Orserdu
elacestrant
Species
MonkeyRat
Longest study
39 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 toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”
Why that species
Monkey chosen as non-rodent because its reproductive system morphology, hormonal changes and menstrual cycle closely resemble humans
“The Applicant provided a justification for the use of non-human primates as non-rodent species, indicating that morphological and hormonal changes in the reproductive system and menstrual cycle phases of monkeys closely resemble those of humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”
Species: general tox
Rat (26-week) and cynomolgus monkey (39-week)
“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”
Species: DART
Rat (EFD only); fertility and pre/postnatal studies not conducted per ICH S9
“The Applicant assessed the effects of elacestrant on reproductive organs in the rat and monkey as part of the GLP-compliant repeat-dose toxicology studies and provided results from a GLP-compliant embryofetal development (EFD) study in rats.”
Species: carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with elacestrant in accordance with ICH S9 guidance”
Surrogate used in
No surrogate used; elacestrant tested directly
“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey daily oral gavage studies
“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”
Route in tox
Oral (daily gavage)
“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and in vivo rat bone marrow micronucleus assays
“In genetic toxicology studies, elacestrant was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or, clastogenic in either in vitro chromosome aberration assays or an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (ICH S9); benign granulosa cell tumors in female rats in 26-week study at ≥25 mg/kg/day
“Carcinogenicity studies were not conducted with elacestrant in accordance with ICH S9 guidance; however, of note, in the rat 26-week repeat dose toxicology study B-granulosa cell tumor was observed at ≥25 mg/kg/day”
Reproductive & developmental
Rat EFD (GD 6–17): embryolethal and teratogenic at ≤30 mg/kg/day
“Elacestrant was embryo lethal and teratogenic when administered to pregnant rats at ≤30 mg/kg via daily oral gavage during the period of organogenesis on gestational days 6 through 17 followed by cesarean section on gestational day 21.”
Safety pharmacology
hERG IC50 0.41 µM (~87% block at 1 µM); complete block of rabbit Purkinje fiber action potential at 10 µM
“Elacestrant blocked the hERG channel up to approximately 87% at 1 µM (IC50= 0.41 µM) and led to a complete block of the cardiac action potential of rabbit Purkinje fibers at 10 µM.”
Genotox: Ames
Negative
“In genetic toxicology studies, elacestrant was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or, clastogenic in either in vitro chromosome aberration assays or an in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
Negative: chromosome aberration in human lymphocytes
“Elacestrant was not mutagenic in bacterial reverse mutation (Ames) assays (Study 7801-100 and Study 15RAD251) and did not induce chromosomal aberrations in human lymphocytes (Study 7801-101 and Study 15RAD252).”
Genotox: in vivo
Negative rat bone marrow micronucleus
“Elacestrant was not aneugenic or clastogenic in an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (ICH S9); granulosa cell tumors seen in 26-week rat study
“Carcinogenicity studies were not conducted with elacestrant in accordance with ICH S9 guidance; however, of note, in the rat 26-week repeat dose toxicology study B-granulosa cell tumor was observed at ≥25 mg/kg/day”
Carcinogenicity timing
Not required; carcinogenicity studies not conducted per ICH S9 (advanced cancer)
“Carcinogenicity studies were not conducted with elacestrant in accordance with ICH S9 guidance”
hERG / QT
hERG IC50 187 ng/mL, ~69-fold above unbound monkey concentration at a dose without QT effects
“A comparison of in vitro hERG inhibition (IC50 187 ng/mL) and estimated unbound elacestrant concentration of 2.7 ng/mL in monkey plasma at 50 mg/kg (a dose that was shown to be devoid of any QT interval effects) showed an approximately 69-fold safety margin.”
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 Orserdu 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: Anti-estrogenic atrophy of uterus, vagina, cervix and mammary gland, ovarian follicular cysts, pituitary atrophy (rats) (EMA assessment report, p. 61)
NOAEL / key findings
Anti-estrogenic atrophy of uterus, vagina, cervix and mammary gland, ovarian follicular cysts, pituitary atrophy (rats)
“Female rats and monkeys displayed decreased weight and atrophy of the uterus, vagina, cervix, and mammary gland, increased weight of the ovaries correlating with the presence of follicular cysts, and atrophy of the pituitary gland (only in rats).”
Risksopen answer page →
Immune & cytokine safety
Macrophage and neutrophilic infiltrates in mesenteric lymph node, lung and intestines of rats and monkeys
“Histopathology changes in rats and monkeys, other than those of the male and female reproductive organs (discussed below under fertility studies), were generally observations of increase in macrophage and/or neutrophilic infiltrates in mesenteric lymph node, lung, small and large intestines”
Biodistribution & persistence
Widespread tissue distribution in rats including ocular melanin (uveal tract); not detected in brain, lens, spinal cord or testes
“Following a single oral administration of elacestrant in rats, radiolabeled elacestrant was detected in the majority of tissues, including ocular melanin containing tissues (eye uveal tract of Long Evans rats), but not in the brain, eye lens, spinal cord, and testes”
Modality-specific risk
Embryofetal toxicity: embryo-fetal mortality in rats at ~0.1 times the human AUC
“(reduced body weight gain, low food consumption, red vulvar discharge) and embryo-fetal mortality (increased resorptions, post-implantation loss, and reduced number of live fetuses) were noted at ≥3 mg/kg/day (approximately 0.1 times the human AUC at the recommended dose).”
