Hyrnuo
sevabertinib
Species
MonkeyRat
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 monkey
“The toxicity, the reversibility of effects, and exposures of sevabertinib were assessed in repeat dose, toxicology studies, up to 13 weeks duration in rats and monkeys.”
Why that species
Both pharmacologically active with metabolism comparable to human; dogs excluded due to insufficient exposure from enzyme induction
“Rats and cynomolgus monkeys were used in the toxicology program; both species are considered to be pharmacologically active and have a metabolism of sevabertinib comparable to that of humans. Dogs could not be used because of insufficient exposure due to enzyme induction after repeated dosing.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The toxicity, the reversibility of effects, and exposures of sevabertinib were assessed in repeat dose, toxicology studies, up to 13 weeks duration in rats and monkeys.”
Species: general tox
Rat and cynomolgus monkey
“The Applicant evaluated the safety of sevabertinib administered orally once daily in 4- and 13- week good laboratory practice (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”
Species: DART
Rat (EFD only)
“The Applicant conducted GLP-compliant embryo-fetal development (EFD) studies in pregnant rats to assess the effect of sevabertinib on embryonic and fetal development.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not conducted for sevabertinib and are not warranted for the proposed indication.”
Surrogate used in
No surrogate used; sevabertinib tested in pharmacologically active rat and monkey
“Rats and cynomolgus monkeys were used in the toxicology program; both species are considered to be pharmacologically active and have a metabolism of sevabertinib comparable to that of humans.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“The toxicity, the reversibility of effects, and exposures of sevabertinib were assessed in repeat dose, toxicology studies, up to 13 weeks duration in rats and monkeys.”
Pivotal GLP studies
4- and 13-week daily oral studies in rats and monkeys
“Daily oral administration of sevabertinib to rats and monkeys over 2, 4, or 13 weeks revealed adverse effects characterized by general signs of toxicity, such as reduced food intake, changes in laboratory parameters, diarrhea, and degenerative and inflammatory processes in epithelial and mucosal tissues.”
Route in tox
Oral, once daily
“The oral route of administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus and in vivo rat micronucleus assays
“Sevabertinib was not genotoxic in a bacterial reverse mutation (Ames) and an in vitro micronucleus assay, or an in vivo micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not conducted for sevabertinib and are not warranted for the proposed indication.”
Reproductive & developmental
Rat EFD: maternal toxicity and reduced fetal weights at ≥6 mg/kg/day (≥0.18x human AUC)
“Sevabertinib treatment resulted in maternal toxicity (reduced body weight and body weight gain) and a reduction in fetal weights at ≥6 mg/kg/day (≥0.18 times the human exposure based on AUC at the clinical dose).”
Safety pharmacology
No major acute effects on dog telemetry hemodynamics, rat CNS function or rat respiratory function
“Sevabertinib, at single oral doses, was devoid of major acute effects (i) on hemodynamic parameters in a dog telemetry study (Module 4.2.1.3, R-14051), (ii) on parameters of CNS function (behavior, locomotor activity, and body temperature) in rats”
Genotox: Ames
Negative
“Sevabertinib was not genotoxic in a bacterial reverse mutation (Ames) and an in vitro micronucleus assay, or an in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
In vitro micronucleus: negative
“Sevabertinib was not genotoxic in a bacterial reverse mutation (Ames) and an in vitro micronucleus assay, or an in vivo micronucleus assay in rats.”
Genotox: in vivo
Rat in vivo micronucleus: negative
“Sevabertinib was not genotoxic in a bacterial reverse mutation (Ames) and an in vitro micronucleus assay, or an in vivo micronucleus assay in rats.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not conducted for sevabertinib and are not warranted for the proposed indication.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“Consistent with the guideline ICH S9, carcinogenicity studies are not warranted to support clinical trials for therapeutics intended to treat patients with advanced cancer. The FDA’s Assessment: FDA agrees.”
hERG / QT
hERG IC50 2.36 µM, 26-fold free Cmax
“In a GLP-compliant study, sevabertinib inhibited hERG potassium current in vitro with an IC50 of 2.36 μM (26-fold the free Cmax of 88 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 Hyrnuo 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: Skin erosion/ulcer, liver fat accumulation and pancreatic acinar atrophy in rats and monkeys (FDA multi-discipline review, p. 43)
NOAEL / key findings
Skin erosion/ulcer, liver fat accumulation and pancreatic acinar atrophy in rats and monkeys
“Additional target organs in both species included the skin (wounds and scab formation; histological findings of up to moderate erosion/ulcer, atrophy, crust, hyperplasia, and inflammation), liver (up to marked fat accumulation), and pancreas (acinar cell atrophy).”
Risksopen answer page →
Immune & cytokine safety
Thymic atrophy and mesenteric lymph node changes in monkeys
“Additional target organs in the monkey included the thymus (up to severe atrophy, severe decreased adipose tissue), and mesenteric lymph node (marked decreased adipose tissue, slight increased cellularity).”
