute neutrophil count in the HIBSAGO group occurred at Week 24, with a mean (SD) change from baseline of -0.795 x 10⁹/L (1.0969) or -20.36% (29.40), from a baseline of 3.33 x 10⁹/L. The mean absolute neutrophil count in the HIBSAGO group recovered to within 5% of baseline values by Week 60 (36 weeks after last dose of HIBSAGO).

eGFR Decreased

During the first 24 weeks, in participants treated with HIBSAGO, 4% had an eGFR decrease >30% of pretreatment levels for 2 or more consecutive readings and <1% (one participant) experienced such declines more than 24 weeks after completion of HIBSAGO treatment [see Warnings and Precautions (5.3)]. No participant met criteria for permanent discontinuation of HIBSAGO treatment based on decreased renal function, but 28 (2%) participants paused treatment because of decreased renal function.

In the pivotal clinical trials, the maximum change from baseline in eGFR in the HIBSAGO group occurred at Week 25, with a mean (SD) change from baseline of -10 mL/min/1.73 m² (9.96) or -10% (10.28), from a baseline of 100.8 mL/min/1.73m². The mean eGFR in the HIBSAGO group recovered to within 5% of baseline values by Week 36 (12 weeks after last dose of HIBSAGO).

Monitor patients for signs of bleeding and thrombocytopenia if HIBSAGO is taken concomitantly with anticoagulants, antiplatelets, or drugs that decrease platelet count [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

Monitor patients for signs of worsening renal function during concomitant administration of HIBSAGO with drugs that may impair renal function. Refer to individual drug information before prescribing [see Warnings and Precautions (5.3), Adverse Reactions (6.1)].

Concomitant administration of HIBSAGO and peginterferon alfa‑2a is not recommended due to the potential for an exacerbated risk of increased ALT, decreased platelet count, and immune-mediated effects.

Risk Summary

There are insufficient data on the use of HIBSAGO in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental or reproductive effects were observed when bepirovirsen was administered subcutaneously to mice and rabbits at less than 1 (mouse) and approximately 3 (rabbits) times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparisons (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data: No adverse effects on embryofetal development, parturition, or on the postnatal development of the offspring were observed following subcutaneous administration of bepirovirsen to pregnant mice during organogenesis and throughout pregnancy and lactation [Gestation day (GD) 0 to 15 and from GD 6 to lactation day (LD) 21], at 0.7 times the MRHD based on BSA comparison. Bepirovirsen was also administered subcutaneously to pregnant rabbits at doses up to 25 mg/kg every other day during organogenesis (GD 6 to 18). Reduced fetal weights associated with maternal toxicity were observed at approximately 3 times the MRHD based on BSA comparison.

Risk Summary

There are insufficient data on the presence of bepirovirsen or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Bepirovirsen was detectable in the milk of lactating mice without an effect on offspring (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HIBSAGO and any potential adverse effects on the breastfed child from HIBSAGO or from the underlying maternal condition.

Data

Animal Data: No adverse effects on lactation or on the offspring were observed following subcutaneous administration of bepirovirsen to pregnant and lactating mice (GD 6 through LD 21) at 0.7 times the MRHD based on BSA comparison. Although bepirovirsen was detected in the milk of lactating mice (on LD 10), systemic exposure of bepirovirsen in the offspring via milk was negligible.

The safety and effectiveness of HIBSAGO have not been established in patients less than 18 years of age.

Of the total number of patients who received treatment with HIBSAGO in the B‑Well 1 and B‑Well 2 trials, 128 (10%) were 65 years of age and older. The efficacy response was generally higher for age <65 versus that for age ≥65 years [see Clinical Studies (14)]. No overall differences in safety of HIBSAGO were observed between patients 65 years of age and older and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

In the B-Well 1 and B-Well 2 trials, 21 (1%) participants were 75 years of age and older. Differences in efficacy in this age group versus younger adult patients cannot be determined due to the small number of participants.

No dosage adjustment is recommended in patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73m²) [see Clinical Pharmacology (12.3)]. Insufficient data are available on the safety of HIBSAGO in patients with moderate or severe renal impairment or end stage renal disease (eGFR less than or equal to 59 mL/min/1.73m²). HIBSAGO can cause worsening renal function [see Warnings and Precautions (5.3)].

