Lifyorli
relacorilant
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“A series of general toxicology studies were completed with relacorilant, including a 28-day study in mice (Table 51), 2-week (Table 52) and 13-week GLP studies in rats (Table 6) and monkeys (Table 7, Table 53), a 26-week GLP study in rats (Table 8), and a 39-week GLP study in monkeys (Table 9).”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Once daily oral gavage administration of relacorilant to cynomolgus monkeys was well tolerated for 39 weeks at dose levels of 0, 3, 10, and 30 mg/kg/day.”
Species: general tox
Rat (13- and 26-week) and cynomolgus monkey (13- and 39-week); 28-day mouse study
“A series of general toxicology studies were completed with relacorilant, including a 28-day study in mice (Table 51), 2-week (Table 52) and 13-week GLP studies in rats (Table 6) and monkeys (Table 7, Table 53), a 26-week GLP study in rats (Table 8), and a 39-week GLP study in monkeys (Table 9).”
Species: DART
Rabbit and rat (EFD)
“oral administration of relacorilant to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortality and structural abnormalities at maternal doses of ≥ 10 mg/kg/day (0.6 times the human exposure based on area under the curve (AUC) at the recommended dose). Oral administration of relacorilant to pregnant rats during the period of organogenesis did not result in fetal malformations”
Species: carcinogenicity
Rat (104-week) and RasH2 mouse (26-week)
“A 26-week carcinogenicity study in RasH2 mice (Study 950-122) and a lifetime (up to 104 weeks) carcinogenicity study in Sprague Dawley rats (Study 950-118) were performed.”
Surrogate used in
No surrogate used; relacorilant itself tested (monkey used as dog showed only partial GR antagonism)
“Relacorilant showed partial agonism in dog hepatocytes, with a half maximal effective concentration (EC50) > 10 µM. For this reason, the dog was not suitable for toxicology studies, and cynomolgus monkeys were used instead.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“A series of general toxicology studies were completed with relacorilant, including a 28-day study in mice (Table 51), 2-week (Table 52) and 13-week GLP studies in rats (Table 6) and monkeys (Table 7, Table 53), a 26-week GLP study in rats (Table 8), and a 39-week GLP study in monkeys (Table 9).”
Pivotal GLP studies
13- and 26-week rat and 13- and 39-week monkey GLP studies
“A series of general toxicology studies were completed with relacorilant, including a 28-day study in mice (Table 51), 2-week (Table 52) and 13-week GLP studies in rats (Table 6) and monkeys (Table 7, Table 53), a 26-week GLP study in rats (Table 8), and a 39-week GLP study in monkeys (Table 9).”
Route in tox
Oral (gavage)
“Once daily oral gavage administration of relacorilant to cynomolgus monkeys was well tolerated for 39 weeks at dose levels of 0, 3, 10, and 30 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat micronucleus assays
“Relacorilant was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro human lymphocyte micronucleus assay, or an in vivo micronucleus assay in rats.”
Carcinogenicity
2-year rat and 26-week mouse: no drug-related neoplasms
“Per the review by Dr. Feleke Eshete in DPT-CHEN and discussion by the Executive Carcinogenicity Assessment Committee, there was no evidence of drug-related neoplasms in rats in the 2-year study or in mice in the 26-week study.”
Reproductive & developmental
Rabbit EFD: embryo-fetal mortality and structural abnormalities at ≥10 mg/kg/day (0.6x human AUC)
“In animal embryo-fetal development studies, oral administration of relacorilant to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortality and structural abnormalities at maternal doses of ≥ 10 mg/kg/day (0.6 times the human exposure based on area under the curve (AUC) at the recommended dose).”
Safety pharmacology
No CNS or respiratory effects in rats or cardiovascular effects in monkeys up to 200 mg/kg; no meaningful hERG inhibition
“Relacorilant showed no remarkable adverse central nervous system or respiratory effects in rats, or cardiovascular system effects in monkeys, following single oral doses of up to 200 mg/kg (highest dose tested). No clinically meaningful human Ether-à-go-go-Related Gene (hERG) inhibition was seen in vitro.”
