Fendrix
hepatitis B vaccine (rDNA), AS04C-adjuvanted
Sources:EMA assessment report ↗
Species
Rabbit
Longest study
2 wk
Genotox
Conducted Conducted
Carcinogenicity
Not stated Not stated
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit (repeat-dose toxicity of the vaccine)
“Serological analysis demonstrated that unlike controls or adjuvant receiving animals, vaccine-treated rabbits showed a seroconversion in the repeat-dose toxicity study.”
Why that species
No explicit rationale; rabbits seroconverted to the vaccine in the repeat-dose study
“Serological analysis demonstrated that unlike controls or adjuvant receiving animals, vaccine-treated rabbits showed a seroconversion in the repeat-dose toxicity study.”
Surrogate molecule
No surrogate; clinical HB-AS04C vaccine and adjuvant tested in rabbit
“Serological analysis demonstrated that unlike controls or adjuvant receiving animals, vaccine-treated rabbits showed a seroconversion in the repeat-dose toxicity study.”
Species: general tox
Rabbit (vaccine, intramuscular repeat-dose)
“Observation of local tolerance in the repeat-dose toxicity study with intramuscular administration in rabbits pointed to minor reactions at the injection sites characterized by an inflammatory reaction with mixed-cell or mononuclear cell infiltrate, which disappeared one month after the last injection.”
Species: DART
Rabbit (teratogenicity) and rat (pre- and postnatal development)
“Reproductive toxicity studies including a teratogenicity study in the rabbit and a pre-and postnatal study in the rat showed no evidence of maternal toxicity, teratogenicity or any effect on the in utero development of the F1 offspring.”
Species: carcinogenicity
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.
Surrogate used in
No surrogate used
“Serological analysis demonstrated that unlike controls or adjuvant receiving animals, vaccine-treated rabbits showed a seroconversion in the repeat-dose toxicity study.”
Study lengthopen answer page →
Longest pivotal study
2 (14-day IV MPL study in Beagle dog; rabbit vaccine study duration not stated)
“Repeated-dose toxicity studies were presented, up to 7 days in rats and 14 days in Beagle dogs, where MPL was given once daily by the intravenous route, maximising the exposure.”
Pivotal GLP studies
Rabbit IM repeat-dose vaccine study; MPL alone IV daily up to 7 days (rat) and 14 days (Beagle dog)
“Repeated-dose toxicity studies were presented, up to 7 days in rats and 14 days in Beagle dogs, where MPL was given once daily by the intravenous route, maximising the exposure.”
Route in tox
Intramuscular (vaccine, rabbit); intravenous for MPL alone
“Observation of local tolerance in the repeat-dose toxicity study with intramuscular administration in rabbits pointed to minor reactions at the injection sites characterized by an inflammatory reaction with mixed-cell or mononuclear cell infiltrate, which disappeared one month after the last injection.”
Skipped studiesopen answer page →
Genotoxicity
MPL only: negative in Ames and CHO clastogenicity tests; vaccine not tested
“An in vitro mutagenicity (Ames) and clastogenicity (CHO cells) test failed to demonstrate a genotoxic potential of MPL.”
Carcinogenicity
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.
Reproductive & developmental
Rabbit teratogenicity and rat pre/postnatal studies: no maternal toxicity, teratogenicity or F1 developmental effects
“Reproductive toxicity studies including a teratogenicity study in the rabbit and a pre-and postnatal study in the rat showed no evidence of maternal toxicity, teratogenicity or any effect on the in utero development of the F1 offspring.”
Safety pharmacology
Dedicated study: no respiratory or cardiovascular effects up to 63-fold the human dose (bodyweight basis)
“A safety pharmacology study did not show any effect on respiratory or cardiovascular parameters when the HBsAg was administered intravenously or when the HB-AS04C vaccine was given intramuscularly, up to a 63-fold of the human dose expressed on a bodyweight basis.”
Genotox: Ames
MPL negative in Ames test
“An in vitro mutagenicity (Ames) and clastogenicity (CHO cells) test failed to demonstrate a genotoxic potential of MPL.”
Genotox: in vitro mammalian
MPL negative in CHO cell clastogenicity test
“An in vitro mutagenicity (Ames) and clastogenicity (CHO cells) test failed to demonstrate a genotoxic potential of MPL.”
Genotox: in vivo
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.
Carcinogenicity 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.
Carcinogenicity timing
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.
hERG / QT
No cardiovascular or respiratory effects in safety pharmacology study up to 63-fold the human dose; no hERG assay
“A safety pharmacology study did not show any effect on respiratory or cardiovascular parameters when the HBsAg was administered intravenously or when the HB-AS04C vaccine was given intramuscularly, up to a 63-fold of the human dose expressed on a bodyweight basis.”
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 Fendrix 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 vaccines 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: No NOAEL stated; minor dose-related immunostimulatory effects with MPL; minor reversible injection-site inflammation in rabbit (EMA assessment report, p. 9)
NOAEL / key findings
No NOAEL stated; minor dose-related immunostimulatory effects with MPL; minor reversible injection-site inflammation in rabbit
“The effects seen were minor and consistent with an immunostimulatory action. The minor effects seen were dose-related.”