The safety and efficacy of HIBSAGO in patients with cirrhosis have not been established. The use of HIBSAGO is contraindicated in chronic hepatitis B patients with acute hepatic impairment, or cirrhosis who have mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Contraindications (4), Clinical Pharmacology (12.3)].

The safety and efficacy of HIBSAGO have not been established in patients with hepatitis C virus (HCV) coinfection.

HIBSAGO is an antiviral drug against HBV [see Microbiology (12.4)].

Exposure Response

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.

Immunostimulant Activity

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. This was demonstrated in an hTLR8-overexpressing cell line and confirmed in transgenic hTLR8 knock-in mice. 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.

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. In addition, treatment with HIBSAGO led to immunophenotypic changes in peripheral B and T cells (including increases in Ki67 positive B and T cells and increases in granzyme B positive cluster of differentiation 8, T cell frequencies). The contribution of immunostimulatory activity to antiviral activity at therapeutic concentrations in humans has not been fully determined.

Cardiac Electrophysiology

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.

The pharmacokinetic parameters of bepirovirsen 300 mg are summarized in Table 7.

Specific Populations

Based on population pharmacokinetic analyses, following subcutaneous administration, there were no clinically meaningful changes in the pharmacokinetics of bepirovirsen by race (Asian, Black, White, Other), ethnicity, age (18-87 years old), sex, body weight (39 kg to 148 kg), injection site location (thigh, upper arm, abdomen) and anti-drug antibodies (ADA) status.

Renal Impairment: Bepirovirsen pharmacokinetics were similar between patients with CHB with an eGFR 60 to 89 mL/min/1.73m² compared to patients with an eGFR ≥90 mL/min/1.73 m². Insufficient data are available in patients with moderate or severe renal impairment.

Hepatic Impairment: The pharmacokinetics of bepirovirsen have not been evaluated in CHB patients with hepatic impairment (Child-Pugh Class A, B, or C) [see Contraindications (4)].

There is a 33% reduction in C_max and a 31% reduction in AUC_0-∞ in participants with moderate hepatic impairment (Child‑Pugh Class B) but without HBV infection when compared to participants with normal hepatic function.

Drug Interaction Studies

No formal clinical drug interaction studies have been conducted with HIBSAGO. In clinical trials, concomitant administration of HIBSAGO with a NrtI did not result in changes in bepirovirsen exposure. In addition, HIBSAGO did not impact NrtI exposure.

Based on in vitro study results, HIBSAGO is not a substrate, inducer or inhibitor of major cytochrome P450 (CYP) enzymes, or drug transporters; therefore, clinically relevant pharmacokinetic interactions are not expected.

Mechanism of Action

Bepirovirsen is a synthetic, single-stranded, chimeric antisense oligonucleotide (ASO) with a gapmer architecture consisting of five 2′-O-(2-methoxyethyl) (2′-MOE)-modified ribonucleotide wings flanking a central 10-deoxynucleotide gap with phosphorothioate linkages throughout. Bepirovirsen is designed to bind a conserved 20-nucleotide site (nucleotides 1581 5’-GCACTTCGCTTCACCTCTGC-3' 1600) present in HBV mRNAs (including the pregenomic RNA [pgRNA], precore, preS1, preS2/S, and X mRNAs), forming a DNA:RNA heteroduplex that recruits endogenous ribonuclease H1 (RNase H1) to catalyze irreversible hydrolysis of the viral RNA strand at the 3’-O-P bonds, resulting in degradation of HBV mRNA and reduction in HBV DNA and viral proteins, including HBsAg. The 20-nucleotide binding site is present within transcripts derived from both cccDNA and integrated HBV DNA.

Bepirovirsen reduced the level of HBV RNA transcripts in a dose-dependent manner in HepG2.2.15 cells (HBV genotype D) using transfection-based delivery resulting in EC₅₀ values of 70 nM (16 hours) and 122 nM (48 hours) as measured by two RT-qPCR primer/probe sets targeting pgRNA, preS1, and preS2/S mRNAs.

Antiviral Activity

In HepG2.2.15 cells (HBV genotype D, transfection-based delivery), bepirovirsen reduced intracellular HBV DNA with EC₅₀ values of approximately 171 nM and 53 nM by qPCR at 48 and 96 hours, respectively, and inhibited extracellular HBsAg and HBeAg secretion with EC₅₀ values of approximately 138 nM and 296 nM by ELISA at 48 hours, respectively.

