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.”
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”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”