Hibsago
bepirovirsen
Sources:US prescribing information ↗
Species
MouseRabbit
Longest study
n/a
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and rabbit in labeled studies (carcinogenicity, reproduction); general-toxicity species not stated
“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).”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Species: general tox
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Species: DART
Mouse and rabbit (animal reproduction studies)
“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).”
Species: carcinogenicity
Mouse (2-year, subcutaneous)
“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).”
Surrogate used in
Yes: transgenic hTLR8 knock-in mice (and an hTLR8-overexpressing cell line) for immunostimulatory pharmacology
“This was demonstrated in an hTLR8-overexpressing cell line and confirmed in transgenic hTLR8 knock-in mice.”
Study lengthopen answer page →
Longest pivotal study
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Pivotal GLP studies
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Route in tox
Subcutaneous (weekly in the 2-year mouse carcinogenicity study)
“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).”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, mammalian cell chromosomal aberration, in vivo mouse micronucleus)
“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.”
Carcinogenicity
2-year subcutaneous mouse study at 3, 10, 30 mg/kg weekly (about 0.05-0.5x RHD, BSA)
“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).”
Reproductive & developmental
Mouse and rabbit: no adverse developmental or reproductive effects at <1x (mouse) and ~3x (rabbit) MRHD, BSA
“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).”
Safety pharmacology
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Genotox: Ames
Bacterial reverse mutation (Ames): negative
“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.”
Genotox: in vitro mammalian
Mammalian cell chromosomal aberration test: negative
“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.”
Genotox: in vivo
Mouse micronucleus test: negative
“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.”
Carcinogenicity model
2-year mouse, weekly subcutaneous 3, 10, 30 mg/kg (about 0.05-0.5x RHD, BSA)
“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).”
Carcinogenicity timing
2-year subcutaneous mouse study completed, described in the approved label
“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).”
hERG / QT
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Hibsago don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL not stated; 2-year mouse: hepatocellular carcinomas at ≥10 mg/kg; liver adenomas and hemangiosarcomas at 30 mg/kg (males)
NOAEL / key findings
NOAEL not stated; 2-year mouse: hepatocellular carcinomas at ≥10 mg/kg; liver adenomas and hemangiosarcomas at 30 mg/kg (males)
“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)”
Risksopen answer page →
Immune & cytokine safety
Sequence-specific, hTLR8-dependent innate immune activity; no activity at other pattern recognition receptors
“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.”
Biodistribution & persistence
Detected in mouse milk (LD 10) with negligible systemic exposure in offspring; tissue distribution not stated
“Although bepirovirsen was detected in the milk of lactating mice (on LD 10), systemic exposure of bepirovirsen in the offspring via milk was negligible.”
Modality-specific risk
Phosphorothioate ASO class effect: increased tumors in 2-year subcutaneous mouse carcinogenicity studies; clinical relevance unknown
“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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
43% (517/1,203) ADA positive in Phase 3 B-Well trials; ADAs lowered clearance by 26.6%
“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.”
Label warnings
Boxed warning: On-treatment hepatic flares and thrombocytopenia
- On-Treatment Hepatic Flares
- Thrombocytopenia
- Worsening Renal Function
- Inflammatory and Immune Effects
- Serious Adverse Reaction with Improper Administration
- Post-Treatment Exacerbations of HBV Infection after NrtI Discontinuation
- Risk of HIV-1 Virologic Failure in Patients with HBV/HIV-1 Coinfection Who Discontinue Nucleos(t)ide Analog Reverse Transcriptase Inhibitor Therapy
- Risk of Hepatitis Flare in Patients with HBV/Hepatitis D Virus Coinfection
- Unknown Effect on Preventing Transmission of HBV
HepatotoxicityThrombocytopeniaNephrotoxicityImmune-mediated reactionsInfections
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Hibsago don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL not stated; 2-year mouse: hepatocellular carcinomas at ≥10 mg/kg; liver adenomas and hemangiosarcomas at 30 mg/kg (males)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Pivotal GLP studies
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
DART package
Species: DART
Mouse and rabbit (animal reproduction studies)
“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).”
Reproductive & developmental
Mouse and rabbit: no adverse developmental or reproductive effects at <1x (mouse) and ~3x (rabbit) MRHD, BSA
“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).”
PPND / ePPND: when
Pre- and postnatal development in mouse (GD 6 to LD 21) completed, described in the approved label
“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.”
Carcinogenicity
Species: carcinogenicity
Mouse (2-year, subcutaneous)
“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).”
Carcinogenicity model
2-year mouse, weekly subcutaneous 3, 10, 30 mg/kg (about 0.05-0.5x RHD, BSA)
“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).”
Carcinogenicity timing
2-year subcutaneous mouse study completed, described in the approved label
“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).”
Safety marginopen answer page →
Safety margin at NOAEL
Mouse embryo-fetal/pre- and postnatal study: no adverse effects at 0.7x MRHD (BSA); no repeat-dose margin stated
“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.”
NOAEL / key findings
NOAEL not stated; 2-year mouse: hepatocellular carcinomas at ≥10 mg/kg; liver adenomas and hemangiosarcomas at 30 mg/kg (males)
“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)”
Efficacy evidenceopen answer page →
Efficacy evidence
Primary human hepatocytes (HBV genotype D, free uptake): HBsAg and HBeAg secretion EC50 47.1 and 29.8 nM
“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.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin in mouse fertility study: no adverse effects up to 0.7 times the MRHD (BSA)
“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).”
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