Biodistribution & persistence
Distribution to melanin-containing eye and skin with long-term ocular retention
“There was notable distribution of sevabertinib to the melanin-containing tissues of the eye and skin with long-term retention in the eye tissue”
Modality-specific risk
Ocular toxicity: lacrimal gland atrophy and optic nerve hemorrhage in rats at ≥0.2x human AUC
“In rats, treatment with ≥10 mg/kg sevabertinib (≥0.2 times the human exposure at the recommended dose of 20 mg BID based on AUC) resulted in slight atrophy of the lacrimal gland and minimal optic nerve hemorrhage.”
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; no immunogenicity assessments conducted in the clinical study
“Immunogenicity Data and the Applicant’s Position: Not applicable; no immunogenicity assessments were conducted as part of Study 21607.”
Label warnings
- Diarrhea
- Hepatotoxicity
- Interstitial Lung Disease/Pneumonitis
- Left Ventricular Dysfunction
- Ocular Toxicity
- Pancreatic Enzyme Elevation
- Embryo-Fetal Toxicity
GastrointestinalHepatotoxicityImmune-mediated reactionsPulmonary toxicityCardiovascularOcular 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 Hyrnuo 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: Skin erosion/ulcer, liver fat accumulation and pancreatic acinar atrophy in rats and monkeys (FDA multi-discipline review, p. 43)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and monkey oral studies with reversibility assessed
“The toxicity, the reversibility of effects, and exposures of sevabertinib were assessed in repeat dose, toxicology studies, up to 13 weeks duration in rats and monkeys.”
Pivotal GLP studies
4- and 13-week daily oral studies in rats and monkeys
“Daily oral administration of sevabertinib to rats and monkeys over 2, 4, or 13 weeks revealed adverse effects characterized by general signs of toxicity, such as reduced food intake, changes in laboratory parameters, diarrhea, and degenerative and inflammatory processes in epithelial and mucosal tissues.”
DART package
Species: DART
Rat (EFD only)
“The Applicant conducted GLP-compliant embryo-fetal development (EFD) studies in pregnant rats to assess the effect of sevabertinib on embryonic and fetal development.”
Reproductive & developmental
Rat EFD: maternal toxicity and reduced fetal weights at ≥6 mg/kg/day (≥0.18x human AUC)
“Sevabertinib treatment resulted in maternal toxicity (reduced body weight and body weight gain) and a reduction in fetal weights at ≥6 mg/kg/day (≥0.18 times the human exposure based on AUC at the clinical 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 indication)
“Carcinogenicity studies were not conducted for sevabertinib and are not warranted for the proposed indication.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not conducted for sevabertinib and are not warranted for the proposed indication.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“Consistent with the guideline ICH S9, carcinogenicity studies are not warranted to support clinical trials for therapeutics intended to treat patients with advanced cancer. The FDA’s Assessment: FDA agrees.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL margin stated; monkey lens degeneration at 5 mg/kg (0.1x human AUC)
“In monkeys, minimal lens degeneration occurred at 5 mg/kg (0.1 times the human exposure at the recommended dose based on AUC).”
NOAEL / key findings
Skin erosion/ulcer, liver fat accumulation and pancreatic acinar atrophy in rats and monkeys
“Additional target organs in both species included the skin (wounds and scab formation; histological findings of up to moderate erosion/ulcer, atrophy, crust, hyperplasia, and inflammation), liver (up to marked fat accumulation), and pancreas (acinar cell atrophy).”
Efficacy evidenceopen answer page →
Efficacy evidence
NSCLC patient-derived xenograft models with HER2 exon 20 insertion YVMA: antitumor activity
“In vivo, sevabertinib exhibited antitumor activity against NSCLC patient-derived xenograft (PDX) models harboring the HER2 exon 20 insertion YVMA.”
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
Inhibits WT HER2 and HER2 exon 20 insertion/point mutants in cells at concentrations below clinical free Cmax
“In cellular assays, sevabertinib inhibited the in vitro proliferation of cells overexpressing WT HER2 (IC50 = 5.30 nM) and a panel of HER2 exon 20 insertion mutations and activating point mutations (IC50 = 0.54 to 13.9 nM) at concentrations below the free Cmax of 88 nM at the recommended dose of 20 mg BID based on ~95% protein binding.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
Embryo-fetal development assessed in rat only; rabbit not usable as no relevant exposure achieved
Why: No relevant exposure to sevabertinib could be achieved in rabbits · Pharmacology or kinetics
“Rabbit did not qualify as a test species for embryo-fetal development assessment, as no relevant exposure to sevabertinib could be achieved.”
Safety marginVerdict not stated
Rat embryo-fetal NOAEL at unbound exposures below or around one times human exposure
“In summary it can be stated that no fetal malformations or adverse fetal variations were noted at unbound exposures of sevabertinib at multiples of exposure below or in the range of 1 compared to the therapeutic human unbound exposure.”
Similar precedents
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