Portrazza
necitumumab
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
“Necitumumab bound to EGFR from humans and cynomolgus monkeys with similar affinity, thus, general toxicology studies were conducted in cynomolgus monkeys.”
Why that species
Comparable EGFR affinity in human and cynomolgus monkey; lower affinity for rodent and rabbit EGFR
“As indicated, the binding affinity for EGFR ECD is comparable between human and cyno. Lower affinities were achieved against rodent and rabbit isoforms.”
Surrogate molecule
Yes: cetuximab (right of reference), used as developmental surrogate via its monkey reproductive toxicity study
“The pharmacological and pharmacokinetic data comparing necitumumab and cetuximab are reasonable to support the use of cetuximab as a surrogate for the purpose of investigating the potential for necitumumab to have effects on a developing organism.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In the 26-week study, monkeys were treated at dose levels of 0, 6, 19, or 60 mg/kg weekly for 26 weeks.”
Pivotal GLP studies
Cynomolgus monkey IV studies with weekly dosing for 5 weeks and 26 weeks
“Monkeys were administered necitumumab weekly for 5 or 26 weeks to investigate the safety of the antibody.”
Route in tox
IV infusion
“Route of administration: Intravenous (1 mL/min) via syringe pump to cephalic or saphenous vein”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for necitumumab.”
Carcinogenicity
Not conducted (advanced cancer)
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
Reproductive & developmental
No dedicated studies; literature on EGFR knockouts and cetuximab monkey data (embryolethality, abortions at 1.6-4x human dose) support fetal-harm warning
“Cetuximab was detected in amniotic fluid and the serum of embryos from treated dams and caused embryolethality and abortions at doses of 1.6 to 4 times the recommended human dose.”
Safety pharmacology
No dedicated studies; ECG, heart rate, blood pressure and respiratory rate in 26-week monkey study: no findings
“No dedicated safety pharmacology studies were provided. The safety pharmacology endpoints were evaluated in the 26-week repeat-dose toxicology study (i.v).”
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 Portrazza 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 monkey study: adverse skin effects (hyperplastic dermatitis) at all doses (EMA assessment report, p. 31)
NOAEL / key findings
No NOAEL in 26-week monkey study: adverse skin effects (hyperplastic dermatitis) at all doses
“A no-observed-adverse-effect level (NOAEL) was not established in the 26-week toxicity study due to adverse skin effects at all dose levels.”
Risksopen answer page →
Immune & cytokine safety
Monkey immunogenicity could not be assessed reliably (drug interference with ADA assay); exposure maintained on repeat dosing
“The immunogenicity of necitumumab could not be accurately assessed in animal models. High levels of circulating necitumumab may have saturated the anti-drug antibody leaving an insufficient quantity of free binding sites for the assay to detect a response.”
Biodistribution & persistence
TCR in human and monkey tissues: consistent binding, no unexpected cross-reactivity
“In most tissues, binding was consistent in both human and monkey tissue, sometimes with minor differences in localization within the organ. There was no unexpected tissue cross-reactivity based on literature and the biology of EGFR”
Modality-specific risk
On-target EGFR-inhibitor skin toxicity, a major clinical adverse reaction
“Skin toxicity has previously been observed with similar EGFR inhibitors (e.g. cetuximab) and is a major adverse reaction clinically.”