Regulatory Decision Summary for Aklief

The purpose of this New Drug Submission (NDS) was to seek market authorization of Aklief (Trifarotene, 50 mcg/g) topical cream for the topical treatment of acne vulgaris of the face and/or trunk in patients 12 years of age and older.

Trifarotene (Aklief), a new chemical entity, is a potent retinoid acid receptor gamma (RARγ) agonist, with no Retinoid X Receptor (RXR) activity.

The benefit of trifarotene 50 mcg/g cream was established in the well-designed phase 3 program. In the two 12 week multicenter, randomized, vehicle-controlled pivotal phase 3 studies (#18251, #18252), all three co-primary facial (Investigators Global Assessment (IGA) success, absolute inflammatory, and non-inflammatory lesion counts) and all three co-secondary truncal (Physicians Global Assessment (PGA) success, absolute inflammatory, and non-inflammatory lesion counts) endpoints were met with high statistical significance (p<0.001) when compared with vehicle cream in the patient population of ≥12 years of age.

Study 18251 recorded differences in facial (IGA) and truncal (PGA) treatment success of trifarotene 50 mcg/g cream compared with vehicle cream in 9.8% and 10.7% of subjects, respectively. Study 18252 recorded differences in facial (IGA) and truncal (PGA) treatment success of trifarotene 50 mcg/g cream compared with vehicle cream in 16.6% and 12.7% of subjects, respectively. In both pivotal studies, a greater reduction in facial and truncal lesion counts from baseline to week 12 was seen for subjects in the trifarotene 50 mcg/g cream group compared with subjects in the vehicle cream group for both inflammatory and non-inflammatory lesions. Based on the established threshold effect size of 10%, the highly significant treatment differences observed in both pivotal studies are considered clinically relevant for the treatment of facial and truncal acne. The clinical improvement is expected to be evident between 4-8 weeks of treatment. The safety and effectiveness of Aklief in pediatric population below the age of 12 years was not established. Therefore, Health Canada has not authorized an indication in pediatric patients <12 years of age.

The risks reported in the clinical development program are known class effects expected to occur with topical retinoids, and are considered acceptable and manageable in clinical use. The most common adverse reactions (≥1% of subjects) were application site pruritus (4.6%), application site irritation (4.2%) and sunburn (1.8%). The identified or potential risks of Aklief include local cutaneous reaction (mainly erythema, scaling, dryness, and stinging/burning), sunburn, dermatitis allergic, pigmentation disorders, and eye disorders. The most common treatment-emergent adverse events (TEAEs) were reported by 206 (16.9%) subjects in the trifarotene 50 µg/g cream group and in 116 (9.7%) subjects in the vehicle cream group in pivotal phase 3 clinical studies. In the one-year open label safety study (#18250), a total of 12.6% of subjects had at least one adverse reaction during the study, and 2.9% of subjects had an adverse reaction leading to treatment discontinuation. Compared with the face, a better local tolerability profile was observed on the trunk in both trifarotene 50 mcg/g cream and vehicle cream groups. Usual warnings and precautions for the topical retinoid class are included in the approved labelling.

The non-clinical profile of Aklief (trifarotene) was established in a comprehensive investigational program. At the proposed clinical use and dose, the safety margins exceeded the maximum recommended human dose (MRHD) by a magnitude of 402/474-fold (mouse, male/female), 612/1913-fold (rat, male/female), and 119/1596-fold (dogs, male/female). Based on the results of general toxicity, mutagenicity, and carcinogenicity studies, trifarotene has reasonable margins of safety relative to the proposed human dose and thus it is unlikely to pose a significant toxicological, mutagenic, or carcinogenic risk under the recommended clinical route and dose.

The most serious risk associated with topical retinoids is related to teratogenicity and embryo-toxicity. Trifarotene like all retinoids may cause fetal harm following systemic exposure in pregnant women. Toxicology studies indicated that trifarotene was teratogenic in pregnant rats at systemic exposure of 4157-fold higher than those observed in humans. Due to the high incidence of skeletal anomalies (variations) in groups dosed at 0.03 and 0.1 mg/kg/day, which is a signal for malformations at higher dose levels, the "lowest-observed-adverse-effect level (LOAEL)" for developmental toxicity in rats is considered to be 0.03 mg/kg/day, which yielded a safety margin of about 51-fold, relative to the MRHD. In rabbits, trifarotene induced fetal malformations (especially skeletal) at all dose levels, and the effects were dose related. The risk of systemic exposure with trifarotene is lower than with marketed topical retinoids. Nevertheless, trifarotene is contraindicated during pregnancy and in women planning to become pregnant. No data are available regarding the presence of trifarotene in human milk. Oral animal studies have shown that trifarotene is excreted in the milk of lactating rats; therefore, caution is advised when trifarotene cream is administered to a nursing woman. The Risk Management Plan indicated that the risks for using trifarotene 50 mcg/g cream were consistent with the currently marketed topical retinoids. The proposed labelling for this product provides adequate warning and precaution statements.

The risk of the serious side effects associated with Aklief is considered minimal based upon the mode of administration and the relatively low systemic absorption. The adverse effects observed in the drug development program were consistent with the pharmacological effects of synthetic retinoids. The risks can be managed effectively with adequate labelling and medical supervision.

Although trifarotene is a new chemical entity, it behaves similarly to the other marketed topical retinoids. Overall, Aklief (Trifarotene, 50 mcg/g) is considered to have a favorable benefit-risk profile for "the topical treatment of acne vulgaris of the face and/or trunk in patients 12 years of age and older".