Winlevi
clascoterone
Species
RatPig
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 minipig
“Regarding clascoterone, the GLP pivotal repeat-doses toxicity studies were performed in two species, in rats and minipigs.”
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
“In a pivotal 26-week subcutaneous repeat dose toxicity study in rats, clascoterone (doses: 0, 0.1 mg/kg/day, 0.5 mg/kg/day, and 2.5 mg/kg/day) was well-tolerated; no clascoterone-related adverse effects were noted.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dermal minipig)
“In a pivotal 39-week dermal repeat dose toxicity study in minipigs, clascoterone cream (concentrations: 0% [untreated], 0% [vehicle], 1%, 2.5%, and 5% applied to ~10% body surface area (BSA);”
Pivotal GLP studies
26-week subcutaneous rat and 39-week dermal minipig studies
“Subcutaneous repeat dose toxicity studies in rats (up to 26 weeks in duration); dermal repeat dose toxicity studies in minipigs (up to 39 weeks in duration)”
Route in tox
Subcutaneous (rat) and dermal (minipig)
“Subcutaneous repeat dose toxicity studies in rats (up to 26 weeks in duration); dermal repeat dose toxicity studies in minipigs (up to 39 weeks in duration)”
Skipped studiesopen answer page →
Genotoxicity
No clear genotoxic potential; negative Ames and in vitro chromosome aberration assays
“Clascoterone did not display clear genotoxic potential in a standard battery of genetic toxicity studies. Clascoterone was not mutagenic in an in vitro reverse bacterial mutation assay or clastogenic in an in vitro chromosome aberration assay.”
Carcinogenicity
2-year topical rat study (0.1-5% cream): not carcinogenic
“Clascoterone cream (0.1%, 1%, or 5%) was not carcinogenic after daily topical administration in a 2-year carcinogenicity study in rats.”
Reproductive & developmental
Rat EFD: malformations at all doses; no developmental NOAEL
“a developmental NOAEL could not be determined because clascoterone-related malformations were noted in three fetuses at the low dose (LD) and 1 fetus each at the mid dose (MD) and HD.”
Safety pharmacology
Low-potency hERG inhibition (40% at 10 uM)
“In a pilot hERG assay, clascoterone produced low potency dose-related inhibition of the hERG potassium current (up to 40% inhibition at the highest concentration evaluated [10μM])”
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 Winlevi 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: 39-week minipig NOAEL 5% cream; day-272 AUC 269-401 ng·h/mL (FDA multi-discipline review, p. 35)
NOAEL / key findings
39-week minipig NOAEL 5% cream; day-272 AUC 269-401 ng·h/mL
“The NOAEL in both sexes was 5% cream, which corresponds to day 272 AUC0-24 and Cmax of 269 ng·hr/mL and 16.8 ng/mL, respectively, in females, and 401 ng·hr/mL and 30.1 ng/mL, respectively, in males.”
Risksopen answer page →
Immune & cytokine safety
Lymphocyte decreases and lymphoid organ atrophy attributed to weak glucocorticoid activity
“The changes observed in the white blood cells population, in the adrenals and in the lymphoid organs (spleen, thymus) were probably related to the weak glucocorticoid activity of the clascoterone.”
Biodistribution & persistence
Significant accumulation on repeat dosing (AUC ratio 6.38-20.3 in 9-month dermal minipig study)
“After repeated administrations in some toxicity studies in rats and in minipigs, a significant accumulation was observed (e.g. in 9 months dermal in minipigs, the ratio of AUC ranged from 6.38 to 20.3), varying in extent depending on the doses and treatment duration.”
Modality-specific risk
Adrenal cortical atrophy, not fully reversible in males
“At the MD and HD, adrenal gland weight decreased in both sexes, corresponding with the microscopic finding of cortical atrophy; these findings were fully reversible in females but not males”