Pasatru
garetosmab
Species
MonkeyRat
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“repeat dose toxicology studies in rats up to 5 weeks and cynomolgus monkeys up to 27 weeks, reproductive and developmental toxicity studies in cynomolgus monkeys”
Why that species
Not stated in public reviews
The reviews list the species but not why. For biologics, ICH S6(R1) asks for species in which the product is pharmacologically active (target binding and activity), usually a cynomolgus monkey.
“A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).”
✓ VerifiedICH 2011: ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived…, p. 7Source ↗
Surrogate molecule
No surrogate; the clinical antibody was tested in rats and cynomolgus monkeys
“repeat dose toxicology studies in rats up to 5 weeks and cynomolgus monkeys up to 27 weeks, reproductive and developmental toxicity studies in cynomolgus monkeys”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In a chronic (26-week) monkey study, garetosmab caused reversible, non-adverse minimal to moderate seminiferous tubule degeneration that did not impact sperm function.”
Pivotal GLP studies
Cynomolgus monkey 26-week IV study, once weekly, up to 50 mg/kg, with reproductive organ and fertility endpoints
“Reproductive organs and fertility-related parameters were assessed in sexually mature cynomolgus monkeys in a 26-week study in which garetosmab was administered intravenously once weekly at doses up to 50 mg/kg”
Route in tox
Intravenous
“In 5-week toxicology studies in male rats, intravenous administration of garetosmab resulted in adverse effects including inflammation, granulomas, and epithelial degeneration in the male reproductive tract (testes, epididymis, and efferent ducts)”
Skipped studiesopen answer page →
Genotoxicity
Not evaluated; monoclonal antibodies not expected to alter DNA or chromosomes
“The mutagenic potential of garetosmab-grts has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.”
Carcinogenicity
Not conducted; weight-of-evidence carcinogenicity assessment
“a weight of evidence carcinogenicity assessment, and tissue cross-reactivity studies.”
Reproductive & developmental
Monkey ePPND: severe developmental toxicity at 50 mg/kg with 100% offspring mortality by postnatal day 6
“Severe developmental toxicity occurred at 50 mg/kg (approximately nine-times the maximum clinical exposure based on AUC), with 100% mortality of all spontaneously delivered offspring by postnatal Day 6.”
Safety pharmacology
Safety pharmacology studies conducted as part of the nonclinical program; results not detailed
“The safety evaluation of garetosmab (REGN2477) was conducted consistent with the nonclinical requirement for novel biologics and included a series of primary, secondary, and safety pharmacology studies”
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 Pasatru 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: Cynomolgus monkey NOAEL 50 mg/kg for both sexes (highest dose; about five-times clinical AUC) (FDA integrated review, p. 59)
NOAEL / key findings
Cynomolgus monkey NOAEL 50 mg/kg for both sexes (highest dose; about five-times clinical AUC)
“A no observed adverse effect level was established at 50 mg/kg (the highest dose tested, approximately five-times the maximum clinical exposure by AUC) for both sexes.”
Risksopen answer page →
Immune & cytokine safety
Systemic hypersensitivity reactions and immunogenicity considered potential risks of treatment
“As a monoclonal antibody, systemic hypersensitivity reactions and immunogenicity were considered additional potential risks of garetosmab treatment.”
Biodistribution & persistence
Placental transfer during organogenesis inferred from embryo-fetal developmental toxicity
“These findings suggest that garetosmab is an embryo-fetal/developmental toxicant due to placental transfer during organogenesis, which is consistent with neutralizing activin A.”
Modality-specific risk
Activin A blockade: male reproductive organ toxicity in rats and adverse embryo-fetal development in monkeys
“The nonclinical program identified two significant safety concerns: male reproductive organ toxicity in rats and adverse embryofetal development (EFD) toxicity in monkeys.”
Similar precedents
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