Regulatory Decision Summary for Arazlo

Health Canada considers that the benefit-harm-uncertainty profile of Arazlo (tazarotene lotion, 0.045% w/w) is favorable for the topical treatment of acne vulgaris in patients 10 years of age and above.

The indication is supported by the results from two multicenter, randomized, double blind, and vehicle-controlled Phase 3 studies conducted in patients ≥10 years of age with a clinical diagnosis of moderate to severe acne vulgaris (i.e., Studies V01-123A-301 and V01-123A-302). The studies were identical in all aspects of study design, methodology, and data analysis, but were conducted in different study centers in the United States and with different subjects. Across both studies, a total of 1614 subjects were randomized, including 799 patients treated with Arazlo and 815 patients treated with Vehicle. The three coprimary efficacy endpoints were (i) success on the Evaluators Global Severity Score (EGSS), (ii) absolute change in noninflammatory lesion count, and (iii) absolute change in inflammatory lesion count. All primary efficacy endpoints were assessed at Week 12. Success on the EGSS was defined as a 2-grade improvement from baseline and an EGSS score of clear (0) or almost clear (1). A difference of ≥10% compared to Vehicle for all three coprimary efficacy endpoints was defined as clinically meaningful.

In both Phase 3 studies and in the integrated analysis, Arazlo showed statistically and clinically significantly superior results (statistically significant difference of ≥10%) for all three coprimary endpoints compared to Vehicle at Week 12. Specifically, a significantly higher proportion of patients achieved treatment success based on EGSS scores (Arazlo: 30.37%; Vehicle: 17.85%, results of the integrated analysis), a significantly reduced mean absolute change in noninflammatory lesions count (Arazlo: -23.1 lesions compared to baseline; Vehicle: -16.4), and a significantly reduced mean absolute change in inflammatory lesions count (Arazlo: -16.3; Vehicle: -13).

The proposed indication included patients <12 years of age, an age group for which the use of tazarotene has not been authorized in Canada. Therefore, Health Canada requested a post-hoc subgroup analysis be conducted for patients <12, 12 to <18, and ≥18 years of age. All three coprimary endpoints were achieved in patients 12 years and above; however, for the subgroup of patients 10 to <12 years of age, while a numerically greater effect was noted for Arazlo compared to the Vehicle, statistical significance was not achieved due to the small number of subjects enrolled in this age group (Arazlo: 14 patients <12 years of age across both Phase 3 studies, accounting for 1.8% of the studied population). However, the efficacy in adolescents could be extrapolated to preadolescents based on the principles of International Council on Harmonisation (ICH) Guideline E11, including that the pathophysiology and disease course of acne vulgaris is similar across these pediatric age groups and the drug’s mechanism of action is likely to be comparable across these pediatric age groups. Therefore, it is expected that the response to Arazlo Lotion in the subgroup of 10 to <12 years of age would be similar to the pediatric age cohort of 12 to <18 years.

Tazarotene has a long history of topical use and has a well-established safety profile for the treatment of acne vulgaris in patients 12 years and above. Arazlo was well-tolerated in the submitted studies. In the two Phase 3 trials, 799 were administered at least 1 dose of Arazlo; however, 779 had a safety assessment conducted post-baseline and were included in the safety dataset. The most commonly identified adverse events were application-site reactions, including pain, dryness, erythema, exfoliation, pruritus, and irritation. The studies additionally included active assessments of cutaneous safety and tolerability in these subjects that showed higher incidence and severity scores of erythema, scaling, burning, stinging, and itching in the Arazlo group compared to the Vehicle group. These adverse events were mild to moderate and are commonly reported adverse events with tazarotene and other topical acne drugs in the retinoid class. Although safety signals specific to the preadolescent age group were not identified in the submitted studies, absorption of tazarotene and systemic exposure were consistently higher in preadolescent patients compared to adolescent patients. Given the uncertainty regarding the safety of Arazlo in the preadolescent age group of 10 to <12 years due to small sample size, higher systemic exposures compared to adolescent and adult age groups, and established reproductive and developmental toxicity characteristics of retinoids, including tazarotene, Arazlo’s indication for preadolescents includes a recommendation to restrict the use of Arazlo to the face, which is expected to reduce systemic exposure in the preadolescent age group. Overall, the risks associated with Arazlo are considered manageable through the modified indication for the preadolescent age group and the inclusion of appropriate warnings and cautionary statements in the Product Monograph. 

Overall, the anticipated benefits of Arazlo are expected to outweigh its risks under the conditions of use recommended in the Arazlo (tazarotene lotion, 0.045% w/w) Product Monograph at this time.