Hernexeos
zongertinib
Sources:FDA multi-discipline review ↗
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The repeat-dose toxicity of zongertinib was evaluated in rats and dogs for up to 13 weeks daily oral treatment.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Toxicokinetic analyses after repeated oral administration demonstrated systemic and dose-related exposure of zongertinib.”
Species: general tox
Rat and dog
“The Applicant evaluated the safety of zongertinib administered orally once daily in rats and dogs in 28-day and 91-day GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”
Species: DART
Rat and rabbit (EFD)
“The Applicant conducted GLP-compliant embryo-fetal development (EFD) studies in rats and rabbits.”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“FDA agrees that carcinogenicity studies are not warranted to support the use of zongertinib in the currently proposed indication per ICH S9.”
Surrogate used in
No surrogate used; zongertinib itself tested in rats and dogs
“The Applicant evaluated the safety of zongertinib administered orally once daily in rats and dogs in 28-day and 91-day GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The repeat-dose toxicity of zongertinib was evaluated in rats and dogs for up to 13 weeks daily oral treatment.”
Pivotal GLP studies
28-day and 91-day oral GLP studies in rats and dogs
“The Applicant evaluated the safety of zongertinib administered orally once daily in rats and dogs in 28-day and 91-day GLP-compliant general toxicology studies”
Route in tox
Oral gavage
“13-week oral (gavage) toxicity study in dogs with a 4-week recovery period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and rat in vivo micronucleus/comet (liver, duodenum) assays
“Zongertinib was negative for genotoxicity in the following studies: an in vitro bacterial reverse mutation (Ames) assay in the presence or absence of microsomal (S9) mix, and an in vivo peripheral blood micronucleus test coupled with comet assays conducted in hepatic and duodenal tissue isolated from male rats”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Consistent with the principles discussed in the ICH S9 guidance, carcinogenicity studies are not expected for development of a drug intended for the treatment of patients with advanced cancer.”
Reproductive & developmental
Rat EFD: delayed urinary system development and kidney hydronephrosis at 60 mg/kg/day (~19x human AUC)
“Zongertinib caused delayed development of the urinary system and kidney hydronephrosis at 60 mg/kg/day (approximately 19 times the human exposure based on AUC at the recommended dose).”
Safety pharmacology
hERG IC50 11.41 µM (~380-fold free Cmax); no cardiovascular toxicity in dog telemetry
“Zongertinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 11.41 µM in a safety pharmacology assessment, which is approximately 380-fold higher than the human free steady-state Cmax of 30 nM. Additional cardiovascular safety pharmacology assessments did not reveal cardiovascular toxicity in telemetered conscious dogs”
Genotox: Ames
Negative
“To clarify, under the conditions of the Ames assay (Study # n00282239), zongertinib did not induce concentration-dependent increases in revertants in vitro.”
Genotox: in vitro mammalian
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.
Genotox: in vivo
Negative: rat peripheral blood micronucleus with liver and duodenum comet assay
“Zongertinib did not induce dose-dependent increases in micronuclei or increases in the Comet tail intensity (a measure of DNA damage) in liver or duodenum tissue in male rats under the condition of the assay.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“Consistent with the principles discussed in the ICH S9 guidance, carcinogenicity studies are not expected for development of a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“FDA agrees that carcinogenicity studies are not warranted to support the use of zongertinib in the currently proposed indication per ICH S9.”
hERG / QT
hERG IC50 11.41 µM, ~380-fold human free steady-state Cmax
“Zongertinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 11.41 µM in a safety pharmacology assessment, which is approximately 380-fold higher than the human free steady-state Cmax of 30 nM.”
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 Hernexeos 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 small molecules (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: Target organs in rats and/or dogs: GI tract, adrenal gland and oral mucosa (FDA multi-discipline review, p. 47)
NOAEL / key findings
Target organs in rats and/or dogs: GI tract, adrenal gland and oral mucosa
“The major target organs of zongertinib in rats and/or dogs included the gastrointestinal (GI) tract, adrenal gland, and oral mucosa.”
