13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Clascoterone cream (0.1%, 1%, or 5%) was not carcinogenic after daily topical administration in a 2-year carcinogenicity study in rats. An increased incidence of the non-neoplastic finding of atrophy of the skin and subcutis at the application site was reported in males and females treated with 1% and 5% clascoterone cream.

Clascoterone was not mutagenic in the Ames reverse mutation assay and was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay. In rats, clascoterone administered via subcutaneous injection did not induce micronuclei in the bone marrow at 500 or 1000 mg/kg but a slight increase in micronuclei occurred in 2 of 5 rats at 2000 mg/kg. The response was considered equivocal. Overall, the weight of evidence indicates that clascoterone does not represent a genotoxic risk.

In a fertility and early embryonic development study in rats, clascoterone was administered subcutaneously at doses of 0.5, 2.5, or 12.5 mg/kg/day from 2 – 4 weeks before mating through mating. Clascoterone increased pre-implantation loss at 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). Clascoterone had no effects on mating or fertility in rats at doses up to 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). No effects were noted on development at doses up to 2.5 mg/kg/day (33 times the MRHD based on AUC comparison).

14 CLINICAL STUDIES

The safety and efficacy of WINLEVI cream 1% applied twice daily for 12 weeks for the treatment of acne vulgaris were assessed in two identically-designed, multicenter, randomized, double-blind, vehicle-controlled clinical trials (Trial 1 [NCT02608450] and Trial 2 [NCT02608476]) enrolling 1440 subjects with facial acne vulgaris. The trials enrolled subjects 9 years or older with Investigator's Global Assessment (IGA) of moderate or severe facial acne vulgaris (score of 3 or 4), 30 to 75 inflammatory lesions (papules, pustules and nodules), and 30 to 100 non-inflammatory lesions (open and closed comedones).

A total of 1421 subjects 12 years and older with facial acne vulgaris were enrolled. Of these subjects, 641 (45%) were 12 to 17 years of age, and 780 (55%) were 18 years of age or older. In addition, 62% of the subjects were female, and 91% were Caucasian. At baseline, subjects had a mean inflammatory lesion count of 42.4 and a mean non-inflammatory lesion count of 61.4. Additionally, approximately 83% of subjects had an IGA score of 3 ("moderate").

Efficacy was assessed at Week 12 by the proportion of subjects in each treatment group with at least a 2-point reduction in IGA compared to baseline and an IGA score of 0 (clear) or 1 (almost clear), absolute change and percent change from baseline in non-inflammatory and inflammatory lesions. The IGA success rate and mean absolute and percent reduction from baseline in acne lesion counts after 12 weeks of treatment for subjects 12 years of age and older are presented in the following table.

Table 2. Clinical Efficacy of WINLEVI Cream 1% in Subjects with Acne Vulgaris at Week 12

	Trial 1	Trial 2
	WINLEVI Cream 1% N=342	Vehicle Cream N=350	WINLEVI Cream 1% N=367	Vehicle Cream N=362
IGA Successa	18.8%	8.7%	20.9%	6.6%
Difference from Vehicle (95% CI)	10.1% (4.1%, 16.0%)	14.3% (8.9%, 19.7%)
Non-inflammatory Lesions
Mean Absolute Reduction	20.4	13.0	19.5	10.8
Difference from Vehicle (95% CI)	7.3 (3.5, 11.1)	8.7 (4.5, 12.4)
Mean Percent Reduction	32.6%	21.8%	29.6%	15.7%
Difference from Vehicle (95% CI)	10.8% (3.9%, 17.6%)	13.8% (7.5%, 20.1%)
Inflammatory Lesions
Mean Absolute Reduction	19.3	15.4	20.1	12.6
Difference from Vehicle (95% CI)	3.9 (1.3, 6.5)	7.5 (5.2, 9.9)
Mean Percent Reduction	44.6%	36.3%	47.1%	29.7%
Difference from Vehicle (95% CI)	8.3% (2.2%, 14.4%)	17.5% (11.8%, 23.1%)
aInvestigator Global Assessment (IGA) success was defined as at least a 2-point reduction in IGA compared to baseline and an IGA score of 0 (clear) or 1 (almost clear).

16 HOW SUPPLIED/STORAGE AND HANDLING

WINLEVI cream 1% is supplied in an epoxy-lined aluminum blind-end tube with a polypropylene cap closure:

NDC 47335-994-36

60-gram tube

Prior to Dispensing: Store the product in a refrigerator between 36°F and 46°F (2°C and 8°C). Do not freeze.

Dispensing Instructions for the Pharmacist: Direct the patient to store the product while in use at room temperature, between 68°F and 77°F (20°C to 25°C). Do not freeze. Discard the unused product 180 days after the date of dispensing or 1 month after first opening, whichever is sooner.