Perjeta
pertuzumab
Species
Monkey
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
Cynomolgus monkey only
“The Cynomolgus monkey was the preferred toxicity species based on the comparable in vitro human and monkey binding affinity and due to lack of binding to the rodent (mouse) ortholog, neu.”
Why that species
99% ErbB2 amino acid homology human vs monkey; comparable binding affinity; no binding to rodent neu
“The amino acid homology of human and monkey ErbB2 was 99%. Therefore, the cynomolgus monkey was selected as the appropriate model for nonclinical evaluation.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The Cynomolgus monkey was the preferred toxicity species based on the comparable in vitro human and monkey binding affinity and due to lack of binding to the rodent (mouse) ortholog, neu.”
Species: general tox
Cynomolgus monkey only
“The Cynomolgus monkey was the preferred toxicity species based on the comparable in vitro human and monkey binding affinity and due to lack of binding to the rodent (mouse) ortholog, neu.”
Species: DART
Cynomolgus monkey (embryo-fetal development, dosing from GD19)
“Pregnant cynomolgus monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg.”
Species: carcinogenicity
Not conducted (ICH S6/S9)
“There were no nonclinical genotoxicity or carcinogenicity studies performed with pertuzumab, as per the guidance provided in the International Conference on Harmonisation (ICH) guidance S6”
Surrogate used in
No surrogate used; pertuzumab itself tested in monkeys and human tumor xenografts
“Nonclinical studies investigating the pharmacology, pharmacokinetics and toxicology of pertuzumab in xenograft mouse models and cynomolgus monkeys”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“tolerability and the 6-month (Q weekly dosing x 26 weeks) repeat-dose toxicity studies in cynomolgus monkeys.”
Pivotal GLP studies
26-week GLP IV monkey study, once weekly, with 8-week recovery
“Study title: Twenty-six week intravenous toxicity and toxicokinetic study with pertuzumab in cynomolgus monkeys with an 8-week recovery period”
Route in tox
Intravenous
“The purpose of this study was to evaluate multiple dose PK of pertuzumab in cynomolgus monkeys following IV administration once per week for 26 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“There were no nonclinical genotoxicity or carcinogenicity studies performed with pertuzumab, as per the guidance provided in the International Conference on Harmonisation (ICH) guidance S6”
Carcinogenicity
Not conducted (ICH S6; advanced cancer, ICH S9)
“According to ICH S6 (R1) guideline standard carcinogenicity bioassays are generally not appropriate for biotechnology derived pharmaceuticals and according to ICH S9 carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with late stage or advanced cancer.”
Reproductive & developmental
Monkey EFD: fetal lethality at loading doses ≥30 mg/kg then ≥10 mg/kg bi-weekly (0.2-2x human exposure)
“Pertuzumab caused fetal lethality in pregnant monkeys treated with loading doses of ≥ 30 mg/kg followed by bi-weekly doses ≥ 10 mg/kg (approximately 0.2 to 2-fold greater than the exposure at the recommended human dose, by AUC).”
Safety pharmacology
No dedicated studies; cardiac (ECG) and respiratory endpoints included in pivotal repeat-dose studies
“Studies not conducted. Evaluations of cardiac (electrocardiogram measurements; ECG) and respiratory safety pharmacology parameters were included in the pivotal, repeat-dose toxicology studies”
Genotox: Ames
Not conducted (ICH S6)
“There were no nonclinical genotoxicity or carcinogenicity studies performed with pertuzumab, as per the guidance provided in the International Conference on Harmonisation (ICH) guidance S6”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“There were no nonclinical genotoxicity or carcinogenicity studies performed with pertuzumab, as per the guidance provided in the International Conference on Harmonisation (ICH) guidance S6”
Genotox: in vivo
Not conducted (ICH S6)
“There were no nonclinical genotoxicity or carcinogenicity studies performed with pertuzumab, as per the guidance provided in the International Conference on Harmonisation (ICH) guidance S6”
Carcinogenicity model
Not conducted: bioassays not appropriate for biologics; not warranted for advanced cancer
“According to ICH S6 (R1) guideline standard carcinogenicity bioassays are generally not appropriate for biotechnology derived pharmaceuticals and according to ICH S9 carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with late stage or advanced cancer.”
