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.”
Species: general tox
Rat (subcutaneous, up to 26 weeks) and minipig (dermal, up to 39 weeks)
“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)”
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“a fertility and early embryonic development study in rats; embryofetal development studies in rats and rabbits”
Species: carcinogenicity
Rat only (2-year dermal)
“a 2-year dermal carcinogenicity study in rats”
Surrogate used in
No surrogate used; clascoterone tested directly in rats and minipigs
“Regarding clascoterone, the GLP pivotal repeat-doses toxicity studies were performed in two species, in rats and minipigs.”
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])”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
In vitro micronucleus test: equivocal
“On the basis of available in vitro studies, clascoterone can be considered negative in the prokaryotic cell gene mutation assay, and equivocal in in vitro the micronucleus test.”
Genotox: in vivo
Rat bone marrow micronucleus (single SC dose): slight increase at 2000 mg/kg only; considered equivocal
“In a micronucleus assay in rats, a single subcutaneous dose of clascoterone produced a slight, statistically significant increase in bone marrow micronuclei at the high dose (2000 mg/kg), but not lower doses (500 mg/kg and 1000 mg/kg); this result was considered equivocal”
Carcinogenicity model
2-year dermal rat study (0.1%, 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.”
Carcinogenicity timing
2-year dermal rat study completed and submitted with the marketing application
“Clascoterone cream (0.1%, 1%, or 5%) was not carcinogenic after daily topical administration in a 2-year carcinogenicity study in rats.”
hERG / QT
Low-potency hERG inhibitor; highest tested concentration 1500x the highest clinical plasma level (7.65 ng/mL); dog in vivo study negative
“The safety pharmacology studies reported that clascoterone can be considered a low-potency hERG-channel inhibitor, but the highest concentration tested is 1500 times higher than the highest plasma concentration measured in the clinical studies (7.65 ng/mL). The in vivo study conducted in dogs at a maximal dose of 250 mg/kg was negative.”
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”
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
- Local Skin Reactions
- Hypothalamic-pituitary-adrenal (HPA) Axis Suppression
Skin reactionsNephrotoxicityMetabolic & endocrine
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Europe: single ascending dose in 24 healthy volunteers
“CB-03-01 1% cream had been assessed in four good clinical practice-compliant clinical studies conducted in Europe involving 156 subjects (106 subjects exposed to CB-03-01 1% cream): 1) A phase 1 randomized, double-blind, vehicle-controlled, single ascending dose, safety/tolerability and pharmacokinetics (PK) study in 24 healthy volunteers,”
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) dermal minipig with 1-month recovery
“CB-03-01: A 9-Month Dermal Toxicity Study in Gottingen Minipigs With a 1-Month Recovery/CB-03-01/31”
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)”
DART package
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“a fertility and early embryonic development study in rats; embryofetal development studies in rats and rabbits”
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.”
PPND / ePPND: when
PPND in rat (subcutaneous) completed and submitted with the marketing application
“In a pre- and postnatal development study in rats, subcutaneous clascoterone (doses: 0, 0.5, 2.5, and 12.5 mg/kg/day) was well-tolerated; no clascoterone-related adverse effects were noted in F0 dams or F1 offspring (NOAEL: 12.5 mg/kg/day).”
Carcinogenicity
Species: carcinogenicity
Rat only (2-year dermal)
“a 2-year dermal carcinogenicity study in rats”
Carcinogenicity model
2-year dermal rat study (0.1%, 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.”
Carcinogenicity timing
2-year dermal rat study completed and submitted with the marketing application
“Clascoterone cream (0.1%, 1%, or 5%) was not carcinogenic after daily topical administration in a 2-year carcinogenicity study in rats.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL margin 4.6x (26-week SC rat) and 7x (39-week dermal minipig) vs clinical systemic exposure
“The safety margin provided in this file, were 1.8 and 4.6 compared to systemic exposure at NOAEL for 13-week toxicity SC study and for 26-week SC toxicity study in rats, respectively. Regarding the 26-week dermal toxicity study in minipigs, the safety margin was 4.9. The safety margins were 8 for the dermal 13-week toxicity study in rats and 7 for dermal 39-week toxicity study in minipigs.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Golden Syrian hamster flank organ (testosterone-induced) model with topical clascoterone
“In vivo, its efficacy was shown in the hamster flank organ model, where topical application reduced testosterone-induced enlargement without systemic effects.”
Why that model
Hamster flank organ model closely replicates the pathogenic mechanism of acne (sebum production, sebocyte proliferation)
“The Golden Syrian Hamster animal model has been extensively used to evaluate anti-seborrheic mechanisms through modulation of sebum production and sebocyte proliferation; this animal model closely replicates the pathogenic mechanism involved in acne.”
Reviewer's view of the efficacy data
EMA: hamster flank organ acne model acceptable, as it contains clusters of large sebaceous glands
“The hamster flank organ acne vulgaris model had been chosen which is acceptable as it composed of clusters of large sebaceous glands.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No developmental NOAEL in the rat embryo-fetal study: malformations at all doses
“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.”
Juvenile toxVerdict not stated
No juvenile toxicity or phototoxicity studies
“Where specific studies were not conducted as part of the nonclinical development program (e.g., juvenile toxicity and phototoxicity studies), this has been discussed.”
Safety pharmacologyVerdict not stated
No respiratory safety pharmacology study; lungs assessed in repeat-dose toxicity studies
Why: No respiratory effects or lung histopathology in repeat-dose toxicity studies
“A respiratory safety pharmacology study was not conducted. However, no clascoterone-related adverse respiratory effects or histopathological changes to the lungs were noted in repeat dose toxicity studies in nonclinical species.”
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