Zegfrovy
sunvozertinib
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 Applicant conducted 13-week repeat-dose toxicology studies in rats and dogs with a recovery period of 4 weeks.”
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
“Beagle dogs were orally administered (gavage) with sunvozertinib at 3, 6, 12/8 (males) or 12 (females) mg/kg/day.”
Species: general tox
Rat and dog (13-week oral studies with 4-week recovery)
“The Applicant conducted 13-week repeat-dose toxicology studies in rats and dogs with a recovery period of 4 weeks.”
Species: DART
Rat and rabbit (embryo-fetal development, oral)
“Sunvozertinib was administered orally to rats and rabbits during the period of organogenesis to assess embryo-fetal development toxicity.”
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“The Applicant did not conduct a carcinogenicity study with sunvozertinib; consistent with ICH S9, these studies are not warranted for the development of a drug intended for the treatment of patients with advanced cancer.”
Surrogate used in
No surrogate used; all notable human metabolites formed in rat and dog
“All notable human metabolites identified were also found in rat and dog hepatocytes.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The Applicant conducted 13-week repeat-dose toxicology studies in rats and dogs with a recovery period of 4 weeks.”
Pivotal GLP studies
4-week and 13-week studies in Wistar Han rats and Beagle dogs, with 4-week recovery
“A series of general toxicology studies in compliance with GLP have been completed, including single-dose oral toxicity studies in Wistar Han rats and Beagle dogs, 4-week and 13-week repeated dose toxicity and toxicokinetics studies in Wistar Han rats and Beagle dogs with 4-week recovery.”
Route in tox
Oral (gavage)
“DZD9008 - 13 Week Oral (Gavage) Toxicity Study in the Rat with a 4 Week Treatment-Free Period (JXB0023)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosome aberration and rat bone marrow micronucleus assays
“Sunvozertinib was not mutagenic in an in vitro bacterial reverse mutation assay. Additionally, sunvozertinib did not cause chromosomal aberrations in an in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells. Sunvozertinib was not clastogenic in an in vivo bone marrow micronucleus test in rats”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“The Applicant did not conduct a carcinogenicity study with sunvozertinib; consistent with ICH S9, these studies are not warranted for the development of a drug intended for the treatment of patients with advanced cancer.”
Reproductive & developmental
Rat and rabbit EFD: abortion, fetal death, reduced fetal weight, heart malformations and skeletal variations
“In the embryo-fetal development toxicity studies, sunvozertinib resulted in decreased body weight and abortion in pregnant rats and/or rabbits, dead fetuses, decreased fetal weight, heart malformations, increased supernumerary bone of fontanelle bone, and misaligned sternebra in fetus.”
Safety pharmacology
hERG IC50 1.21 μM; no effects on respiratory, CNS or cardiovascular systems
“Sunvozertinib inhibited the function of hERG channel with an IC50 value of 1.21 μM. In addition, sunvozertinib showed no effect on respiratory system, CNS or cardiovascular system in the above studies, indicating that it has a favourable safety profile.”
Genotox: Ames
Negative
“Sunvozertinib was not mutagenic in an in vitro bacterial reverse mutation assay.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Additionally, sunvozertinib did not cause chromosomal aberrations in an in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Sunvozertinib was not clastogenic in an in vivo bone marrow micronucleus test in rats”
Carcinogenicity model
Not conducted; not warranted for advanced cancer (ICH S9)
“The Applicant did not conduct a carcinogenicity study with sunvozertinib; consistent with ICH S9, these studies are not warranted for the development of a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9)
“The Applicant did not conduct a carcinogenicity study with sunvozertinib; consistent with ICH S9, these studies are not warranted for the development of a drug intended for the treatment of patients with advanced cancer.”
hERG / QT
hERG IC50 1.21 µM, ~20-fold over unbound Cmax (~60 nM); no QT prolongation in dogs
“Sunvozertinib inhibited human ether-a-go-go related gene (hERG) current at a concentration of 1.21 μM, which corresponds to a ~20-fold exposure margin from the unbound Cmax of sunvozertinib (~60 nM), thereby suggesting low potential for QT prolongation.”
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 Zegfrovy 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: Dose-limiting GI toxicity; main target organs GI tract, eyes, skin, lungs and immune organs (FDA multi-discipline review, p. 51)
NOAEL / key findings
Dose-limiting GI toxicity; main target organs GI tract, eyes, skin, lungs and immune organs
“Dose-limiting toxicity was gastrointestinal (GI) tract effects (including diarrhea, low food consumption and body weight loss), consistent with clinical symptoms in human. The main target organs were GI tract, eyes, skin, lungs, and immune organs, etc.”
Risksopen answer page →
Immune & cytokine safety
Immune organs among the main target organs
“The main target organs were GI tract, eyes, skin, lungs, and immune organs, etc.”
Biodistribution & persistence
Melanin binding (uveal tract, meninges, pigmented fur); low blood-brain barrier penetration
“Distribution of sunvozertinib-derived radioactivity in the uveal tract, meninges, and pigmented fur indicated melanin binding. Radioactivity in the brain and spinal cord remained below the limit of quantification, indicating that sunvozertinib has a low tendency to cross the blood-brain barrier.”
