Rybrevant
amivantamab
Species
Monkey
Longest study
13 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The cynomolgus monkey was selected as the only pharmacologically relevant species for the nonclinical pharmacokinetic (PK) and toxicology assessments of amivantamab based on a comparison of sequence homology, cross-species comparisons of relative target-binding affinities, and functional activity in cell-based assays.”
Why that species
Similar binding to human and cyno EGFR/MET ECD, no rat binding; ~10-fold lower pEGFR inhibition in cyno cells
“Amivantamab bound to the ECD of human and cynomolgus monkey EGFR and MET with similar EC50 values (Table 3), but not to the ECD of rat EGFR or MET (data not included in review).”
Surrogate molecule
No surrogate; clinical molecule in monkey (comparator data from lazertinib and zalutumumab used for repro WoE)
“The cynomolgus monkey is considered the pharmacologically relevant species for the toxicology program of amivantamab (see Section 0, Safety Pharmacology).”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Janssen conducted a GLP-compliant 13-week toxicology study in cynomolgus monkeys. Monkeys received intravenous amivantamab once weekly at doses of 0, 60, or 120 mg/kg.”
Pivotal GLP studies
Cynomolgus IV weekly: 4-week non-GLP tolerability, 6-week GLP (6-week recovery), 13-week GLP; 2-week SC local tolerance
“The repeat-dose toxicity of amivantamab in cynomolgus monkeys was evaluated in a 4-week tolerability non-GLP study, and 6-week toxicity with 6-week recovery and 13-week toxicity GLP studies.”
Route in tox
Intravenous (slow bolus, weekly); SC for local tolerance
“Route of administration: Intravenous; slow bolus injection”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not appropriate for antibodies)
“Janssen did not conduct genetic toxicology studies as they are not appropriate for antibody therapies.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
Not conducted; weight-of-evidence (EGFR/MET knockouts, lazertinib rat EFD, zalutumumab monkey EFD); embryofetal warning
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
Safety pharmacology
Incorporated into 1-month, 6-week and 3-month monkey studies (CV, respiratory, observational CNS)
“Separate safety pharmacology studies were not conducted with amivantamab; however, the 1-month non-Good Laboratory Practice (GLP) tolerability study, and the 6-week and the 3-month toxicity GLP studies in cynomolgus monkeys incorporated cardiovascular and respiratory assessments as well as observational central nervous system (CNS) assessments (body temperature and clinical signs).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NOAEL 120 mg/kg/wk (highest dose; >=5.3x human AUC); minimal liver, kidney, stomach findings
“The no-observed-adverse-effect level (NOAEL) in the toxicology studies was 120 mg/kg/week (highest tested dose) for the 6-week and 3-month toxicity GLP studies.”
Risksopen answer page →
Immune & cytokine safety
Low CRS risk in human blood cytokine release assay; ADA in 17/67 monkeys; no immunotoxicity
“In an in vitro assay using human blood, the cytokine release profile for amivantamab was similar to that of the negative control, indicating a low risk for cytokine release syndrome.”
Biodistribution & persistence
No distribution/metabolism/excretion studies (IgG mAb); nonlinear TMDD PK below 20 mg/kg/week
“Conventional distribution, metabolism, and excretion studies were not conducted for amivantamab since it is a immunoglobulin G (IgG)-based monoclonal antibody (mAb) with a molecular weight of approximately 148,000 Daltons (kD).”
Modality-specific risk
On-target EGFR/MET epithelial toxicity under-tested: only ~5x margin and lower cyno potency; embryofetal risk
“However, the exposure margin at the highest dose was only about 5-fold the clinical AUC indicating that the high dose levels were not set at an appropriate level.”