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.”
Species: general tox
Cynomolgus monkey only (5- and 26-week studies)
“Necitumumab bound to EGFR from humans and cynomolgus monkeys with similar affinity, thus, general toxicology studies were conducted in cynomolgus monkeys. Monkeys were administered necitumumab weekly for 5 or 26 weeks to investigate the safety of the antibody.”
Species: DART
Not conducted with necitumumab; literature-based assessment plus cetuximab monkey developmental data
“Reproductive toxicity studies with necitumumab were not conducted. Instead, the Applicant submitted a literature-based assessment of the antibody’s potential for reproductive toxicity.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
Surrogate used in
Yes: cetuximab developmental study in non-human primates (right of reference) as surrogate for DART
“In order look specifically at potential developmental effects following an anti-EGFR antibody, the Applicant provided data by right of reference to a developmental study in non-human primates conducted using cetuximab.”
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).”
Genotox: Ames
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for necitumumab.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for necitumumab.”
Genotox: in vivo
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for necitumumab.”
Carcinogenicity model
Not conducted; not warranted for advanced cancer (ICH S9), no concern from structure or mechanism
“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer (ICH S9 [ICH 2009]) and there is no cause for concern (ICH S1A) based on the structure or mechanism of action of necitumumab.”
Carcinogenicity timing
Not required for a product to treat advanced cancer
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
hERG / QT
No hERG assay; no effects on heart rate, blood pressure or ECGs in 26-week monkey study
“There were no treatment-related effects on body weight, food consumption, ophthalmoscopy, heart rate, blood pressure, respiratory rate, electrocardiograms (ECGs), coagulation, urinalysis, or organ weight at any dose level.”
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)
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 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.”
Anti-drug antibodies: animals
ADA evaluation in monkeys confounded by high drug levels; exposure did not decrease on repeated dosing
“Attempts to evaluate the formation of ADA were confounded by high circulating concentrations of necitumumab. However, monkeys were exposed to necitumumab throughout the toxicity evaluations and exposure did not decrease upon repeated dosing.”
Anti-drug antibodies: patients
ADA in 4.1% (33/814) of patients; neutralizing in 1.4% (11/814)
“In clinical trials, treatment-emergent anti-necitumumab antibodies (ADA) were detected in 4.1% (33/814) of patients using an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 1.4% (11/814) of patients post exposure to PORTRAZZA.”
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 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)
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 monkey study: adverse skin effects (hyperplastic dermatitis) at all doses (EMA assessment report, p. 31)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey IV study (weekly) with 8-week recovery
“Study 023.07: A 26-week toxicity, toxicokinetic, and immunogenicity study of IMC-11F8 administered intravenously weekly to cynomolgus monkeys with an 8-week recovery period”
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.”
DART package
Species: DART
Not conducted with necitumumab; literature-based assessment plus cetuximab monkey developmental data
“Reproductive toxicity studies with necitumumab were not conducted. Instead, the Applicant submitted a literature-based assessment of the antibody’s potential for reproductive toxicity.”
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.”
PPND / ePPND: when
Not conducted: no reproductive toxicity studies with necitumumab; literature-based assessment submitted instead
“Reproductive toxicity studies with necitumumab were not conducted. Instead, the Applicant submitted a literature-based assessment of the antibody’s potential for reproductive toxicity.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
Carcinogenicity model
Not conducted; not warranted for advanced cancer (ICH S9), no concern from structure or mechanism
“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer (ICH S9 [ICH 2009]) and there is no cause for concern (ICH S1A) based on the structure or mechanism of action of necitumumab.”
Carcinogenicity timing
Not required for a product to treat advanced cancer
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL in 26-week monkey study; 5-week NOAEL (40 mg/kg) exposure approximately equal to median human exposure at maximum clinical dose
“In the 5-week study, exposure at the NOAEL dose level (40 mg/kg) was approximately the same as the median exposure expected at the maximum clinical dose level”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenografts of human NSCLC, pancreatic and colorectal tumour cell lines; tumour growth inhibition depending partly on EGFR status
“Treatment of mice implanted with tumor cell lines derived from NSCLC, pancreatic, and colorectal tumors with necitumumab resulted in varying degrees of tumor growth inhibition, depending, in part, on EGFR status of cells.”
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
Pharmacology adequately addressed; activity very similar to cetuximab in vitro and in vivo
“The pharmacology of necitumumab has been adequately addressed. It is to note that in several cases, necitumumab has been compared in vitro and in vivo with another anti-EGFR IgG1, cetuximab (Erbitux). In all cases the biological activity was very similar.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No reproductive toxicity studies; EGFR knockout literature and cetuximab embryo-fetal data used instead
Why: Surrogate data from cetuximab reproductive study; ICH S9 basis for not requiring additional DART studies · Class precedent · Within the guideline
“In order to investigate the potential effects of incomplete blockade of EGFR signaling with an antibody, the Applicant was able to provide surrogate data by right of reference to the reproductive toxicology study conducted as a post-marketing requirement for the anti-EGFR antibody cetuximab.”
“the CHMP agreed that additional DART studies are not necessary.”
Safety marginVerdict not stated
No NOAEL in the 26-week monkey study; 5-week NOAEL exposure about equal to human exposure at maximum dose
“In the 5-week study, exposure at the NOAEL dose level (40 mg/kg) was approximately the same as the median exposure expected at the maximum clinical dose level”
GLPCriticised but acceptedBeyond the letter
Toxicokinetic and immunogenicity analyses in the repeat-dose toxicity studies not GLP-compliant
Why: Exposure values not critical for the safety evaluation · Other reason
“Lack of GLP status for the TK part is a deficiency that may impact on the conclusions drawn from the toxicity study. However, in this case the exposure values are not considered critical for the safety evaluation.”
OtherQuestioned
Tissue cross-reactivity study evaluated each tissue in only one species, preventing human-monkey comparison
“While the purpose of tissue-cross-reactivity studies is typically to demonstrate comparability of binding between nonclinical and clinical species, and to potentially identify patterns of drug-related toxicity, in this study, the Applicant chose to evaluate each tissue in only one species, and therefore, it is not possible to conclude that the binding pattern was similar between the two species”
Similar precedents
VectibixAntibodies · panitumumab · EGFRMonkey only · 26 wkErbituxAntibodies · cetuximab · EGFRMonkey + rodent · 39 wkRybrevantMultispecifics · amivantamab · EGFR x METMonkey only · 13 wkLazcluzeSmall molecules · lazertinib · EGFR (mutant-selective)Rodent + dog or minipig · 13 wkBavencioAntibodies · avelumab · PD-L1Monkey only · 13 wkCyramzaAntibodies · ramucirumab · VEGFR2Monkey only · 39 wk