Andembry
garadacimab
Species
MonkeyMouse
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and cynomolgus monkey
“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes.”
Why that species
Garadacimab cross-reacts with mouse, rabbit and cynomolgus βFXIIa
“Garadacimab affinity is cross reactive with mouse, rabbit and cynomolgus βFXIIa (700pM, 400pM and 19nM respectively).”
Surrogate molecule
No surrogate; the clinical antibody was tested in mice, cynomolgus monkeys and rabbits
“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes.”
Species: general tox
Mouse (4-week) and cynomolgus monkey (26-week), IV and SC
“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes.”
Species: DART
Rabbit (male and female fertility, EFD, pre/postnatal development)
“The potential reproductive toxicity of garadacimab was evaluated in fertility and early embryonic development studies with male and female rabbits, an embryofetal development study with female rabbits, and a pre- and postnatal development study with female rabbits.”
Species: carcinogenicity
Not conducted; rodent carcinogenicity study not technically feasible
“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible.”
Surrogate used in
No surrogate used; garadacimab cross-reacts with mouse, rabbit and cynomolgus FXIIa
“Garadacimab affinity is cross reactive with mouse, rabbit and cynomolgus βFXIIa (700pM, 400pM and 19nM respectively).”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes.”
Pivotal GLP studies
GLP 4-week CD-1 mouse and 26-week cynomolgus monkey studies, IV and SC; immunogenicity precluded longer mouse studies
“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes. Immunogenicity in mice precluded conducting longer toxicology studies in this species.”
Route in tox
Intravenous and subcutaneous
“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies with biologics such as garadacimab are not required.”
Carcinogenicity
Not conducted; weight of evidence (26-week monkey study, literature) indicates low or negligible carcinogenic potential; rodent study not feasible
“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible. Further, there appears to be a low or negligible carcinogenic potential based on the results of the 26-week monkey study and review of the published literature regarding chronic inhibition of FXIIa.”
Reproductive & developmental
Rabbit PPND study: no effects on F1 survival, development, neurobehavior or reproductive performance
“For the F1 generation, no garadacimab-related effects were observed on mortality, clinical signs, body weight, developmental signs, functional observation battery, eye-blink response, presence of motile sperm, reproductive performance, cesarean section parameters, or preweaning or postweaning macroscopic observations.”
Safety pharmacology
Incorporated into 26-week monkey study: no effects on ECG, blood pressure, respiration or pulse up to 100 mg/kg IV, 200 mg/kg SC
“Safety pharmacology parameters were incorporated into the pivotal repeat-dose 26-week monkey toxicology study. With intravenous (IV) doses up to 100 mg/kg/week and subcutaneous (SC) doses up to 200 mg/kg/week, no treatment-related effects on electrocardiogram, blood pressure, respiration rate, or pulse rate were observed during the 26-week Treatment Period.”
Genotox: Ames
Not conducted (ICH S6)
“As per International Council for Harmonisation (ICH) guideline, S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (June 2011), standard in vitro and in vivo genotoxicity studies are not applicable to biologics because these molecules are unlikely to interact directly with DNA or chromosomal material.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“As per International Council for Harmonisation (ICH) guideline, S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (June 2011), standard in vitro and in vivo genotoxicity studies are not applicable to biologics because these molecules are unlikely to interact directly with DNA or chromosomal material.”
Genotox: in vivo
Not conducted (ICH S6)
“As per International Council for Harmonisation (ICH) guideline, S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (June 2011), standard in vitro and in vivo genotoxicity studies are not applicable to biologics because these molecules are unlikely to interact directly with DNA or chromosomal material.”
Carcinogenicity model
Not conducted; rodent study not technically feasible; weight-of-evidence assessment instead
“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible.”
Carcinogenicity timing
Not required; Division agreed a rodent carcinogenicity study was not technically feasible
“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible.”
hERG / QT
No ECG, blood pressure, respiration or pulse effects in 26-week monkey study up to 100 mg/kg/week IV and 200 mg/kg/week SC
“With intravenous (IV) doses up to 100 mg/kg/week and subcutaneous (SC) doses up to 200 mg/kg/week, no treatment-related effects on electrocardiogram, blood pressure, respiration rate, or pulse rate were observed during the 26-week Treatment Period.”
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 Andembry 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: 26-week monkey NOAEL 30 mg/kg/week IV and 60 mg/kg/week SC, based on deaths at 100 mg/kg IV and 200 mg/kg SC (FDA integrated review, p. 118)
NOAEL / key findings
26-week monkey NOAEL 30 mg/kg/week IV and 60 mg/kg/week SC, based on deaths at 100 mg/kg IV and 200 mg/kg SC
“NOAELs were identified as the mid doses (MDs) of 30 mg/kg/week (IV) and 60 mg/kg/week (SC) based upon deaths observed at 100 mg/kg/week (IV) and 200 mg/kg/week (SC).”
Risksopen answer page →
Immune & cytokine safety
Mouse deaths and premature euthanasia, mainly at low IV dose, attributed to immunogenicity to the human protein
“The deaths and/or premature euthanasia of the remaining animals, primarily in the LD IV group, were attributed to immunogenicity based upon observed adverse clinical signs, although there were no histopathological findings.”