Carcinogenicity timing
Not required (ICH S6/S9, advanced cancer)
“According to ICH S6 (R1) guideline standard carcinogenicity bioassays are generally not appropriate for biotechnology derived pharmaceuticals and according to ICH S9 carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with late stage or advanced cancer.”
hERG / QT
No hERG assay; no ECG, heart rate, blood pressure or troponin effects in 6-month monkey study up to 150 mg/kg
“no remarkable treatment-related effects on electrocardiogram waveform patterns, heart rate, blood pressure or troponin levels in monkeys during the 6-month, repeat-dose toxicity study with pertuzumab, given weekly at doses of 15, 50, or 150 mg/kg/dose (study #00-458-1821).”
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 Perjeta 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: No NOAEL in 26-week study: severe diarrhoea and increased urea nitrogen at all dose levels (EMA assessment report, p. 38)
NOAEL / key findings
No NOAEL in 26-week study: severe diarrhoea and increased urea nitrogen at all dose levels
“Due to the severe diarrhoea and increased urea nitrogen values at all dose levels, a No Observed Adverse Effect Level (NOAEL) could not be determined.”
Risksopen answer page →
Immune & cytokine safety
No anti-pertuzumab antibodies detected in 7- and 26-week monkey studies; not immunogenic
“No antibodies to pertuzumab were detected in the 7- and 26-week toxicity studies. Despite possible interference in the ELISA assays, it appears that pertuzumab was not immunogenic in Cynomolgus monkeys.”
Biodistribution & persistence
TCR similar in human and monkey: haired skin, mammary gland, prostate, urinary bladder, stomach, consistent with HER2 distribution
“In vitro tissue cross-reactivity studies showed similar patterns of pertuzumab binding to human and cynomolgus monkey tissues, with haired skin, mammary gland, prostate, urinary bladder and stomach identified as the major target organs, consistent with the known distribution of HER2.”
Modality-specific risk
Embryo-fetal toxicity: fetal abnormalities secondary to oligohydramnios from HER2 blockade
“Hence, the observed external, visceral and skeletal abnormalities were considered secondary to intrauterine restriction resulting from the oligohydramnios (low amniotic fluid volume).”
Anti-drug antibodies: animals
No anti-pertuzumab antibodies detected in 7- and 26-week monkey studies (possible assay interference)
“No antibodies to pertuzumab were detected in the 7- and 26-week toxicity studies. Despite possible interference in the ELISA assays, it appears that pertuzumab was not immunogenic in Cynomolgus monkeys.”
Anti-drug antibodies: patients
3% (13/389) ADA with PERJETA vs 7% (25/372) placebo in CLEOPATRA
“3% (13/389) of patients in the PERJETA-treated group and 7% (25/372) of patients in the placebo-treated group tested positive for anti-pertuzumab antibodies.”
Label warnings
Boxed warning: LEFT VENTRICULAR DYSFUNCTION and EMBRYO-FETAL TOXICITY
- Left Ventricular Dysfunction
- Embryo-Fetal Toxicity
- Infusion-Related Reactions
- Hypersensitivity Reactions/Anaphylaxis
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 Perjeta 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: No NOAEL in 26-week study: severe diarrhoea and increased urea nitrogen at all dose levels (EMA assessment report, p. 38)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey IV study with 8-week recovery
“In the 26-week repeat-dose toxicity study, increased blood urea nitrogen values were observed in almost all pertuzumab treated animals and the finding persisted following a 8-week recovery period.”
Pivotal GLP studies
26-week GLP IV monkey study, once weekly, with 8-week recovery
“Study title: Twenty-six week intravenous toxicity and toxicokinetic study with pertuzumab in cynomolgus monkeys with an 8-week recovery period”
DART package
Species: DART
Cynomolgus monkey (embryo-fetal development, dosing from GD19)
“Pregnant cynomolgus monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg.”