Genotox: Ames
Negative
“Relacorilant was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro human lymphocyte micronucleus assay, or an in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
Negative in vitro human lymphocyte micronucleus assay
“Relacorilant was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro human lymphocyte micronucleus assay, or an in vivo micronucleus assay in rats.”
Genotox: in vivo
Negative rat micronucleus up to 250 mg/kg
“Relacorilant at doses up to and including 250 mg/kg was concluded to be negative in the in vivo micronucleus assay in rats.”
Carcinogenicity model
Rat 104-week (up to 1.3x males/0.7x females human AUC) and RasH2 mouse 26-week
“Carcinogenicity studies were conducted in rats over 104 weeks (≤ 10 mg/kg for males and ≤ 3 mg/kg for females; up to 1.3 and 0.7 times the human exposure at the recommended dose for males and females, respectively, based on AUC) and in RasH2 mice over 26 weeks (≤100 mg/kg).”
Carcinogenicity timing
2-year rat and 26-week mouse completed before the marketing application
“there was no evidence of drug-related neoplasms in rats in the 2-year study or in mice in the 26-week study.”
hERG / QT
26.5% hERG inhibition at 2.5 µM (highest soluble); free human Cmax >10-fold lower
“At the highest nominal concentration of relacorilant that was soluble (2.5 µM [1466 ng/mL]) the hERG current was inhibited by a mean of 26.5%. Plasma levels of free relacorilant in human at the maximum dose (150 mg) are expected to be < 10 ng/mL (after adjusting for > 99% protein binding), > 10-fold lower than the concentrations that impacted ERG currents.”
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 Lifyorli 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: 39-week monkey NOAEL 30 mg/kg/day; observed changes considered non-adverse (FDA multi-discipline review, p. 59)
NOAEL / key findings
39-week monkey NOAEL 30 mg/kg/day; observed changes considered non-adverse
“None of these changes were considered adverse. Therefore, the NOAEL was considered to be 30 mg/kg/day. The NOAEL was associated with a Week 39 relacorilant AUC0-24 of 22510.9 ng.h/mL and 22847.1 ng.h /mL respectively, in female and male monkeys.”
Risksopen answer page →
Immune & cytokine safety
Generalized lymphoid depletion contributed to deaths in 2-week rat studies at ≥200 mg/kg/day
“In the 2-week studies, mortality was noted following repeated doses ≥ 200 mg/kg/day in rats and doses ≥ 200/80 mg/kg/day in monkeys. In rats, the deaths were attributed to inappetence and generalized lymphoid depletion.”
Biodistribution & persistence
Crosses the blood-brain barrier in mice and rats
“Relacorilant crossed the blood-brain barrier in both mice and rats (Studies S-COR-101 and S-COR-065).”
Modality-specific risk
GR modulation and compensatory HPA-axis perturbation
“Furthermore, relacorilant produced primarily effects related to GR modulation and/or compensatory perturbations of the hypothalamic-pituitary-adrenal axis.”
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
- Neutropenia and Severe Infections
- Adrenal Insufficiency
- Exacerbation of Conditions Treated with Glucocorticoids
- Embryo-Fetal Toxicity
CytopeniasInfectionsNephrotoxicityMetabolic & 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 Lifyorli 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: 39-week monkey NOAEL 30 mg/kg/day; observed changes considered non-adverse (FDA multi-discipline review, p. 59)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (oral gavage); recovery phase not stated
“Once daily oral gavage administration of relacorilant to cynomolgus monkeys was well tolerated for 39 weeks at dose levels of 0, 3, 10, and 30 mg/kg/day.”
Pivotal GLP studies
13- and 26-week rat and 13- and 39-week monkey GLP studies
“A series of general toxicology studies were completed with relacorilant, including a 28-day study in mice (Table 51), 2-week (Table 52) and 13-week GLP studies in rats (Table 6) and monkeys (Table 7, Table 53), a 26-week GLP study in rats (Table 8), and a 39-week GLP study in monkeys (Table 9).”