Biodistribution & persistence
Monkey SC bioavailability ~66%; half-life 147-581 h (IV) and 206-424 h (SC)
“The SC bioavailability of garadacimab (6 mg/kg) was ~66% in monkeys. Mean estimated t1/2 values for garadacimab in the single-dose PK study with monkeys ranged from 147 to 581 h (IV) and 206 to 424 h (SC).”
Modality-specific risk
FXIIa inhibition prolongs aPTT; no associated bleeding events in animals
“Prolongation of aPTT was observed in all four studies with F0 male and female rabbits, but not associated with any bleeding events.”
Anti-drug antibodies: animals
Monkey: ADA in some animals; exposure maintained (possibly reduced) at high doses; no impact on toxicity assessment
“Anti-drug antibody (ADA) development in some of the test item-treated animals was considered not to have any impact on the overall toxicity assessment of CSL312 in this study, since -due to the high doses used- continued (although possibly reduced) exposure was seen in all of the animals.”
Anti-drug antibodies: patients
2.6% (1/39) ADA-positive over 6 months; no effect on PK, safety or clinical response
“In VANGUARD, 2.6% (1/39) of patients who received garadacimab-gxii tested positive for anti- garadacimab-antibodies during the 6-month treatment period. The development of ADA against garadacimab-gxii did not affect pharmacokinetics (PK), safety, or clinical response.”
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 Andembry 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: 26-week monkey NOAEL 30 mg/kg/week IV and 60 mg/kg/week SC, based on deaths at 100 mg/kg IV and 200 mg/kg SC (FDA integrated review, p. 118)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week study (TH43GT, with 13-week interim) followed by 8-week recovery
“Following 26-week administration (with a 13-week interim and 8-week recovery period) with garadacimab (TH43GT), prolongation of aPTT irrespective of the route of administration was seen.”
Pivotal GLP studies
GLP 4-week CD-1 mouse and 26-week cynomolgus monkey studies, IV and SC; immunogenicity precluded longer mouse studies
“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes. Immunogenicity in mice precluded conducting longer toxicology studies in this species.”
DART package
Species: DART
Rabbit (male and female fertility, EFD, pre/postnatal development)
“The potential reproductive toxicity of garadacimab was evaluated in fertility and early embryonic development studies with male and female rabbits, an embryofetal development study with female rabbits, and a pre- and postnatal development study with female rabbits.”
Reproductive & developmental
Rabbit PPND study: no effects on F1 survival, development, neurobehavior or reproductive performance
“For the F1 generation, no garadacimab-related effects were observed on mortality, clinical signs, body weight, developmental signs, functional observation battery, eye-blink response, presence of motile sperm, reproductive performance, cesarean section parameters, or preweaning or postweaning macroscopic observations.”
PPND / ePPND: when
PPND in rabbit: completed before the marketing application (with rabbit fertility and EFD studies)
“The potential reproductive toxicity of garadacimab was evaluated in fertility and early embryonic development studies with male and female rabbits, an embryofetal development study with female rabbits, and a pre- and postnatal development study with female rabbits.”
Carcinogenicity
Species: carcinogenicity
Not conducted; rodent carcinogenicity study not technically feasible
“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible.”
Carcinogenicity model
Not conducted; rodent study not technically feasible; weight-of-evidence assessment instead
“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible.”
Carcinogenicity timing
Not required; Division agreed a rodent carcinogenicity study was not technically feasible
“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey SC NOAEL AUC ~37x clinical AUC at 200 mg once monthly
“The AUC0- 30days at the monkey SC NOAEL is approximately 37-fold higher than the clinical AUC at the recommended human dose of 200 mg once monthly.”
NOAEL / key findings
26-week monkey NOAEL 30 mg/kg/week IV and 60 mg/kg/week SC, based on deaths at 100 mg/kg IV and 200 mg/kg SC
“NOAELs were identified as the mid doses (MDs) of 30 mg/kg/week (IV) and 60 mg/kg/week (SC) based upon deaths observed at 100 mg/kg/week (IV) and 200 mg/kg/week (SC).”
Efficacy evidenceopen answer page →
Efficacy evidence
Captopril-induced edema in heterozygous C1-INH-deficient mice: garadacimab inhibited vascular permeability increase
“In an angiotensin converting enzyme inhibitor (captopril)-induced edema murine model (heterozygous C1-INH-deficient (C1INH+/-) mice treated with 2.5 mg/kg captopril), garadacimab significantly inhibited the angiotensin-converting enzyme inhibitor-induced increase of vascular permeability.”
Why that model
Garadacimab cross-reacts with mouse FXIIa, allowing in vivo efficacy testing in mouse oedema models
“Since garadacimab and the parental antibody 3F7 demonstrated cross-reactivity in mice, an in vivo efficacy was investigated in murine PSA and PCA models.”
Reviewer's view of the efficacy data
EMA: oedema reduction in both mouse models provides proof of concept for HAE treatment via reduced KKS activity
“Considering that garadacimab and the parental antibody 3F7 effectively reduced oedema in both models, it could be concluded that FXII targeting results in decreased activity of KKS; thus providing a proof of concept for HAE treatment.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity study for a chronic prophylaxis indication; rodent study judged not technically feasible, weight-of-evidence assessment instead
Why: Rodent study not technically feasible; 26-week monkey study and literature on chronic FXIIa inhibition indicate low or negligible potential · Weight of evidence
“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible. Further, there appears to be a low or negligible carcinogenic potential based on the results of the 26-week monkey study and review of the published literature regarding chronic inhibition of FXIIa.”
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