Reproductive & developmental
Monkey EFD: fetal lethality at loading doses ≥30 mg/kg then ≥10 mg/kg bi-weekly (0.2-2x human exposure)
“Pertuzumab caused fetal lethality in pregnant monkeys treated with loading doses of ≥ 30 mg/kg followed by bi-weekly doses ≥ 10 mg/kg (approximately 0.2 to 2-fold greater than the exposure at the recommended human dose, by AUC).”
PPND / ePPND: when
Not conducted: not submitted per ICH S6(R1) and ICH S9
“No segment III studies (pre- and postnatal development) were submitted in accordance with ICH S6 (R1) and ICH S9 guidelines.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6/S9)
“There were no nonclinical genotoxicity or carcinogenicity studies performed with pertuzumab, as per the guidance provided in the International Conference on Harmonisation (ICH) guidance S6”
Carcinogenicity model
Not conducted: bioassays not appropriate for biologics; not warranted for advanced cancer
“According to ICH S6 (R1) guideline standard carcinogenicity bioassays are generally not appropriate for biotechnology derived pharmaceuticals and according to ICH S9 carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with late stage or advanced cancer.”
Carcinogenicity timing
Not required (ICH S6/S9, advanced cancer)
“According to ICH S6 (R1) guideline standard carcinogenicity bioassays are generally not appropriate for biotechnology derived pharmaceuticals and according to ICH S9 carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with late stage or advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL in 26-week monkey study: severe diarrhoea and increased urea nitrogen at all doses
“Due to the severe diarrhoea and increased urea nitrogen values at all dose levels, a No Observed Adverse Effect Level (NOAEL) could not be determined.”
NOAEL / key findings
No NOAEL in 26-week study: severe diarrhoea and increased urea nitrogen at all dose levels
“Due to the severe diarrhoea and increased urea nitrogen values at all dose levels, a No Observed Adverse Effect Level (NOAEL) could not be determined.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumor xenografts (breast, prostate, NSCLC, ovarian; HER2 low or high) in mice treated with pertuzumab
“Weekly IV/IP administrations of pertuzumab demonstrated anti-tumour efficacy in various tumour xenografts models based on breast cancer, prostate, non-small cell lung cancer and ovarian cell lines expressing either low or high levels of HER2.”
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
EMA: in vitro and in vivo pharmacodynamic data give a clear rationale for combination use in breast cancer
“Based on in vitro and in vivo pharmacodynamic data, there is a clear rationale for the inclusion of pertuzumab in a drug combination regimen in the treatment of breast cancer.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No NOAEL in the 26-week monkey study: severe diarrhoea and increased urea nitrogen at all doses
“Due to the severe diarrhoea and increased urea nitrogen values at all dose levels, a No Observed Adverse Effect Level (NOAEL) could not be determined.”
Safety marginAccepted with a conditionBeyond the letter
No fetal NOAEL in the monkey embryo-fetal study; fetal toxicity may occur at therapeutic concentrations
Why: Pertuzumab to be avoided during pregnancy, as with trastuzumab · Class precedent
“However, as no NOAEL for foetal toxicity was established in this study, it cannot be excluded that the observed foetal toxicity may occur at therapeutic pertuzumab concentrations in human. Hence, as with trastuzumab, pertuzumab should be avoided during pregnancy.”
Similar precedents
HerceptinAntibodies · trastuzumab · HER2Monkey only · 26 wkMargenzaAntibodies · margetuximab · HER2Monkey only · 13 wkBizengriMultispecifics · zenocutuzumab · HER2 x HER3Monkey only · 13 wkZiiheraMultispecifics · zanidatamab · HER2 x HER2 (biparatopic)Monkey only · 13 wkEnhertuADCs · fam-trastuzumab deruxtecan · HER2Monkey + rodent · 13 wkHernexeosSmall molecules · zongertinib · HER2 (mutant)Rodent + dog or minipig · 13 wk