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 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.
Label warnings
- Dyslipidemia
- Embryo-Fetal Toxicity
Metabolic & endocrineEmbryo-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 Orserdu 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: Anti-estrogenic atrophy of uterus, vagina, cervix and mammary gland, ovarian follicular cysts, pituitary atrophy (rats) (EMA assessment report, p. 61)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey oral gavage study with 4-week recovery
“Study/ID: 39-Week Toxicity and Toxicokinetic Oral Gavage Study with RAD1901 in Cynomolgus Monkeys with a 4-Week Recovery Phase/15RAD216”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey daily oral gavage studies
“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”
DART package
Species: DART
Rat (EFD only); fertility and pre/postnatal studies not conducted per ICH S9
“The Applicant assessed the effects of elacestrant on reproductive organs in the rat and monkey as part of the GLP-compliant repeat-dose toxicology studies and provided results from a GLP-compliant embryofetal development (EFD) study in rats.”
Reproductive & developmental
Rat EFD (GD 6–17): embryolethal and teratogenic at ≤30 mg/kg/day
“Elacestrant was embryo lethal and teratogenic when administered to pregnant rats at ≤30 mg/kg via daily oral gavage during the period of organogenesis on gestational days 6 through 17 followed by cesarean section on gestational day 21.”
PPND / ePPND: when
PPND not conducted; not needed for advanced cancer under ICH S9
“Dedicated fertility, early embryonic development, pre- and postnatal development studies were not conducted with elacestrant in accordance with ICH S9 guidance and the intended indication for the treatment of patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with elacestrant in accordance with ICH S9 guidance”
Carcinogenicity model
Not conducted (ICH S9); granulosa cell tumors seen in 26-week rat study
“Carcinogenicity studies were not conducted with elacestrant in accordance with ICH S9 guidance; however, of note, in the rat 26-week repeat dose toxicology study B-granulosa cell tumor was observed at ≥25 mg/kg/day”
Carcinogenicity timing
Not required; carcinogenicity studies not conducted per ICH S9 (advanced cancer)
“Carcinogenicity studies were not conducted with elacestrant in accordance with ICH S9 guidance”
Safety marginopen answer page →
Safety margin at NOAEL
No repeat-dose NOAEL established; rat EFD maternal toxicity and embryo-fetal mortality at ~0.1x human AUC
“(reduced body weight gain, low food consumption, red vulvar discharge) and embryo-fetal mortality (increased resorptions, post-implantation loss, and reduced number of live fetuses) were noted at ≥3 mg/kg/day (approximately 0.1 times the human AUC at the recommended dose).”
NOAEL / key findings
Anti-estrogenic atrophy of uterus, vagina, cervix and mammary gland, ovarian follicular cysts, pituitary atrophy (rats)
“Female rats and monkeys displayed decreased weight and atrophy of the uterus, vagina, cervix, and mammary gland, increased weight of the ovaries correlating with the presence of follicular cysts, and atrophy of the pituitary gland (only in rats).”
Efficacy evidenceopen answer page →
Efficacy evidence
ER+ breast cancer xenograft and patient-derived xenograft mouse models (≥96% TGI at ≥30 mg/kg/day)
“In in vivo ER+/PR+/HER2- xenograft and ER+ patient derived xenograft (PDX) breast cancer models, elacestrant led to ≥96% tumor growth inhibition (TGI) at ≥30 mg/kg/day.”
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 data are proof of concept only; predictive value of in vivo models for patient efficacy is limited
“Thus, the predictive value of the in vivo models for the efficacy of elacestrant in (specific) patient (populations) is limited.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin for rat embryo-fetal toxicity: maternal toxicity and embryo-fetal mortality at about 0.1 times human AUC
“(reduced body weight gain, low food consumption, red vulvar discharge) and embryo-fetal mortality (increased resorptions, post-implantation loss, and reduced number of live fetuses) were noted at ≥3 mg/kg/day (approximately 0.1 times the human AUC at the recommended dose).”
Safety marginVerdict not stated
Gastrointestinal findings in the 39-week monkey study at about 70% of human exposure (no margin)
“In monkeys this effect occurred at a level of systemic exposure of about 70% of the human exposure. (See SmPC section 5.3).”
OtherVerdict not stated
Early toxicity studies conducted in female animals only; later studies included both sexes
“Initial studies were only performed in female animals, but later studies were conducted in both sexes.”
Similar precedents
InluriyoSmall molecules · imlunestrant · Estrogen receptor (SERD)Monkey + rodent · 26 wkVeppanuSmall molecules · vepdegestrant · Estrogen receptor (PROTAC degrader)Rodent + dog or minipig · 39 wkNextstellisSmall molecules · drospirenone and estetrol · Estrogen / progestin receptorsMonkey + rodent · 39 wkAvmapki Fakzynja Co-packSmall molecules · avutometinib and defactinib · RAF/MEK clamp; FAKMonkey + rodent · 13 wkInqoviSmall molecules · decitabine and cedazuridine · DNMT (decitabine); cytidine deaminase (cedazuridine)Monkey + rodent · 13 wkKoselugoSmall molecules · selumetinib · MEK1/2Monkey + rodent · 26 wk