Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted
Species
MonkeyRatMouseRabbit
Longest study
8 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse, rat and cynomolgus monkey (repeat-dose); rabbit and baboon escalation studies
“The CpG 1018 adjuvant alone was evaluated in 3 genotoxicity studies, 2 safety escalation studies (rabbit and baboons) and 3 repeated toxicology studies (mice, rats, and cynomolgus monkeys).”
Why that species
Adjuvanted vaccine immunogenic in mice, rats and baboons despite rodent-primate differences in TLR9 expression
“These studies demonstrated that despite some known differences in TLR9 expression pattern between rodent and primate hematopoietic cells, the 1018 ISS adjuvanted vaccine is immunogenic in all three animal species. This provides support to the choice of mice, rat and monkeys (baboons and cynomolgus monkeys) for the safety studies.”
Surrogate molecule
No surrogate; the clinical vaccine (HBsAg + CpG 1018) and CpG 1018 alone were tested
“Repeat-dose toxicity and reproductive and developmental toxicity studies were performed with HBsAg plus CpG 1018 and single-dose, repeat-dose and genotoxicity studies were performed with the CpG 1018 adjuvant alone.”
Species: general tox
Mouse, rat and cynomolgus monkey
“The CpG 1018 adjuvant alone was evaluated in 3 genotoxicity studies, 2 safety escalation studies (rabbit and baboons) and 3 repeated toxicology studies (mice, rats, and cynomolgus monkeys).”
Species: DART
Rat (fertility, embryo-fetal and pre/postnatal development in a single combined study)
“HBsAg plus CpG 1018 was also tested in rats in a reproductive and developmental toxicity study which assessed the potential effects on mating behavior, fertility, gestation, embryo-fetal development, parturition, lactation and maternal behavior”
Species: carcinogenicity
Not conducted
“No studies assessing the carcinogenicity of Heplisav B or 1018 ISS adjuvant have been performed. This is acceptable for this type of product in line with EMAs guidelines for vaccines and adjuvants and compliant with ICH S1A, considering that the exposure to this vaccine will be sporadic.”
Surrogate used in
No surrogate used; vaccine and CpG adjuvant alone tested directly
“Repeat-dose toxicity and reproductive and developmental toxicity studies were performed with HBsAg plus CpG 1018 and single-dose, repeat-dose and genotoxicity studies were performed with the CpG 1018 adjuvant alone.”
Study lengthopen answer page →
Longest pivotal study
8 (rat and cynomolgus monkey, weekly SC CpG 1018 alone)
“rats or cynomolgus monkey received subcutaneously (SC) either 0.5, 1.5, 12.5 mg/kg/week of 1018 ISS adjuvant or PBS weekly for 8 weeks.”
Pivotal GLP studies
Adjuvanted vaccine IM repeat-dose studies in mice (3 doses, days 0, 14, 28) and rats (4 doses, days 0-42)
“The general safety of the 1018 ISS adjuvanted HBsAg vaccine was investigated in two pivotal studies were the vaccine was administrated by the IM injection, the clinical route of administration: a repeated-dose toxicity study in mice (study 00-95) where 3 IM doses were given (at day 0, 14 and 28) and a repeated dose toxicity study in rats (study 12-728) where 4 IM doses were given (at day 0, 14, 28 and 42).”
Route in tox
IM for the adjuvanted vaccine (every second week); SC once weekly for CpG 1018 alone
“Of importance, no kidney or heart findings were observed in monkeys or in the rat study of 1018 ISS adjuvanted HBsAg administered with a dosing regimen (4 IM every second week) more similar to the clinical dosing regimen of 2 IM doses 1 month apart than in the rat study of 1018 ISS alone (8 SC doses every week).”
Skipped studiesopen answer page →
Genotoxicity
CpG adjuvant negative in Ames, in vitro chromosome aberration and in vivo mouse micronucleus tests
“No genotoxicity was observed in the standard battery of tests composed of in vitro bacterial mutation, chromosome aberration and in vivo mouse erythrocyte micronucleus test.”
