Margenza
margetuximab
Species
Monkey
Longest study
13 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
Cynomolgus monkey only
“The Applicant conducted GLP-compliant 6-week (doses up to 150 mg/kg/dose) and 13-week (doses up to 100 mg/kg/dose) repeat-dose toxicology studies of margetuximab in cynomolgus monkeys.”
Why that species
Engineered Fc binds activating cynomolgus Fc receptors CD16A and CD32A, making the monkey appropriate
“In a molecular binding study applying SPR, margetuximab Fc domain showed enhanced binding to activating cynomolgus Fc receptors CD16A and CD32A but also increased binding to inhibitory Fc receptor CD32B.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Margetuximab was administered through IV infusion once weekly. No target organs for margetuximab were identified”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Dose and frequency of dosing: 0, 15, 50, and 100 mg/kg/dose; once weekly for 13 consecutive weeks (13 doses)”
Pivotal GLP studies
GLP cynomolgus monkey 6-week (up to 150 mg/kg/dose) and 13-week (up to 100 mg/kg/dose) repeat-dose studies
“The Applicant conducted GLP-compliant 6-week (doses up to 150 mg/kg/dose) and 13-week (doses up to 100 mg/kg/dose) repeat-dose toxicology studies of margetuximab in cynomolgus monkeys.”
Route in tox
IV infusion (1 hour), once weekly
“Route of administration: IV infusion (1 hour)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Not performed per ICH S6(R1).”
Carcinogenicity
Not conducted (ICH S6(R1), S1A, S9; advanced cancer)
“Not performed per ICH S6(R1), ICH S1A, and ICH S9.”
Reproductive & developmental
Monkey ePPND: oligohydramnios at 50 and 100 mg/kg from GD 75; infant death at 100 mg/kg
“Treatment with 50 and 100 mg/kg margetuximab-cmkb resulted in oligohydramnios beginning on GD 75. An infant mortality occurred on post-natal day 63 following maternal exposure to 100 mg/kg margetuximab-cmkb.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no changes in blood pressure, heart rate or ECG intervals
“Cardiovascular (CV) safety assessment in a 6-week study of weekly margetuximab in cynomolgus monkeys (Report UOK00019) found no margetuximab-related changes in blood pressure, heart rate or ECG intervals.”
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 Margenza 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 oncology monoclonal antibodies (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: NOAEL 150 mg/kg/dose (highest dose) after 6 weekly IV doses in monkeys (FDA multi-discipline review, p. 43)
NOAEL / key findings
NOAEL 150 mg/kg/dose (highest dose) after 6 weekly IV doses in monkeys
“or 6 weekly doses of 0, 15, 50 or 150 mg/kg/dose (Report UOK00019). These data support a no-observed-adverse-effect level (NOAEL) of 150 mg/kg/dose.”
Risksopen answer page →
Immune & cytokine safety
No serum IFN-γ, IL-2, IL-5, IL-6, IL-10 or TNF-α increase in monkeys; partially reversible NK-cell decreases
“No target organs for margetuximab were identified, nor were there margetuximab-related increased release of IFN-γ, IL-2, IL-5, IL-6, IL-10, or TNF-α in serum. Margetuximab treatment resulted in partially reversible decreases in blood CD3-/CD159a+ and CD16+/CD159a+ NK cells when compared to vehicle controls.”
Biodistribution & persistence
TCR in human and monkey tissues matched HER2 expression sites; similar to trastuzumab
“These studies revealed margetuximab staining patterns consistent with reported sites of HER2 expression on human and cynomolgus monkey tissues. Direct comparison of margetuximab and trastuzumab revealed similar tissue staining.”
Modality-specific risk
Embryo-fetal toxicity: oligohydramnios and fetal renal toxicity, a HER2-directed antibody class effect
“Oligohydramnios and associated renal toxicity are class effects of HER2-directed antibodies.”