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.”
Species: general tox
Cynomolgus monkey only
“The cynomolgus monkey was selected as the most relevant species for toxicology testing based on considerations of sequence homology and affinity binding to HER2.”
Species: DART
Not conducted; HER2 antibody class embryo-fetal toxicity (weight of evidence)
“Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab.”
Species: carcinogenicity
Not conducted (ICH S9)
“No carcinogenicity studies have been conducted with zanidatamab.”
Surrogate used in
No surrogate used; clinical molecule tested in cynomolgus monkey
“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.”
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”
Genotox: Ames
Not conducted (ICH S6(R1), ICH S9)
“Thus, mutagenicity studies are considered inappropriate and were not conducted.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1), ICH S9)
“Thus, mutagenicity studies are considered inappropriate and were not conducted.”
Genotox: in vivo
Not conducted (ICH S6(R1), ICH S9)
“Thus, mutagenicity studies are considered inappropriate and were not conducted.”
Carcinogenicity model
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)”
Carcinogenicity timing
Not required; FDA: carcinogenicity studies not warranted
“Carcinogenicity studies were not warranted.”
hERG / QT
No hERG assay; no cardiovascular effects in 13-week monkey study
“No test article-related adverse events were found in cardiovascular, respiratory, or central nervous system assessments.”
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 Ziihera 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 multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: NOAEL 150 mg/kg QW x13 weeks (highest dose); only non-adverse soft/watery feces, mild BUN increase (FDA multi-discipline review, p. 44)
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”
Anti-drug antibodies: animals
No confirmed ADA in monkeys, but drug levels exceeded assay drug tolerance; ADA may be undetected
“No zanidatamab-treated animals had detectable ADA in a confirmatory assay postdose, but the majority had serum concentrations of zanidatamab that exceeded the specific drug tolerance level of the confirmatory assay; thus, ADA may be present but undetectable due to high drug concentrations.”
Anti-drug antibodies: patients
3.4% (18/534) treatment-emergent ADA; 17% (3/18) of these neutralizing
“In patients who received ZIIHERA at the approved recommended dosages, 3.4% (18/534) of patients developed treatment-emergent anti-zanidatamab antibodies. Of the patients who developed treatment-emergent anti-zanidatamab antibodies, 17% (3/18) also developed neutralizing antibodies.”
Label warnings
Boxed warning: Diarrhea and embryo-fetal toxicity
- Diarrhea
- Embryo-Fetal Toxicity
- Left Ventricular Dysfunction (LVD)
- Infusion-Related Reactions
Embryo-fetal toxicityGastrointestinalCardiovascularHypersensitivity & infusion reactions
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
North America and South Korea: first-in-human study ZWI-ZW25-101 in HER2-expressing cancers
“Supportive ZWI-ZW25-101 (Phase 1) NCT02892123 N Am (12) S Korea (5) Locally advanced (unresectable) and/or metastatic HER2-expressing cancers”
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 Ziihera 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 multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: NOAEL 150 mg/kg QW x13 weeks (highest dose); only non-adverse soft/watery feces, mild BUN increase (FDA multi-discipline review, p. 44)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week weekly IV GLP cynomolgus monkey study (8-week interim termination) with 8-week recovery
“ZW25: A 13-Week Intravenous Infusion Toxicity Study With an 8-Week Interim Termination in Cynomolgus Monkeys With 8-Week Recovery Periods (GLP).”
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”
DART package
Species: DART
Not conducted; HER2 antibody class embryo-fetal toxicity (weight of evidence)
“Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab.”
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.”
PPND / ePPND: when
Not conducted: de novo developmental and reproductive toxicity studies not warranted (zanidatamab considered an embryofetal toxicant)
“Jazz proposes that zanidatamab should be considered an embryofetal toxicant. Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“No carcinogenicity studies have been conducted with zanidatamab.”
Carcinogenicity model
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)”
Carcinogenicity timing
Not required; FDA: carcinogenicity studies not warranted
“Carcinogenicity studies were not warranted.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 150 mg/kg: exposure ~10-fold above clinically relevant exposure
“In repeat-dose toxicity studies in cynomolgus monkeys (28DTOX and 13WTOX), no mortality or signs of acute toxicity was noted following the first administration of zanidatamab at dose levels up to 150 mg/kg resulting in exposure multiples approximately 10-fold higher than clinically relevant exposure.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
HER2 3+ xenografts in nude mice (SKOV-3, NCI-N87, patient-derived GXA 3054); no effect in HER2-negative model
“In a third assay, the antitumour activity of a single high dose level of zanidatamab was evaluated in GXA 3054, a patient-derived HER2 3+ gastric cancer xenograft model in nude mice (ZW25-29).”
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
EMA: variable xenograft responses; higher doses needed, may not beat trastuzumab + pertuzumab
“The non-clinical in vivo data therefore indicates that higher dose levels of zanidatamab is needed to induce a significant clinical response, but also that zanidatamab may not be superior to the combination of trastuzumab and pertuzumab, depending on the setting and tumour type.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No reproductive and developmental toxicity studies; HER2-antibody class weight-of-evidence assessment instead
Why: Embryo-fetal toxicity a likely class effect of HER2-binding antibodies per literature (ICH S5(R3)) · Within the guideline · Class precedent · Weight of evidence
“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 (ICH S5(R3) Section 1.2.2) (ICH, 2020), Jazz proposes that zanidatamab should be considered an embryofetal toxicant.”
“Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab. The FDA’s Assessment: The FDA generally agrees with the Applicant’s Position.”
DARTVerdict not stated
No fertility studies; fertility assessed by reproductive organ histopathology and weights in the repeat-dose monkey study
“Fertility studies have not been performed with zanidatamab but its potential to impair fertility was assessed by histopathology and organ weight analysis as part of the pivotal repeat dose toxicity study.”
Similar precedents
BizengriMultispecifics · zenocutuzumab · HER2 x HER3Monkey only · 13 wkHerceptinAntibodies · trastuzumab · HER2Monkey only · 26 wkMargenzaAntibodies · margetuximab · HER2Monkey only · 13 wkPerjetaAntibodies · pertuzumab · HER2Monkey only · 26 wkEnhertuADCs · fam-trastuzumab deruxtecan · HER2Monkey + rodent · 13 wkHernexeosSmall molecules · zongertinib · HER2 (mutant)Rodent + dog or minipig · 13 wk