Carcinogenicity
Not conducted (vaccine and adjuvant guidelines, ICH S1A; sporadic exposure)
“No studies assessing the carcinogenicity of Heplisav B or 1018 ISS adjuvant have been performed. This is acceptable for this type of product in line with EMAs guidelines for vaccines and adjuvants and compliant with ICH S1A, considering that the exposure to this vaccine will be sporadic.”
Reproductive & developmental
Rat multigeneration DART study: stillbirths and skeletal anomalies only secondary to maternal toxicity at 200-fold the clinical CpG 1018 dose
“In a multigeneration reprotoxicological study in rats, effects on the offspring (stillborn pups and skeletal abnormalities) occurred secondary to maternal toxicity at a dose 200-fold the proposed clinical dose of Heplisav B with respect to 1018 ISS on a body weight basis.”
Safety pharmacology
Dedicated rabbit and baboon escalation studies: no adverse effects up to 1.6 mg/kg (rabbit) and 25 mg (baboon) CpG 1018
“No adverse effects were identified in 2 safety-pharmacology studies with doses of 1018 ISS up to 1.6 mg/kg in rabbits and 25 mg in baboons.”
Genotox: Ames
Bacterial mutation test negative up to 5 mg/plate
“In conclusion, the test article 1018 ISS did not show any evidence or genotoxicity in this in vitro test for mutagenicity when tested up to the maximum concentration of 5 mg/plate.”
Genotox: in vitro mammalian
In vitro chromosome aberration test: negative
“In conclusion, the test article 1018 ISS did not show any evidence or genotoxicity in this in vitro test for induction of chromosome damage when tested up to the maximum concentration 5 mg/plate.”
Genotox: in vivo
Mouse micronucleus assay: negative
“Therefore, 1018 ISS did not show any evidence of genotoxic activity and was found negative in the mouse micronucleus assay.”
Carcinogenicity model
Not conducted (ICH S1A; sporadic vaccine exposure)
“No studies assessing the carcinogenicity of Heplisav B or 1018 ISS adjuvant have been performed. This is acceptable for this type of product in line with EMAs guidelines for vaccines and adjuvants and compliant with ICH S1A, considering that the exposure to this vaccine will be sporadic.”
Carcinogenicity timing
Not required for this type of product
“No studies assessing the carcinogenicity of Heplisav B or 1018 ISS adjuvant have been performed. This is acceptable for this type of product in line with EMAs guidelines for vaccines and adjuvants and compliant with ICH S1A, considering that the exposure to this vaccine will be sporadic.”
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 Heplisav-B 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: Monkey NOAEL 0.5 mg/kg CpG 1018 (>10-fold clinical) for systemic immunostimulation; spleen and lymph node hyperplasia, liver inflammation at higher doses (EMA assessment report, p. 28)
NOAEL / key findings
Monkey NOAEL 0.5 mg/kg CpG 1018 (>10-fold clinical) for systemic immunostimulation; spleen and lymph node hyperplasia, liver inflammation at higher doses
“It should be noted that other systemic manifestations of TLR9 immunostimulation were seen in monkeys (i.e. spleen hyperplasia from 2.5 mg/kg/w and lymph node hyperplasia and liver inflammation at 12.5 mg/kg/w). Of importance, a NOAEL of 0.5 mg/kg 1018 ISS (>10-fold the clinical dose on mg/kg basis) for systemic immunostimulatory effects was identified in this study.”
Risksopen answer page →
Immune & cytokine safety
Serum IL-12p40 rose only 2-fold at ~20x the human CpG 1018 dose; no IL-12p40 or IFN-gamma increase at the 1x human dose
“The 300 mcg 1018 ISS + HBsAg dose (approximately 20 times the human dose) induced only a 2-fold increase in IL-12p40 levels over baseline, and the 15 mcg 1018 ISS + HBsAg dose (a 1 X human dose) did not induce an increase in either IL-12p40 or IFN-g levels after the first or last injection.”
