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”
Species: general tox
Cynomolgus monkey only (6-week and 13-week 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.”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development study); no fertility or early embryonic studies
“An enhanced pre- and postnatal development (ePPND) study was conducted in cynomolgus monkeys (Report 8329256) to evaluate potential effects of margetuximab on pregnancy, embryo-fetal development, parturition, and postnatal development.”
Species: carcinogenicity
Not conducted (ICH S6(R1), S1A, S9)
“Not performed per ICH S6(R1), ICH S1A, and ICH S9.”
Surrogate used in
No surrogate molecule; hCD16A knock-in transgenic mice used for in vivo anti-tumor pharmacology
“Margetuximab also showed dose-dependent enhanced activity against trastuzumab-resistant JIMT-1 compared to RES120 in a hCD16A knock-in transgenic mouse model expressing low-binding allele CD16A-158F”
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.”
Genotox: Ames
Not conducted (ICH S6(R1))
“Not performed per ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Not performed per ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Not performed per ICH S6(R1).”
Carcinogenicity model
Not conducted (ICH S6(R1), S1A, S9; advanced cancer)
“Not performed per ICH S6(R1), ICH S1A, and ICH S9.”
Carcinogenicity timing
Not required for the proposed indication (FDA agreed)
“FDA agrees that carcinogenicity studies are not needed to support approval of Margenza for the proposed indication.”
hERG / QT
No hERG assay; no changes in blood pressure, heart rate or ECG intervals in the 6-week monkey study
“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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
Anti-drug antibodies: animals
Minimal: ADA in 6 of 108 monkeys, mainly at lower doses; faster drug clearance in ADA-positive animals
“Margetuximab produced a minimal immunogenic response in cynomolgus monkeys. Positive confirmation of ADA following margetuximab administration was detected in 6 of 108 animals across all 4 studies, primarily at lower dose levels. A more rapid decline in margetuximab serum concentrations was observed in animals that had confirmed ADAs.”
Anti-drug antibodies: patients
2% (7/350) anti-margetuximab antibodies; no treatment-emergent neutralizing antibodies
“the incidence of anti-margetuximab antibodies was 2% (7/350). No patients developed treatment-emergent neutralizing antibodies.”
Label warnings
Boxed warning: Left ventricular dysfunction and embryo-fetal toxicity
- Left Ventricular Dysfunction
- Embryo-Fetal Toxicity
- Infusion-Related Reactions
CardiovascularEmbryo-fetal toxicityHypersensitivity & infusion reactions
US prescribing information, Boxed Warning and 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 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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey (weekly IV infusion) GLP study with 10-week recovery
“13-Week GLP intravenous infusion chronic toxicity study with margetuximab in cynomolgus monkeys with a 10-week recovery (Study 8321179)”
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.”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development study); no fertility or early embryonic studies
“An enhanced pre- and postnatal development (ePPND) study was conducted in cynomolgus monkeys (Report 8329256) to evaluate potential effects of margetuximab on pregnancy, embryo-fetal development, parturition, and postnatal development.”
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.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed and submitted with the marketing application
“The Applicant conducted a GLP-compliant enhanced pre- and postnatal development (ePPND) toxicology study in pregnant cynomolgus monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6(R1), S1A, S9)
“Not performed per ICH S6(R1), ICH S1A, and ICH S9.”
Carcinogenicity model
Not conducted (ICH S6(R1), S1A, S9; advanced cancer)
“Not performed per ICH S6(R1), ICH S1A, and ICH S9.”
Carcinogenicity timing
Not required for the proposed indication (FDA agreed)
“FDA agrees that carcinogenicity studies are not needed to support approval of Margenza for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 100 mg/kg/dose (13-week high dose): 8.6x (males) and 6.6x (females) human steady-state Cmax
“In the 13-week study, mean Cmax fold differences at the 100 mg/kg/dose after the 13th dose were 8.6× and 6.6× in males and females, respectively.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
HER2+ human breast cancer xenografts in mice, including hCD16A knock-in transgenic mice
“Margetuximab activities were demonstrated in in vivo efficacy studies applying different mouse xenograft models with HER2+ human breast cancer lines.”
Why that model
Engineered Fc binds mouse Fc receptors differently from human, so hCD16A knock-in mice were used
“The modified Fc domain reduced binding to mFcγRIII (mCD16), mFcγRII (mCD32), and mFcγRI (mCD64).”
Reviewer's view of the efficacy data
FDA: mouse xenograft models may be limited for evaluating the anti-tumor effects of the modified Fc domain
“Due to these differences, results from mouse xenograft models with human tumor cells may be limited in evaluating the anti-tumor effects of the modified Fc domain of margetuximab”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No dedicated fertility studies; embryo-fetal and postnatal effects assessed in a monkey ePPND study only
Why: Not needed for the current (metastatic breast cancer) indication · Serious disease
“Dedicated fertility studies were not needed or conducted to support marketing of Margenza for the current indication.”
Efficacy modelQuestioned
Mouse xenograft models cannot fully evaluate the engineered Fc domain because of species differences in Fc receptor binding
Why: Modified Fc binds mouse Fc gamma receptors differently from human receptors
“Due to these differences, results from mouse xenograft models with human tumor cells may be limited in evaluating the anti-tumor effects of the modified Fc domain of margetuximab (Study RND MGAH22-09-1013).”
Similar precedents
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