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.”
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”
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)
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: 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).”