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”
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.”
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)
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: 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).”