AKLIEF (Page 3 of 4)

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Trifarotene was not carcinogenic when topically applied to mice daily for up to 24 months in the vehicle of the product (AKLIEF Cream) at concentrations of 0.0005% or 0.001% w/w. The systemic exposures at the highest doses evaluated in mice were approximately 82 (males) and 99 (females) times higher than the human exposure at the MRHD of AKLIEF Cream.
Trifarotene was not carcinogenic when administered orally to rats daily for up to 24 months at doses up to 0.75 mg/kg/day in males and 0.2 mg/kg/day in females. The systemic exposures at the highest doses evaluated in rats were approximately 645 (males) and 1642 (females) times higher than the human exposure at the MRHD of AKLIEF Cream.

Trifarotene was negative in an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in primary human lymphocytes, an in vitro mouse lymphoma assay with L5178Y/TK+/- cells, and an in vivo micronucleus assay in rats.
Trifarotene was assessed for effects on fertility or general reproductive function in rats. Males received trifarotene via oral gavage for 4 weeks prior to mating, during mating, and up to scheduled termination (approximately 6 weeks in total), and females were treated via oral gavage for 2 weeks prior to mating through Day 7 of gestation. No adverse effects on fertility or reproductive parameters, including sperm motility and concentration, were observed at the highest doses evaluated, which resulted in systemic exposures approximately 1755 (males) and 1726 (females) times higher than the human exposure at the MRHD of AKLIEF Cream.

14 CLINICAL STUDIES

AKLIEF Cream applied once daily in the evening was evaluated in the treatment of moderate facial and truncal acne vulgaris in two randomized, multicenter, parallel group, double-blind, vehicle-controlled trials of identical design, Study 1 (NCT02566369) and Study 2 (NCT02556788). The trials were conducted in a total of 2420 subjects aged 9 years and older, who were treated for up to 12 weeks with either AKLIEF Cream (1214 subjects) or vehicle cream (1206 subjects). Subjects were encouraged to use a moisturizer as desired, while allowing an interval of approximately 1 hour before or after the study treatment application.
Acne severity was evaluated using a 5-point Investigator’s Global Assessment (IGA) scale for the face and a 5-point Physician’s Global Assessment (PGA) scale for the trunk with moderate acne vulgaris defined as a score of 3. Overall, 87% of subjects were Caucasian and 55% were female. Thirty-four (1.4%) subjects were 9 to 11 years of age, 1128 (47%) subjects were 12 to 17 years of age, and 1258 (52%) subjects were 18 years and older. All subjects had moderate acne vulgaris on the face and 99% of subjects had moderate acne vulgaris on the trunk. At baseline, subjects had between 7 and 200 (average 36) inflammatory lesions on the face and between 0 and 220 (average 38) on the trunk. Additionally, subjects had 21 to 305 (average 52) non-inflammatory lesions on the face and 0 to 260 (average 46) on the trunk.
Success on the IGA/PGA scale was defined as achieving a score of 0 (clear) or 1 (almost clear) and at least a 2-grade improvement from baseline. The co-primary endpoints (evaluated on the face) were the percentage of subjects achieving success on the IGA scale, the mean absolute change in facial inflammatory lesion count from baseline, and the mean absolute change in facial non-inflammatory lesion count from baseline, all evaluated at Week 12. The co-secondary endpoints (evaluated on the trunk) were the percentage of subjects achieving success on the PGA scale, the mean absolute change in truncal inflammatory lesion count from baseline, and the mean absolute change in truncal non-inflammatory lesion count from baseline, all evaluated at Week 12. Efficacy results for acne on the face and trunk after 12 weeks of treatment are presented in Tables 3 and 4 respectively.

Table 3. Acne of the Face Efficacy Results at Week 12 (Intent-to-Treat; Multiple Imputation)
*
Means presented in table are Least Square (LS) means
Study 1 Study 2
AKLIEF Cream Vehicle Cream AKLIEF Cream Vehicle Cream
(N=612) (N=596) (N=602) (N=610)
IGA Success At least a 2-grade improvement and “Clear” (0) or”Almost Clear” (1) 29.4% 19.5% 42.3% 25.7%
Inflammatory Lesions Mean * Absolute (Percent) Change from Baseline -19.0 (-54.4%) -15.4 (-44.8%) -24.2 (-66.2%) -18.7 (-51.2%)
Non-inflammatory Lesions Mean * Absolute (Percent) Change from Baseline -25.0 (-49.7%) -17.9 (-35.7%) -30.1 (-57.7%) -21.6 (-43.9%)
Table 4. Acne of the Trunk Efficacy Results at Week 12 (Intent-to-Teat on the Trunk; Multiple Imputation)
*
Means presented in table are Least Square (LS) means
Study 1 Study 2
AKLIEF Cream Vehicle Cream AKLIEF Cream Vehicle Cream
(N=600) (N=585) (N=598) (N=609)
PGA Success At least a 2-grade improvement and “Clear” (0) or “Almost Clear” (1) 35.7% 25.0% 42.6% 29.9%
Inflammatory Lesions Mean * Absolute (Percent) Change from Baseline -21.4 (-57.4%) -18.8 (-50.0%) -25.5 (-65.4%) -19.8 (-51.1%)
Non-inflammatory Lesions Mean * Absolute (Percent) Change from Baseline -21.9 (-49.1%) -17.8 (-40.3%) -25.9 (-55.2%) -20.8 (-45.1%)

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