Inluriyo (imlunestrant): genotox, carcinogenicity and repro: done or skipped?

Precedia/Small molecules/Inluriyo/Skipped studies

Inluriyo: genotox, carcinogenicity and repro: done or skipped?

imlunestrant · Estrogen receptor (SERD)

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.”

✓ VerifiedFDA multi-discipline review, p. 70Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 70Source ↗

Instead of carcinogenicity

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.

Instead of genotoxicity

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.

DRG histopathology

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.

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.”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 46Source ↗

Genotox: Ames

Negative

“Imlunestrant was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

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”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

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.”

✓ VerifiedEMA assessment report, p. 36Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 70Source ↗

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.”

✓ VerifiedEMA assessment report, p. 25Source ↗

Summary across all 211 small molecules →

Inluriyo: genotox, carcinogenicity and repro: done or skipped?

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