Risksopen answer page →
Immune & cytokine safety
4-week rat: slight to moderate fluctuations in blood, spleen and thymocyte populations
“Immunotoxicology: slight to moderate fluctuations in blood, spleen, and thymocyte populations”
Biodistribution & persistence
Minimal BBB crossing (brain:plasma ≤0.01); prolonged retention in melanin-containing ocular tissues (~470 h)
“Brain-to-plasma ratios were ≤0.01, suggesting zongertinib showed minimal crossing of the blood-brain barrier in rats. Zongertinib was detected for up to ~200 hours in the total eyeball, and up to ~470 hours in the melanin-containing region of the ocular bulb of the eye”
Modality-specific risk
Oral mucosal lesions in dogs at subclinical exposure (≥0.3x human AUC)
“In the 4-week repeat-dose toxicology study in dogs, zongertinib induced redness and lesions of the oral mucosa (hard palate, buccal mucosa, tongue, lips) at doses ≥10 mg/kg/day (≥0.3 times the human exposure based on AUC at the recommended dose)”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
Not applicable (small molecule)
“8.2.4.11 Immunogenicity Data: Not applicable. The Applicant’s Position: Not applicable.”
Label warnings
- Hepatotoxicity
- Left Ventricular Dysfunction
- Interstitial Lung Disease/Pneumonitis
- Embryo-Fetal Toxicity
HepatotoxicityCardiovascularImmune-mediated reactionsPulmonary toxicityEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
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 Hernexeos 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 small molecules (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: Target organs in rats and/or dogs: GI tract, adrenal gland and oral mucosa (FDA multi-discipline review, p. 47)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and dog oral GLP studies, each with 4-week recovery
“13-week oral (gavage) toxicity study in rats with a 4-week recovery period”
Pivotal GLP studies
28-day and 91-day oral GLP studies in rats and dogs
“The Applicant evaluated the safety of zongertinib administered orally once daily in rats and dogs in 28-day and 91-day GLP-compliant general toxicology studies”
DART package
Species: DART
Rat and rabbit (EFD)
“The Applicant conducted GLP-compliant embryo-fetal development (EFD) studies in rats and rabbits.”
Reproductive & developmental
Rat EFD: delayed urinary system development and kidney hydronephrosis at 60 mg/kg/day (~19x human AUC)
“Zongertinib caused delayed development of the urinary system and kidney hydronephrosis at 60 mg/kg/day (approximately 19 times the human exposure based on AUC at the recommended dose).”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“FDA agrees that carcinogenicity studies are not warranted to support the use of zongertinib in the currently proposed indication per ICH S9.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“Consistent with the principles discussed in the ICH S9 guidance, carcinogenicity studies are not expected for development of a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“FDA agrees that carcinogenicity studies are not warranted to support the use of zongertinib in the currently proposed indication per ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog NOAEL approximately at clinical AUC; rat NOAEL ~1.5 to 3-fold (applicant)
“When comparing animal exposure at the NOAELs with preliminary available clinical exposure (AUCꚍ,ss at the 120 mg dose), there are reasonable exposure multiples in rats (~ 1.5 to 3 fold) while there are low exposure multiples in dogs (approximately the clinical exposure).”
NOAEL / key findings
Target organs in rats and/or dogs: GI tract, adrenal gland and oral mucosa
“The major target organs of zongertinib in rats and/or dogs included the gastrointestinal (GI) tract, adrenal gland, and oral mucosa.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mice implanted with patient-derived lung cancer cells (ST-3107, HER2 exon 20-YVMA): dose-dependent tumor growth inhibition
“In one model, mice implanted with patient-derived lung cancer cells (ST-3107) expressing HER2 exon 20-YVMA demonstrated dose-dependent tumor growth inhibition (TGI) of ≥119% following twice daily oral administration of ≥30 mg/kg zongertinib.”
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
In vitro data show inhibition of wild-type and TKD-mutant HER2 at clinical concentrations; non-TKD HER2 mutations not evaluated
“The Applicant did not evaluate the effect of zongertinib on non-TKD HER2 mutations in lung cancer cells. Overall, in vitro studies demonstrated that zongertinib inhibits wild-type HER2 and TKD HER2 mutations at clinically relevant concentrations.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No dedicated fertility and early embryonic development studies; fertility assessed from repeat-dose reproductive organ histopathology
Why: Not needed for the proposed advanced-cancer indication per ICH S9 · Within the guideline
“Fertility and early embryonic development studies were not conducted or needed to support the use of zongertinib in the proposed indication per ICH S9.”
Safety marginVerdict not stated
Dog NOAEL exposures only approximately equal to clinical exposure; rat margins about 1.5 to 3-fold
Why: Applicant: adverse findings not severe and reversible, so multiples acceptable for an oncology indication
“there are reasonable exposure multiples in rats (~ 1.5 to 3 fold) while there are low exposure multiples in dogs (approximately the clinical exposure). The adverse findings in the repeat dose toxicity studies were not severe and reversible, therefore the exposure multiples regarding the clinical situation are considered acceptable in the proposed oncological indications.”
Similar precedents
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