Risksopen answer page →
Immune & cytokine safety
Anti-HBs seroconversion in rabbits; rat dams and offspring exposed to high anti-HBs titres
“Furthermore, rat dams and offspring were shown to be exposed to high titres of circulating anti-HBs antibodies during the reproductive toxicity study.”
Biodistribution & persistence
No distribution or excretion data for vaccine or AS04C; assumed to follow unadsorbed aluminium particle disposition
“Neither distribution nor excretion data are available for the final HB-AS04C vaccine or the AS04C adjuvant. However, the applicant assumes that aluminium salt particles containing adsorbed materials follow the same distribution and elimination as for unadsorbed aluminium particles.”
Modality-specific risk
Adjuvant (MPL) immunostimulation: possible autoimmune disease to be watched after approval
“attention to autoimmune disease events will have to be paid in the post-marketing phase.”
Anti-drug antibodies: animals
Seroconversion in vaccine-treated rabbits (not controls or adjuvant-only), confirming exposure; high anti-HBs in rat dams and offspring
“Serological analysis demonstrated that unlike controls or adjuvant receiving animals, vaccine-treated rabbits showed a seroconversion in the repeat-dose toxicity study.”
Anti-drug antibodies: patients
Intended response: seroprotection 90.9% at Month 7 in (pre-)haemodialysis patients vs 84.4% with double-dose comparator
“In studies HBV-MPL 032 and 042 in (pre-) haemodialysis patients, primary vaccination with Fendrix elicited a seroprotection of 90.9% at Month 7 as compared to 84.4% with a double dose of a commercially available HepB vaccine, which is standard in these patients.”
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 Fendrix 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 vaccines 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: No NOAEL stated; minor dose-related immunostimulatory effects with MPL; minor reversible injection-site inflammation in rabbit (EMA assessment report, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
14-day IV MPL study in Beagle dog; rabbit IM vaccine study duration not stated
“Repeated-dose toxicity studies were presented, up to 7 days in rats and 14 days in Beagle dogs, where MPL was given once daily by the intravenous route, maximising the exposure.”
Pivotal GLP studies
Rabbit IM repeat-dose vaccine study; MPL alone IV daily up to 7 days (rat) and 14 days (Beagle dog)
“Repeated-dose toxicity studies were presented, up to 7 days in rats and 14 days in Beagle dogs, where MPL was given once daily by the intravenous route, maximising the exposure.”
DART package
Species: DART
Rabbit (teratogenicity) and rat (pre- and postnatal development)
“Reproductive toxicity studies including a teratogenicity study in the rabbit and a pre-and postnatal study in the rat showed no evidence of maternal toxicity, teratogenicity or any effect on the in utero development of the F1 offspring.”
Reproductive & developmental
Rabbit teratogenicity and rat pre/postnatal studies: no maternal toxicity, teratogenicity or F1 developmental effects
“Reproductive toxicity studies including a teratogenicity study in the rabbit and a pre-and postnatal study in the rat showed no evidence of maternal toxicity, teratogenicity or any effect on the in utero development of the F1 offspring.”
PPND / ePPND: when
Rat pre- and postnatal study completed before the marketing application
“Reproductive toxicity studies including a teratogenicity study in the rabbit and a pre-and postnatal study in the rat showed no evidence of maternal toxicity, teratogenicity or any effect on the in utero development of the F1 offspring.”
Carcinogenicity
Species: carcinogenicity
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.
Carcinogenicity 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.
Carcinogenicity timing
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.
Safety marginopen answer page →
Safety margin at NOAEL
Safety pharmacology only: no cardiorespiratory effects up to 63-fold the human dose (bodyweight basis); no repeat-dose margin stated
“A safety pharmacology study did not show any effect on respiratory or cardiovascular parameters when the HBsAg was administered intravenously or when the HB-AS04C vaccine was given intramuscularly, up to a 63-fold of the human dose expressed on a bodyweight basis.”
NOAEL / key findings
No NOAEL stated; minor dose-related immunostimulatory effects with MPL; minor reversible injection-site inflammation in rabbit
“The effects seen were minor and consistent with an immunostimulatory action. The minor effects seen were dose-related.”
Efficacy evidenceopen answer page →
Efficacy evidence
Immunogenicity in mice: HBsAg with AS04C more immunogenic than with alum
“A better immunogenicity was obtained in mice when HBsAg was formulated with AS04C than with alum, as in a commercially available HepB vaccine.”
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
Immunostimulatory effect of AS04C and good immunogenicity in three species
“The studies indicate an immunostimulatory effect of the AS04C adjuvant and a good immunogenicity of the HB-AS04C vaccine in three animal species studied.”
Flexibilityopen answer page →
Flexibility accepted
BiodistributionAccepted with a conditionBeyond the letter
No distribution or excretion data for the final vaccine or AS04C adjuvant
Why: Applicant assumes adsorbed materials follow unadsorbed aluminium particle distribution and elimination; applicant committed to report study results · Pharmacology or kinetics
“Only limited pharmacokinetic data were generated in this study. Neither distribution nor excretion data are available for the final HB-AS04C vaccine or the AS04C adjuvant. The Applicant committed to report the results of this study.”
“Neither distribution nor excretion data are available for the final HB-AS04C vaccine or the AS04C adjuvant. However, the applicant assumes that aluminium salt particles containing adsorbed materials follow the same distribution and elimination as for unadsorbed aluminium particles.”
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