Ziihera
zanidatamab
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 toxicology program was carried out in cynomolgus monkeys, as it was demonstrated that the cynomolgus monkey and human have relevant HER2 sequence homology and affinity.”
Why that species
Similar HER2 ECD affinity human 0.74 nM vs monkey 0.47 nM; weaker for dog, no binding in rodents
“It was demonstrated that zanidatamab binds with similar affinity to human and cynomolgus monkey HER2 ECD (Kd = 0.74 and 0.47 nM, respectively), while the affinity for dog was lower (Kd = 4.07 nM) and no affinity was demonstrated for rodents”
Surrogate molecule
No surrogate; clinical molecule tested in cynomolgus monkey
“The cynomolgus monkey is considered a suitable species for characterizing the PK of zanidatamab as it binds both human and monkey HER2 molecules with similar subnanomolar affinity.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“A comprehensive series of non-GLP and GLP studies have been conducted. The program included tissue cross-reactivity studies in panels of human tissues and IV toxicology studies of up to 13 treatment cycles (13 weeks duration) performed in cynomolgus monkeys.”
Pivotal GLP studies
GLP cynomolgus 13-week weekly IV infusion study (8-week interim, 8-week recovery), 5/50/150 mg/kg
“Doses of 0 (vehicle control), 5, 50, and 150 mg/kg QW Route of administration: 1 hour IV infusion Formulation/Vehicle: sucrose, pH Species/Strain: Cynomolgus monkey”
Route in tox
IV infusion
“Intravenous dosing was utilized in all pivotal toxicology studies since it is the intended route of administration in the clinic.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1), ICH S9)
“Thus, mutagenicity studies are considered inappropriate and were not conducted.”
Carcinogenicity
Not conducted (ICH S9; advanced cancer, no mechanistic concern)
“Thus, given the intended patient population and lack of mechanistic concern, carcinogenicity studies are not planned with zanidatamab (ICH S9)”
Reproductive & developmental
Not conducted; weight-of-evidence, HER2 antibody class embryo-fetal toxicant (oligohydramnios)
“Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab.”
Safety pharmacology
Incorporated into 13-week monkey study (CV, respiratory, CNS); no effects
“Stand-alone safety pharmacology studies were not performed; however, appropriate safety assessments were included in the 13- week repeat-dose toxicology study”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NOAEL 150 mg/kg QW x13 weeks (highest dose); only non-adverse soft/watery feces, mild BUN increase
“No adverse effects were observed at any dose tested (up to 150 mg/kg QW) for animals in either the 8-week or 13-week dosing cohorts.”
Risksopen answer page →
Immune & cytokine safety
Low immunogenic potential (PBMC assay); no immunotoxicity in 13-week study; ADA assay drug interference
“Zanidatamab displayed low immunogenic potential in a functional human PBMC proliferation assay.”
Biodistribution & persistence
No in vivo tissue distribution studies performed (mAb)
“In vivo tissue distribution studies have not been performed with zanidatamab.”
Modality-specific risk
Embryo-fetal toxicity (HER2 class effect); diarrhea/GI findings in monkeys; no CRS signal
“On the basis of a weight-of-evidence analysis supported by published literature indicating that embryo-fetal toxicity is a likely class effect of HER2 binding antibodies”