Raxibacumab
raxibacumab
Species
MonkeyRabbit
Longest study
3 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Healthy rabbit and cynomolgus monkey
“Drug safety assessed in human volunteers and in a battery of nonclinical studies in healthy rabbits and non-human primates showed no evidence of toxicity at the maximum proposed, single therapeutic dose of intravenous raxibacumab to be administered to human adults of 40 mg/kg.”
Why that species
Target is a bacterial toxin; rabbit and cynomolgus macaque are the inhalation anthrax efficacy models
“several drug efficacy studies of raxibacumab with and without antibiotic in inhalation anthrax animal models (NZW rabbit and cynomolgus macaque)”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys and rabbits
“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days”
Species: general tox
Healthy rabbit and non-human primate
“Drug safety assessed in human volunteers and in a battery of nonclinical studies in healthy rabbits and non-human primates showed no evidence of toxicity at the maximum proposed, single therapeutic dose of intravenous raxibacumab to be administered to human adults of 40 mg/kg.”
Species: DART
New Zealand White rabbit (embryo-fetal development only)
“A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered two intravenous doses of raxibacumab up to 120 mg/kg (three times the human dose on a mg/kg basis) on gestation days 7 and 14.”
Species: carcinogenicity
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Surrogate used in
No surrogate used; raxibacumab itself tested in healthy cynomolgus macaques
“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects, including no effects up to 120 days post-dosing.”
Study lengthopen answer page →
Longest pivotal study
3 weeks
“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days”
Pivotal GLP studies
Healthy cynomolgus monkey: 3 IV or SC doses of 40 mg/kg every 12 days, or single IM dose; 120-day follow-up
“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects, including no effects up to 120 days post-dosing.”
Route in tox
IV, SC and IM (monkey); IV (rabbit)
“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Carcinogenicity
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Reproductive & developmental
No fertility studies; rabbit EFD (IV up to 120 mg/kg, GD 7 and 14): no harm to dams or fetuses
“A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered two intravenous doses of raxibacumab up to 120 mg/kg (three times the human dose on a mg/kg basis) on gestation days 7 and 14. No evidence of harm to the pregnant dam or the fetuses due to raxibacumab was observed.”
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
Not conducted (ICH S6)
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Genotox: in vivo
Not conducted (ICH S6)
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Carcinogenicity model
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Carcinogenicity timing
Not required: no additional nonclinical studies recommended
“No additional nonclinical studies are recommended.”
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 Raxibacumab 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: Greater CNS lesion severity (bacteria, inflammation, hemorrhage) in anthrax-infected non-survivors given 40 mg/kg (FDA pharmacology/toxicology review, p. 7)
NOAEL / key findings
Greater CNS lesion severity (bacteria, inflammation, hemorrhage) in anthrax-infected non-survivors given 40 mg/kg
“Anthrax infected rabbits and monkeys administered an intravenous injection of raxibacumab (40 mg/kg) at time of PA toxemia reproducibly showed greater severity of CNS lesions (bacteria, inflammation, hemorrhage, and necrosis) in non-surviving animals compared to dead placebo control animals”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
No brain tissue cross-reactivity (rabbit, monkey, human); enters CNS only after blood-brain barrier compromise
“Studies with raxibacumab in rabbit, cynomolgus macaque, and human donor tissues showed no cross reactivity with brain.”
Modality-specific risk
Exaggerated CNS inflammation and hemorrhage in infected non-survivors after blood-brain barrier compromise
“The raxibacumab monoclonal antibody appears unable to penetrate the CNS until compromise of the blood brain barrier (BBB) during the later stages of anthrax infection.”
Anti-drug antibodies: animals
ADA in most treated rabbits; increased raxibacumab clearance in survivors after 7 days, without impact on efficacy
“Anti-drug antibodies to raxibacumab were detected in a majority of animals after raxibacumab treatment in both studies; pre-existing antibodies to raxibacumab were detected in only a few animals. Increased clearance of raxibacumab detected in survivors > 7 days post challenge likely resulted from binding to anti-drug antibodies.”
Anti-drug antibodies: patients
No anti-raxibacumab antibodies detected in any treated subjects
“Immunogenic responses against raxibacumab were not detected in any raxibacumab-treated human subjects following single or repeat doses of raxibacumab.”
