Inluriyo
imlunestrant
Species
MonkeyRat
Longest study
26 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 cynomolgus monkey
“Repeat-dose toxicity studies were conducted with imlunestrant in rats (≤ 150 mg/kg/day) up to 6- months duration and monkeys (≤ 600 mg/kg/day) up to 3-months duration.”
Why that species
Pharmacokinetics and toxicokinetics in rat and monkey similar enough to human to be representative
“Overall, it can be concluded that rats and monkeys are suitable non-clinical species for the safety assessment of imlunestrant. The pharmaco-and toxicokinetics are similar enough to human pharmacokinetics to be representative.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Imlunestrant has been administered by QD oral gavage to rats for up to 6 months and to monkeys for up to 3 months.”
Study lengthopen answer page →
Longest pivotal study
26 (6-month rat)
“Repeat-dose toxicity studies were conducted with imlunestrant in rats (≤ 150 mg/kg/day) up to 6- months duration and monkeys (≤ 600 mg/kg/day) up to 3-months duration.”
Pivotal GLP studies
6-month rat and 3-month cynomolgus monkey oral gavage studies
“Imlunestrant has been administered by QD oral gavage to rats for up to 6 months and to monkeys for up to 3 months.”
Route in tox
Oral gavage
“Imlunestrant has been administered by QD oral gavage to rats for up to 6 months and to monkeys for up to 3 months.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; positive in vitro micronucleus; negative in vivo rat comet and bone marrow micronucleus assays
“Imlunestrant was not mutagenic in the Ames bacterial reverse mutation assay. Imlunestrant produced chromosomal damage in the in vitro micronucleus assay but did not cause chromosomal damage or DNA strand breaks in vivo when tested up to 2000 mg/kg in the rat comet and bone marrow micronucleus assays.”
Carcinogenicity
Not conducted (advanced cancer indication); studies ongoing for other indications
“Carcinogenicity studies have not been conducted to support the advanced cancer indication for imlunestrant but are ongoing to support other indications.”
Reproductive & developmental
Rat EFD: embryo-fetal death at ≥0.3 mg/kg and malformations at ≥3 mg/kg, below human exposure
“resulted in embryo-fetal mortality at ≥ 0.3 mg/kg and structural abnormalities at ≥ 3 mg/kg at maternal exposures that were below the human AUC0-24 at the recommended dose.”
Safety pharmacology
No cardiovascular, CNS or respiratory effects in 4-week and 3-month monkey studies
“Imlunestrant had no effect on the cardiovascular, central nervous, and respiratory systems of monkeys in 4-week or 3-month toxicology repeat-dose toxicology studies.”
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 Inluriyo 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: Ovarian follicular cysts and vagina, cervix and uterus atrophy at ≥10 mg/kg/day in rats and ≥15 mg/kg/day in monkeys (FDA multi-discipline review, p. 42)
NOAEL / key findings
Ovarian follicular cysts and vagina, cervix and uterus atrophy at ≥10 mg/kg/day in rats and ≥15 mg/kg/day in monkeys
“Daily oral administration of imlunestrant resulted in follicular cysts in the ovary and atrophy in the vagina, cervix, and uterus at doses ≥ 10 mg/kg/day in female rats (≥ 4 times the human AUC at the recommended dose) and ≥ 15 mg/kg/day in female cynomolgus monkeys”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity studies; TDAR effects in rats judged non-adverse as immune responses were still mounted
“Imlunestrant affected T-cell dependent antibody responses across studies but because animals mounted anti-KLH IgM and IgG responses it was concluded that effects on seroconversion did not functionally suppress the immune response and were considered non-adverse.”
Biodistribution & persistence
Persistent uveal tract retention in rat whole-body distribution, declining very slowly through 672 hours
“Concentrations in uveal tract were high through to the end of the study at 672 hours and concentrations seem to be declining only very slowly.”
Modality-specific risk
On-target male and female reproductive organ toxicity; also hematopoietic/lymphatic, kidney, urinary bladder and eye findings
“The major target organs of toxicity in the general rat and monkey toxicology studies were male and female reproductive organs, hematopoietic/lymphatic system, kidney, urinary bladder, and eye and were generally consistent across the short and long-term studies.”