Regulatory Decision Summary for Eucrisa
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
The overall purpose of this New Drug Submission (NDS) was to seek regulatory approval of Eucrisa (crisaborole ointment, 2%) for topical treatment of mild to moderate atopic dermatitis (AD) in patients 2 years of age and older.
The efficacy and safety of eucrisa (crisaborole ointment, 2 %) for the proposed indication was evaluated in two pivotal phase 3 trials and one long-term safety trial (48 weeks).
Why was the decision issued?
The efficacy and safety of Eucrisa (crisaborole ointment, 2 %) for the proposed indication was evaluated in two pivotal phase 3 trials and one long-term safety trial (48 weeks). Pivotal phase 3 trials (AN2728-AD-301 and AN2728-AD-302) were multicenter, randomized, double-blind, parallel-group, vehicle-controlled clinical studies with identical study design. Patients with mild to moderate atopic dermatitis were randomized 2:1 to receive Eucrisa or vehicle applied twice daily for 28 days. The primary efficacy endpoint was the proportion of patients at Day 29 who achieved success, defined as an Investigators Static Global Assessment (ISGA) grade of Clear (score of 0) or Almost Clear (score of 1) with a 2-grade or greater improvement from baseline, comparing Eucrisa-treated patients to vehicle-treated patients. The secondary efficacy endpoints were the proportion of patients at Day 29 with ISGA grade of Clear (score of 0) or Almost Clear (score of 1), and the time to success in ISGA.
A total of 1,522 patients 2 to 79 years of age were enrolled in the pivotal trials. The mean age was 12.3 years in the Eucrisa group and 12.1 years in the vehicle group. About 62% of patients in both treatment groups were 2 to 11 years of age and 31-37% of patients were 2 to 6 years of age. At baseline, 38.5% of the patients had an ISGA score of 2 (mild), and 61.5% had an ISGA score of 3 (moderate), in the overall assessment of atopic dermatitis (erythema, induration/papulation, and oozing/crusting) on a severity scale of 0 to 4. The mean treatable percent body surface area at baseline was 18% (range between 5% and 95%). Overall, demographic characteristics and baseline disease characteristics were balanced between treatment groups.
The results of the primary efficacy endpoint showed that patients treated with Eucrisa (crisaborole ointment, 2 %) had a statistically significant higher rate (32.8% and 31.4%) of success in ISGA at Day 29 when compared with those treated with Vehicle (25.4% and 18.0%) in both pivotal trials, respectively. Similarly, the results of the secondary efficacy endpoints showed that patients treated with Eucrisa (crisaborole ointment, 2 %) had a statistically significant higher rate (51.7% and 48.5%) of Clear or Almost Clear ISGA ratings at Day 29 when compared with those treated with Vehicle (40.6% and 29.7%) in both pivotal trials, respectively. The time to success in ISGA was also statistically significantly earlier in Eucrisa group than in the vehicle group in both trials.
In both pivotal trials, the duration of randomized treatment period was 4 weeks and the study population included patients 2 years of age and older with mild to moderate AD. Therefore, efficacy of Eucrisa in patients with severe AD and in pediatric patients under 2 years of age, and efficacy of Eucrisa beyond 4 weeks of treatment have not been well established.
The most common drug-related adverse events reported in pivotal trials have been application site pain. Based on the pooled data, application site pain was reported in 4.4% of patients in the Eucrisa group and 1.2% of patients in the vehicle group. Application site pain was reported in a greater proportion of Eucrisa-treated patients than vehicle-treated patients across all 3 age groups (2-11, 12-17, and ≥18 years). No patients experienced a serious adverse event (SAE) due to application site pain. Less common (<1%) adverse reactions in patients treated with Eucrisa included application site reactions (including contact dermatitis and pruritus) and flare of atopic dermatitis.
In an open-label long-term safety study, 517 patients 2 to 72 years of age (including 454 patients 2 to 17 years of age), who had completed one of the Phase 3 studies without safety issues were treated with Eucrisa twice daily intermittently for up to 48 weeks in 28 day on-treatment or off-treatment cycles. The most frequently reported adverse events in the long-term safety study included atopic dermatitis, application site pain, and application site infection.
The pivotal trials for Eucrisa were 4 weeks in treatment duration. Although the long-term safety trial was 48 weeks, patients were not treated for 48 weeks continuously; instead, they were treated with Eucrisa twice daily intermittently in 28 day on-treatment or off-treatment cycles. Therefore long-term safety data of Eucrisa from clinical trials was not optimal. Safety data from post-marketing surveillance and post-marketing clinical studies are warranted to further define the long-term safety profile of Eucrisa. It is also unknown as to whether Eucrisa is irritating to sensitive skin areas (e.g. head, face, neck, eyelid and intertriginous) among patients with AD. Risk minimization measures were adequately described in the Product Monograph (PM) of Eucrisa.
In conclusion, the totality of evidence submitted in this NDS supports the efficacy and safety of Eucrisa (crisaborole ointment, 2 %) for the recommended indication/clinical use and dosage administration. The benefit-risk profile of Eucrisa (crisaborole ointment, 2 %) is considered favorable.
For more information on Health Canadas decision, please view the Summary Basis of Decision.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.