Modality-specific risk
Embryo-fetal toxicity (labeled warning)
“Overall, given the nonclinical data, the pharmacology/toxicology team recommends a warning for embryo-fetal toxicity in the label for ZEGFROVY (sunvozertinib).”
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 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.
Label warnings
- Interstitial Lung Disease/Pneumonitis
- Gastrointestinal Adverse Reactions
- Dermatologic Adverse Reactions
- Ocular Toxicity
- Embryo-Fetal Toxicity
Immune-mediated reactionsPulmonary toxicityGastrointestinalSkin reactionsOcular toxicityEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human dose escalation/expansion study in patients with advanced NSCLC (multinational WU-KONG1A)
“WU-KONG1A was a first-in-human study, including dose escalation, dose expansion and food effect cohorts.”
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 Zegfrovy 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: Dose-limiting GI toxicity; main target organs GI tract, eyes, skin, lungs and immune organs (FDA multi-discipline review, p. 51)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and beagle dog oral studies, each with 4-week recovery
“4-week and 13-week repeated dose toxicity and toxicokinetics studies in Wistar Han rats and Beagle dogs with 4-week recovery.”
Pivotal GLP studies
4-week and 13-week studies in Wistar Han rats and Beagle dogs, with 4-week recovery
“A series of general toxicology studies in compliance with GLP have been completed, including single-dose oral toxicity studies in Wistar Han rats and Beagle dogs, 4-week and 13-week repeated dose toxicity and toxicokinetics studies in Wistar Han rats and Beagle dogs with 4-week recovery.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development, oral)
“Sunvozertinib was administered orally to rats and rabbits during the period of organogenesis to assess embryo-fetal development toxicity.”
Reproductive & developmental
Rat and rabbit EFD: abortion, fetal death, reduced fetal weight, heart malformations and skeletal variations
“In the embryo-fetal development toxicity studies, sunvozertinib resulted in decreased body weight and abortion in pregnant rats and/or rabbits, dead fetuses, decreased fetal weight, heart malformations, increased supernumerary bone of fontanelle bone, and misaligned sternebra in fetus.”
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 (ICH S9, advanced cancer)
“The Applicant did not conduct a carcinogenicity study with sunvozertinib; consistent with ICH S9, these studies are not warranted for the development of a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity model
Not conducted; not warranted for advanced cancer (ICH S9)
“The Applicant did not conduct a carcinogenicity study with sunvozertinib; consistent with ICH S9, these studies are not warranted for the development of a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9)
“The Applicant did not conduct a carcinogenicity study with sunvozertinib; consistent with ICH S9, these studies are not warranted for the development of a drug intended for the treatment of patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL margin stated; rat ocular toxicity at 35 mg/kg, ~0.8x clinical AUC at 200 mg
“Ocular toxicities (hemorrhage of the anterior chamber of the eye) were observed in rats at 35 mg/kg (approximately 0.8 times the clinical AUC at the 200 mg human dose) and persisted through the recovery period.”
NOAEL / key findings
Dose-limiting GI toxicity; main target organs GI tract, eyes, skin, lungs and immune organs
“Dose-limiting toxicity was gastrointestinal (GI) tract effects (including diarrhea, low food consumption and body weight loss), consistent with clinical symptoms in human. The main target organs were GI tract, eyes, skin, lungs, and immune organs, etc.”
Efficacy evidenceopen answer page →
Efficacy evidence
Patient-derived NSCLC xenografts with EGFR exon20ins (LU0387, LU3075) and A431 WT EGFR xenograft in nude mice
“The Applicant investigated the in vivo anti-tumor activity of sunvozertinib in nude mice (6-9/group) implanted subcutaneously (SC) with a human squamous cell carcinoma cell line expressing WT EGFR (A431) or patient-derived NSCLC xenograft models carrying EGFR exon20ins mutations (LU0387 and LU3075).”
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
FDA: in vitro activity on the exon 20 insertion mutation was similar to wild-type EGFR
“FDA notes that the activity of sunvozertinib and DZ0753 on exon 20 insertion mutation (EGFR D770_N771insNPG) was similar to wild-type EGFR (Applicant’s Table 3).”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin: persistent ocular toxicity in rats at about 0.8 times the clinical AUC at 200 mg
“Ocular toxicities (hemorrhage of the anterior chamber of the eye) were observed in rats at 35 mg/kg (approximately 0.8 times the clinical AUC at the 200 mg human dose) and persisted through the recovery period.”
Similar precedents
ExkivitySmall molecules · mobocertinib · EGFR exon 20 insertionRodent + dog or minipig · 13 wkAyvakitSmall molecules · avapritinib · KIT/PDGFRARodent + dog or minipig · 39 wkBalversaSmall molecules · erdafitinib · FGFR1-4Rodent + dog or minipig · 13 wkEnsacoveSmall molecules · ensartinib · ALKRodent + dog or minipig · 13 wkFruzaqlaSmall molecules · fruquintinib · VEGFR1-3Rodent + dog or minipig · 13 wkHernexeosSmall molecules · zongertinib · HER2 (mutant)Rodent + dog or minipig · 13 wk