In primary human hepatocytes (HBV genotype D, free uptake), 4 doses of bepirovirsen every ~72 to 96 hours inhibited extracellular HBsAg and HBeAg secretion with EC₅₀ values of 47.1±0.7 nM and 29.8±2.9 nM, respectively, as assessed by ELISA ~96 hours after the last dose.

An HBV RNA launch system was used to assess the activity of bepirovirsen against other HBV genotypes in the U.S. Capped, full-length pgRNA was co-transfected in Huh-7.5-NTCP cells with bepirovirsen to initiate replication independently of viral entry and cccDNA formation. Bepirovirsen inhibited extracellular HBsAg with an EC₅₀ value of approximately 0.20–0.30 nM by chemiluminescent immunoassay (HBV genotype A; at ~96 hours) and reduced intracellular HBV DNA by approximately 3.5 to 5 log₁₀ across genotypes A, B, C, and D by qPCR (at ~48 hours) at a fixed molar ratio.

Conservation of the bepirovirsen target site across HBV genotypes indicates broad antiviral activity. Bioinformatic analysis of 9,139 HBV genomes in the HBV database showed that the target sequence is conserved across genotypes A-H and recombinant forms, with full identity to 97.6% of sequences, and to 99.7% of sequences when allowing for one nucleotide mismatch.

Combining bepirovirsen with entecavir or tenofovir disoproxil fumarate in HepG2.2.15 cells (HBV genotype D, transfection-based delivery) resulted in no antagonism and greater reductions of intracellular HBV DNA by qPCR compared to the individual drugs.

Clinical Trials

In pooled data from the B-Well 1 and B-Well 2 clinical trials, rates of sustained off-treatment suppression of HBV DNA below the lower limit of quantification (20 IU/mL) and HBsAg not detected (LOD = 0.05 IU/mL) at 24 weeks off all HBV treatment among participants who received HIBSAGO varied by HBV genotype and baseline HBsAg level. 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.

Resistance

Among participants in the B-Well 1 and B-Well 2 trials who received HIBSAGO and had next generation sequencing data available, the proportion of participants with nucleotide polymorphisms in the bepirovirsen binding site ranged from 3% to 12% at baseline and for participants with treatment-emergent mutations the proportion ranged from 0% to 6% (Table 8).

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.

Cross-Resistance

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.

The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the trials described below with the incidence of ADAs in other trials, including those of HIBSAGO.

In the Phase 3 B-Well trials, 43% (517/1,203) of participants treated with HIBSAGO tested positive for ADAs. The presence of ADAs resulted in a 26.6% lower systemic clearance of bepirovirsen. The development of these antibodies did not appear to be associated with a reduced treatment response or differences in the safety profile.

Carcinogenesis

In a 2-year carcinogenicity study in mice, bepirovirsen sodium was administered by subcutaneous injection weekly at doses of 3, 10, and 30 mg/kg (approximately 0.05, 0.2, and 0.5 times the RHD, respectively, based on BSA comparison). In male mice, statistically significant increases in tumor incidences were observed compared to controls in liver (hepatocellular carcinomas at ≥10 mg/kg; hepatocellular adenomas, combined hepatocellular adenomas/carcinomas, hemangiosarcomas, and combined hemangiosarcomas/hemangiomas at 30 mg/kg), in stomach (adenomas and combined adenomas/adenocarcinomas at 30 mg/kg), and at the injection sites (fibrosarcomas at 30 mg/kg). In female mice, hepatocellular adenoma and combined hepatocellular adenoma/carcinoma were increased at 30 mg/kg. Increased tumor findings have been observed in 2-year carcinogenicity studies in mice dosed subcutaneously with phosphorothioate ASO class drugs; the clinical relevance is unknown.

Mutagenesis

Bepirovirsen did not exhibit a genotoxic potential in a battery of studies, including an in vitro bacterial reverse mutation (Ames) test, mammalian cell chromosomal aberration test and an in vivo micronucleus test in mice.

Impairment of Fertility

No adverse effects on male or female mating or fertility were observed following subcutaneous administration of bepirovirsen to mice up to 0.7 times the MRHD (based on BSA comparison).