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.”
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.”
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 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: 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.”