DART package
Species: DART
Rabbit and rat (EFD)
“oral administration of relacorilant to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortality and structural abnormalities at maternal doses of ≥ 10 mg/kg/day (0.6 times the human exposure based on area under the curve (AUC) at the recommended dose). Oral administration of relacorilant to pregnant rats during the period of organogenesis did not result in fetal malformations”
Reproductive & developmental
Rabbit EFD: embryo-fetal mortality and structural abnormalities at ≥10 mg/kg/day (0.6x human AUC)
“In animal embryo-fetal development studies, oral administration of relacorilant to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortality and structural abnormalities at maternal doses of ≥ 10 mg/kg/day (0.6 times the human exposure based on area under the curve (AUC) at the recommended dose).”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre-/postnatal toxicity study in rats (Study 950-125, Table 57), relacorilant was administered to pregnant rats from GD 6 through lactation day (LD) 20 at doses of 0 (vehicle), 1, 2.5, or 10 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Rat (104-week) and RasH2 mouse (26-week)
“A 26-week carcinogenicity study in RasH2 mice (Study 950-122) and a lifetime (up to 104 weeks) carcinogenicity study in Sprague Dawley rats (Study 950-118) were performed.”
Carcinogenicity model
Rat 104-week (up to 1.3x males/0.7x females human AUC) and RasH2 mouse 26-week
“Carcinogenicity studies were conducted in rats over 104 weeks (≤ 10 mg/kg for males and ≤ 3 mg/kg for females; up to 1.3 and 0.7 times the human exposure at the recommended dose for males and females, respectively, based on AUC) and in RasH2 mice over 26 weeks (≤100 mg/kg).”
Carcinogenicity timing
2-year rat and 26-week mouse completed before the marketing application
“there was no evidence of drug-related neoplasms in rats in the 2-year study or in mice in the 26-week study.”
Safety marginopen answer page →
Safety margin at NOAEL
No repeat-dose margin stated; rabbit EFD skeletal variations at ≥1 mg/kg/day, below human AUC
“Additional adverse effects included skeletal variations of bipartite interparietal bone of the skull observed at doses ≥ 1 mg/kg/day (lower than the human exposure based on AUC at the recommended dose).”
NOAEL / key findings
39-week monkey NOAEL 30 mg/kg/day; observed changes considered non-adverse
“None of these changes were considered adverse. Therefore, the NOAEL was considered to be 30 mg/kg/day. The NOAEL was associated with a Week 39 relacorilant AUC0-24 of 22510.9 ng.h/mL and 22847.1 ng.h /mL respectively, in female and male monkeys.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenografts of human ovarian, endometrial and cervical cancer with relacorilant plus paclitaxel
“Antitumor activity was evaluated for relacorilant in combination with paclitaxel or paclitaxel alone in mouse xenograft studies with human ovarian (SK-OV-3), human endometrial (MFE-280, Ishikawa), and human cervical (HeLa) cancer cells.”
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
FDA: combination gave significantly higher antitumor activity than paclitaxel alone in ovarian, endometrial and cervical xenografts
“The combination of relacorilant and paclitaxel resulted in significantly higher antitumor activity than paclitaxel alone in mouse models with ovarian cancer cells, endometrial, and cervical cancer cells.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteAcceptedBeyond the letter
Predominant human metabolite CORT125295 absent in rodents; qualified by weight-of-evidence assessment instead of dedicated toxicity studies
Why: Structural similarity to parent, lower pharmacodynamic potency, similar target selectivity, non-mutagenic, hERG inhibition like parent · Weight of evidence · Pharmacology or kinetics
“A predominant metabolite, CORT125295, was identified in human plasma that was not present in rodent species. The Applicant provided a weight of evidence assessment for the safety of CORT125295.”
“FDA concluded that CORT125295 did not pose an additional safety risk based on its structural similarity to the parent compound, lower pharmacodynamic potency, similar target selectivity, non-mutagenicity, and hERG channel inhibition like the parent.”
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