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”
Species: general tox
Rat (up to 5 weeks) and cynomolgus monkey (up to 27 weeks)
“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”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development); no dedicated fertility studies
“In an enhanced pre- and postnatal development study in cynomolgus monkeys, weekly intravenous infusion of garetosmab at 5 or 50 mg/kg from gestation Day 20 until delivery resulted in no maternal toxicity.”
Species: carcinogenicity
Not conducted; weight-of-evidence carcinogenicity assessment
“Carcinogenicity studies have not been conducted with garetosmab-grts.”
Surrogate used in
No surrogate used; garetosmab itself 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”
Genotox: Ames
Not conducted; monoclonal antibodies not expected to alter DNA
“The mutagenic potential of garetosmab-grts has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.”
Genotox: in vitro mammalian
Not conducted; monoclonal antibodies not expected to alter DNA
“The mutagenic potential of garetosmab-grts has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.”
Genotox: in vivo
Not conducted; monoclonal antibodies not expected to alter DNA
“The mutagenic potential of garetosmab-grts has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.”
Carcinogenicity model
Not conducted; weight-of-evidence carcinogenicity assessment instead
“a weight of evidence carcinogenicity assessment, and tissue cross-reactivity studies.”
Carcinogenicity timing
Not conducted
“Carcinogenicity studies have not been conducted with garetosmab-grts.”
hERG / QT
Not conducted; antibody with low likelihood of ion channel interaction, thorough QT study not warranted
“Garetosmab is a monoclonal antibody, and antibodies have a low likelihood of direct ion channel interaction. A thorough QT/QTc study is not warranted.”
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
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: 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.”
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
1.3% (1/76) of FOP patients developed anti-garetosmab antibodies over up to 76 weeks
“Among patients with FOP who received PASATRU 10 mg/kg or 3 mg/kg every 4 weeks in clinical trials for up to 76 weeks, 1.3% (1/76) developed anti-garetosmab-grts antibodies.”
Label warnings
- Embryo-Fetal Toxicity
- Skin and Soft Tissue Infections
- Epistaxis
Embryo-fetal toxicityInfectionsSkin reactions
US prescribing information, 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 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
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: Cynomolgus monkey NOAEL 50 mg/kg for both sexes (highest dose; about five-times clinical AUC) (FDA integrated review, p. 59)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey IV study (weekly, up to 50 mg/kg) with treatment-free recovery period
“in a 26-week study in which garetosmab was administered intravenously once weekly at doses up to 50 mg/kg (14 times or 49 times the recommended human doses of garetosmab 3 mg/kg or 10 mg/kg every 4 weeks, respectively, based on AUC). Minimal to moderate seminiferous tubule degeneration was observed in male monkeys, which was reversible after a treatment-free recovery period.”
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”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development); no dedicated fertility studies
“In an enhanced pre- and postnatal development study in cynomolgus monkeys, weekly intravenous infusion of garetosmab at 5 or 50 mg/kg from gestation Day 20 until delivery resulted in no maternal toxicity.”
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.”
PPND / ePPND: when
ePPND in cynomolgus monkey (IV 5 or 50 mg/kg weekly) completed before the marketing application
“In an enhanced pre- and postnatal development study in cynomolgus monkeys, weekly intravenous infusion of garetosmab at 5 or 50 mg/kg from gestation Day 20 until delivery resulted in no maternal toxicity.”
Carcinogenicity
Species: carcinogenicity
Not conducted; weight-of-evidence carcinogenicity assessment
“Carcinogenicity studies have not been conducted with garetosmab-grts.”
Carcinogenicity model
Not conducted; weight-of-evidence carcinogenicity assessment instead
“a weight of evidence carcinogenicity assessment, and tissue cross-reactivity studies.”
Carcinogenicity timing
Not conducted
“Carcinogenicity studies have not been conducted with garetosmab-grts.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 26-week NOAEL 50 mg/kg ~5x maximum clinical AUC
“A no observed adverse effect level was established at 50 mg/kg (the highest dose tested, approximately fivetimes the maximum clinical exposure by AUC) for both sexes.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Garetosmab reduced heterotopic ossification in two conditional knock-in FOP mouse models
“reduced HO formation in two conditional knock-in mouse models of FOP, along with efficacy data from the phase 2 Trial R2477-FOP-1623 (Trial 1623, LUMINA-1).”
Why that model
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.
Reviewer's view of the efficacy data
FDA: knock-in FOP mouse models count as confirmatory evidence supporting substantial evidence of effectiveness
“The persuasive phase 3 results with confirmatory evidence from garetosmab’s mechanism of action, two knock-in mouse models of FOP and the phase 2 trial, based on the considerations above, constitute sufficient evidence to establish substantial evidence of effectiveness,”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAccepted with a conditionBeyond the letter
No NOAEL in the repeat-dose rat study; adverse male reproductive tract toxicity at exposures below clinical exposure
Why: Testicular toxicity consistent with on-target blockade of activin A signalling; potential human risk communicated through labeling · Pharmacology or kinetics
“A no observed adverse effect level was not established in the study due to the adverse testicular effects, with rat testicular findings occurring at exposure below clinical exposures at the recommended clinical doses (by area under the concentration-time curve [AUC] comparison).”
“Due to the established role of activin A in testicular development, we concluded that testicular toxicity seen in healthy rats and monkeys was consistent with a mechanistic effect of blocking activin A-mediated signal transduction and identified a potential human risk that will be communicated through labeling.”
DARTAccepted with a condition
No dedicated male or female fertility studies; reproductive organs assessed in the 26-week monkey study
Why: Fertility studies generally not practical in monkeys · Within the guideline
“No dedicated standalone male or female fertility studies were conducted and are generally not practical in monkeys; however, garetosmab may potentially reduce fertility.”
“The PI should describe the effects on the male reproductive organs and sperm observed in nonclinical studies and should include a statement that garetosmab may impair male fertility.”
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