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.”
Species: general tox
Rat (up to 6 months) and cynomolgus monkey (up to 3 months)
“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.”
Species: DART
Rat (EFD only); no dedicated fertility study (ICH S9, advanced cancer)
“A dedicated fertility study was not conducted with imlunestrant in accordance with ICH S9 guidance and the intended advanced cancer indication.”
Species: carcinogenicity
Tg rasH2 mouse (6-month), conducted to support possible other indications
“Nevertheless, a 6-month carcinogenicity study in transgenic rasH2 mouse was conducted to support possible extensions to other indications.”
Surrogate used in
No surrogate used; imlunestrant itself tested in rats and monkeys
“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.”
Genotox: Ames
Negative
“Imlunestrant was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.”
Genotox: in vitro mammalian
Positive: in vitro micronucleus in TK6 lymphoblastoid cells
“Imlunestrant produced chromosomal damage (increase in the percent micronuclei) in the in vitro micronucleus assay in lymphoblastoid TK6 cells”
Genotox: in vivo
Negative: rat bone marrow micronucleus and rat liver/duodenum comet assays up to 2000 mg/kg
“but it did not cause chromosomal damage in the rat bone marrow micronucleus test or DNA strand breaks in the rat liver and duodenum comet assays in vivo when administered up to 2000 mg/kg.”
Carcinogenicity model
Not required (ICH S9, advanced cancer); 6-month Tg rasH2 mouse study done for other indications
“According to the ICH S9 Guideline, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer. Nevertheless, a 6-month carcinogenicity study in transgenic rasH2 mouse was conducted to support possible extensions to other indications.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); studies for other indications ongoing at approval
“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer. Carcinogenicity studies have not been conducted to support the advanced cancer indication for imlunestrant but are ongoing to support other indications.”
hERG / QT
Up to 27.8% hERG inhibition at 1 μM; higher concentrations could not be tested
“In a GLP hERG patch clamp assay (190112.FMD), imlunestrant inhibited potassium current through the cardiac hERG channel by up to 27.8% at 1 μM. Higher concentrations of imlunestrant could not be tested due to practical limitations.”
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)
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: 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.”
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
“Immunogenicity The Applicant’s Position: Not applicable. The FDA’s Assessment: Not applicable.”
Label warnings
- Embryo-Fetal Toxicity
Embryo-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 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)
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week (6-month) rat oral study with 13-week (3-month) recovery; longest monkey study 3 months
“In a 6-month repeat-dose toxicity study, oral administration of imlunestrant to rats resulted in epithelial hyperplasia in the urinary bladder, granulosa cell hyperplasia in the ovary, and hyperplasia in the mammary gland at doses ≥ 10 mg/kg/day (≥ 4 times the human AUC at the recommended dose). These effects, except urinary bladder effects, were reversible after a 3-month recovery period.”
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.”
DART package
Species: DART
Rat (EFD only); no dedicated fertility study (ICH S9, advanced cancer)
“A dedicated fertility study was not conducted with imlunestrant in accordance with ICH S9 guidance and the intended advanced cancer indication.”
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.”
PPND / ePPND: when
Not conducted: PPND not required for an advanced cancer indication (ICH S9)
“No early embryonic development study, pre- and postnatal development study or juvenile toxicity study was conducted. This is in line with the recommendations for an indication falling under the ICH S9 Guideline and therefore agreed.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month), conducted to support possible other indications
“Nevertheless, a 6-month carcinogenicity study in transgenic rasH2 mouse was conducted to support possible extensions to other indications.”
Carcinogenicity model
Not required (ICH S9, advanced cancer); 6-month Tg rasH2 mouse study done for other indications
“According to the ICH S9 Guideline, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer. Nevertheless, a 6-month carcinogenicity study in transgenic rasH2 mouse was conducted to support possible extensions to other indications.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); studies for other indications ongoing at approval
“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer. Carcinogenicity studies have not been conducted to support the advanced cancer indication for imlunestrant but are ongoing to support other indications.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL margin: female reproductive tract effects in monkeys at ≥15 mg/kg/day (≥1x human AUC)
“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 (≥ 1 times the human AUC at the recommended dose).”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
ER+ breast cancer xenograft and PDX mouse models, including ESR1-Y537S mutant PDX
“Imlunestrant was well tolerated and induced significant tumor growth inhibition and tumor regressions in multiple ER+ breast cancer xenograft models, including an ESR1-Y537S mutant PDX model.”
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
EMA: xenograft primary pharmacology studies relevant for the indicated patient populations
“Cellular and murine xenograft studies were conducted in oestrogen receptor (ER)-positive breast cancer models, with or without oestrogen receptor gene 1 (ESR1) mutations, along with an evaluation of imlunestrant’s functional additivity or synergy with the CDK4/6 inhibitor abemaciclib. These primary pharmacology studies are, therefore, relevant for the indicated patient populations.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No fertility/early embryonic, pre- and postnatal development or juvenile toxicity studies
Why: ICH S9 recommendations for an advanced cancer indication · Within the guideline
“No early embryonic development study, pre- and postnatal development study or juvenile toxicity study was conducted. This is in line with the recommendations for an indication falling under the ICH S9 Guideline and therefore agreed.”
Safety marginVerdict not stated
No embryo-fetal NOAEL: embryo-fetal mortality in rats at the lowest dose, about 0.1 times human AUC
“Imlunestrant caused embryo-fetal mortality (increased resorption, reduced number of live fetuses) at ≥0.3 mg/kg/day, approximately 0.1 times the human AUC at the recommended dose.”
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