Label warnings
Boxed warning: HYPERSENSITIVITY and ANAPHYLAXIS
- Hypersensitivity and Anaphylaxis
Hypersensitivity & infusion reactions
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 Raxibacumab 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: Greater CNS lesion severity (bacteria, inflammation, hemorrhage) in anthrax-infected non-survivors given 40 mg/kg (FDA pharmacology/toxicology review, p. 7)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Healthy cynomolgus monkey: 3 IV or SC doses every 12 days, followed up to 120 days post-dosing
“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects, including no effects up to 120 days post-dosing.”
Pivotal GLP studies
Healthy cynomolgus monkey: 3 IV or SC doses of 40 mg/kg every 12 days, or single IM dose; 120-day follow-up
“Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects, including no effects up to 120 days post-dosing.”
DART package
Species: DART
New Zealand White rabbit (embryo-fetal development only)
“A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered two intravenous doses of raxibacumab up to 120 mg/kg (three times the human dose on a mg/kg basis) on gestation days 7 and 14.”
Reproductive & developmental
No fertility studies; rabbit EFD (IV up to 120 mg/kg, GD 7 and 14): no harm to dams or fetuses
“A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered two intravenous doses of raxibacumab up to 120 mg/kg (three times the human dose on a mg/kg basis) on gestation days 7 and 14. No evidence of harm to the pregnant dam or the fetuses due to raxibacumab was observed.”
PPND / ePPND: when
Not conducted: DART limited to a single rabbit embryo-fetal development study
“A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered two intravenous doses of raxibacumab up to 120 mg/kg (three times the human dose on a mg/kg basis) on gestation days 7 and 14.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Carcinogenicity model
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”
Carcinogenicity timing
Not required: no additional nonclinical studies recommended
“No additional nonclinical studies are recommended.”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit EFD at 120 mg/kg (no harm): Cmax more than 3 and 4 times mean human Cmax
“Cmax values in rabbits after dosing with 120 mg/kg were 3629 mcg/mL and 4337 mcg/mL after the first and second dose of raxibacumab respectively; these are more than 3 and 4 times the mean Cmax values in humans.”
NOAEL / key findings
Greater CNS lesion severity (bacteria, inflammation, hemorrhage) in anthrax-infected non-survivors given 40 mg/kg
“Anthrax infected rabbits and monkeys administered an intravenous injection of raxibacumab (40 mg/kg) at time of PA toxemia reproducibly showed greater severity of CNS lesions (bacteria, inflammation, hemorrhage, and necrosis) in non-surviving animals compared to dead placebo control animals”
Efficacy evidenceopen answer page →
Efficacy evidence
Inhalational anthrax spore challenge in rabbits and non-human primates, alone and with antibiotics
“HGS submitted the BLA for Raxibacumab to the FDA on May 14, 2009, containing efficacy studies of raxibacumab alone and in combination with antibiotic treatment against inhalational anthrax in both rabbits and non-human primates.”
Why that model
Licensed under the Animal Rule: efficacy established in animal models of inhalational anthrax
“Raxibacumab is the first monoclonal antibody antitoxin against anthrax to seek licensure under Animal Rule (21 CFR 601, Subpart H, 2002).”
Reviewer's view of the efficacy data
FDA: positive rabbit and NHP placebo-controlled trials plus safety data justify use in inhalation anthrax
“When combined with safety data in healthy animals and human volunteers, as well as with positive results from previously conducted placebo trials with raxibacumab in rabbits and non-human primates, the complementary mechanism of action to the antibiotic appears to justify its use in patients diagnosed with inhalation anthrax disease.”
Flexibilityopen answer page →
Flexibility accepted
Efficacy modelAccepted
Efficacy established in rabbit and monkey inhalational anthrax models under the Animal Rule instead of human efficacy trials
Why: Positive placebo-controlled rabbit and non-human primate trials plus safety in healthy animals and volunteers · Within the guideline · Serious disease
“Raxibacumab is the first monoclonal antibody antitoxin against anthrax to seek licensure under Animal Rule (21 CFR 601, Subpart H, 2002).”
“When combined with safety data in healthy animals and human volunteers, as well as with positive results from previously conducted placebo trials with raxibacumab in rabbits and non-human primates, the complementary mechanism of action to the antibiotic appears to justify its use in patients diagnosed with inhalation anthrax disease.”
DARTVerdict not stated
Reproductive toxicity limited to a single rabbit embryo-fetal development study with two IV doses
“A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered two intravenous doses of raxibacumab up to 120 mg/kg (three times the human dose on a mg/kg basis) on gestation days 7 and 14.”
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