Arazlo (Page 3 of 5)

12.1 Mechanism of Action

Tazarotene is a retinoid prodrug which is converted to its active form, tazarotenic acid, the carboxylic acid of tazarotene, by deesterification. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ and RARγ, but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings for the treatment of acne vulgaris is unknown.

12.3 Pharmacokinetics

Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Tazarotenic acid is highly bound to plasma proteins (greater than 99%).

Systemic exposure following topical application of ARAZLO was evaluated in 28 subjects in an open-label, randomized, pharmacokinetic study. Subjects aged 9 years and older with moderate to severe acne applied approximately 4 grams of ARAZLO to the entire face (excluding eyes and lips), neck, upper chest, upper back and shoulders once daily for 14 Days.

The majority of collected samples had concentrations below the limit of quantification (LOQ) for tazarotene (0.005 ng/mL). The mean Cmax and mean AUC(0-t) values for tazarotene from quantifiable samples were 0.007 ng/mL and 0.164 ng•hr/mL on Day 14 to 15, respectively. The mean Cmax and AUC(0-t) of tazarotene in subjects aged 9 to less than 12 years was approximately 3.7 and 3.6 fold higher, respectively, compared to that observed in subjects 12 years and older.

Tazarotenic acid concentrations were measurable in the majority of samples following single and repeated topical administration of ARAZLO (LOQ = 0.005 ng/mL). The mean Cmax and AUC(0-t) values for tazarotenic acid from quantifiable samples were 0.365 ng/mL and 5.72 ng•hr/mL on Days 14 to 15, respectively. The mean Cmax and AUC(0-t) of tazarotenic acid in subjects aged 9 to less than 12 years was approximately 2.4 and 2.3 fold higher, respectively, compared to that observed in subjects 12 years and older.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from a shorter-term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in the rat equivalent to the MRHD (based on AUC comparison).

A long-term study with topical application of up to 0.1% of tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared to vehicle control animals. Tazarotenic acid systemic exposures at the highest dose was 7 times the MRHD (based on AUC comparison).

Tazarotene was non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in human lymphocytes. Tazarotene was non-mutagenic in CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in an in vivo mouse micronucleus test.

No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of a tazarotene gel formulation up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat at the highest dose was equivalent to the MRHD (based on AUC comparison).

No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of tazarotene up to 1 mg/kg/day which produced a systemic exposure 4 times the MRHD (based on AUC comparison).

No impairment of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses of tazarotene up to 2 mg/kg/day. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose which produced a systemic exposure 6 times the MRHD (based on AUC comparison).

14 CLINICAL STUDIES

The safety and efficacy of once daily use of ARAZLO for the treatment of acne vulgaris were assessed in two multicenter, randomized, double-blind clinical trials in subjects 9 years and older with facial acne vulgaris. Enrolled subjects had a score of moderate (3) or severe (4) on the Evaluator’s Global Severity Score (EGSS), 20 to 50 inflammatory lesions (papules, pustules, and nodules), 25 to 100 non-inflammatory lesions (open and closed comedones) and two or fewer facial nodules. The majority of subjects were White (74%) and female (66%). Approximately 22% were Hispanic/Latino and 42% were younger than 18 years of age. The efficacy endpoints of success on the EGSS, absolute change in noninflammatory lesion count, and absolute change in inflammatory lesion count were assessed at Week 12. Success on the EGSS was defined as at least a 2-grade improvement from Baseline and an EGSS score of clear (0) or almost clear (1). Table 3 lists the efficacy results for trials 1 (NCT03168321) and 2 (NCT03168334).

Table 3: Efficacy Results at Week 12

Trial 1

ARAZLO Lotion N=402

Vehicle N=411

Treatment Difference

(95% Confidence Interval)

EGSS

Clear or Almost Clear and

25.5%

13%

12.5% (7.1%, 17.9%)

2-Grade Reduction from Baseline

Non-Inflammatory Facial Lesions

Mean Absolute Reduction

21.0

16.4

4.5 (2.6, 6.4)

Mean Percent Reduction

51.4%

41.5%

Inflammatory Facial Lesions

Mean Absolute Reduction

15.6

12.4

3.3 (1.9, 4.7)

Mean Percent Reduction

55.5%

45.7%

Trial 2

ARAZLO Lotion N=397

Vehicle N=404

EGSS

Clear or Almost Clear and

2-Grade Reduction from Baseline

29.6%

17.3%

12.3% (6.5%, 18.1%)

Non-Inflammatory Facial Lesions

Mean Absolute Reduction

24.6

16.6

8.1 (5.9, 10.2)

Mean Percent Reduction

60%

41.6%

Inflammatory Facial Lesions

Mean Absolute Reduction

16.7

13.4

3.2 (1.9, 4.5)

Mean Percent Reduction

59.5%

49%

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