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.”
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.”
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)
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: 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.”