Biodistribution & persistence
Rapid plasma decline; PS-ODN binds plasma proteins (95%) and distributes to kidney (up to 20% of dose), liver and spleen
“According to published data the rapid decline is due to initial low affinity binding to plasma proteins (95%) and to significant distribution to kidney (up to 20 % of the dose), liver, and to a minor extent spleen.”
Modality-specific risk
Oligonucleotide class effect: CpG 1018 kidney accumulation in rats with non-reversible tubular degeneration and interstitial inflammation
“Most of the observed changes were reversible, except for accumulation of the CpG 1018 in the kidneys in male rats of all groups as well as female rats receiving 2.5 and 12.5 mg/kg/week which led to minimal to moderate tubular degeneration and minimal to moderate chronic interstitial inflammation in a dose dependent manner.”
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
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
Monkey NOAEL 0.5 mg/kg CpG adjuvant, >10-fold the clinical mg/kg dose, for systemic immunostimulation
“It should be noted that other systemic manifestations of TLR9 immunostimulation were seen in monkeys (i.e. spleen hyperplasia from 2.5 mg/kg/w and lymph node hyperplasia and liver inflammation at 12.5 mg/kg/w). Of importance, a NOAEL of 0.5 mg/kg 1018 ISS (>10-fold the clinical dose on mg/kg basis) for systemic immunostimulatory effects was identified in this study.”
NOAEL / key findings
Monkey NOAEL 0.5 mg/kg CpG 1018 (>10-fold clinical) for systemic immunostimulation; spleen and lymph node hyperplasia, liver inflammation at higher doses
“It should be noted that other systemic manifestations of TLR9 immunostimulation were seen in monkeys (i.e. spleen hyperplasia from 2.5 mg/kg/w and lymph node hyperplasia and liver inflammation at 12.5 mg/kg/w). Of importance, a NOAEL of 0.5 mg/kg 1018 ISS (>10-fold the clinical dose on mg/kg basis) for systemic immunostimulatory effects was identified in this study.”
Efficacy evidenceopen answer page →
Efficacy evidence
Anti-HBsAg immunogenicity of the adjuvanted vaccine in mice, rats and baboons
“The immunogenicity of HBsAg adjuvanted with 1018 ISS has been evaluated in mice, rat and baboons.”
Why that model
Animal anti-HBV responses read against the human seroprotection threshold (>=10 mIU/ml); response depended on CpG adjuvant dose
“The immunogenicity studies also demonstrated that the anti-HBV antibody response and more importantly the frequency of animals responding with antibody levels ≥10 mIU/ml (the defined threshold for seroprotection in humans) is depending on the 1018 ISS dose.”
Reviewer's view of the efficacy data
CpG adjuvant judged potent: far higher anti-HBV responses than HBsAg alone or alum-adjuvanted comparator
“The anti-HBV antibody response after two administrations of the vaccine candidate was much higher in magnitude in comparison to injections with an equal dose of HBsAg alone or a licensed comparator (HBsAg antigen plus aluminium). This indicates that the 1018 ISS is a potent adjuvant.”
Similar precedents
Cyfendusanthrax vaccine adsorbed, adjuvanted · TLR9 (CpG 7909 adjuvant)Rodent only · 4 wkAmondys 45casimersen · DMD exon 45 (PMO)Monkey + rodent · 39 wkAmvuttravutrisiran · TTR (siRNA)Monkey + rodent · 40 wkDawnzeradonidalorsen · Prekallikrein / KLKB1 (ASO)Monkey + rodent · 39 wkExondys 51eteplirsen · DMD exon 51 (PMO)Monkey + rodent · 39 wkGivlaarigivosiran · ALAS1 (siRNA)Monkey + rodent · 39 wk