1Windsor Clinical Research Inc., Windsor, ON, Canada
2Schulich School of Medicine and Dentistry, Western University, Windsor Campus, ON, Canada
Conflict of interest:
Jerry Tan has served as an advisor, consultant, investigator and speaker for Galderma. Maegan Miklas has no conflicts to declare.
Trifarotene 50 μg/g cream is a fourth generation topical retinoid with retinoic acid receptor gamma selectivity. It was recently approved by the US FDA and Health Canada for the topical treatment of facial and truncal acne for those aged 9 and older based on two identically designed phase 3 trials demonstrating superiority in lesion count reduction and global acne improvement compared to vehicle. These studies and a 1 year study also demonstrated safety and tolerability with cutaneous adverse events developing in an anticipated timeframe (1 week) for the face. These were of lesser degree and tended to develop later at the trunk. Future studies will be required to evaluate the comparative efficacy of trifarotene 50 μg/g cream against other treatments for acne.
Topical retinoids serve as cornerstone therapy for acne with efficacy demonstrated across the spectrum of acne severity. Retinoids are classified by their common biological pathway, where the molecules themselves or their metabolites bind to a retinoid receptor: either retinoic acid receptors (RARs) or retinoid X receptors (RXRs), both of which have three subtypes: alpha, beta, and gamma.1 Since tretinoin, subsequent generations of topical retinoids, determined by structural modifications, have sought to either increase efficacy, improve tolerability, or both.2 Trifarotene (chemical name 4-[3-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-4-(2-hydroxyethoxy)phenyl]benzoic acid; C29H33NO4) is a fourth generation retinoid with higher selectivity and agonist activity for RAR gamma (RARγ), the most abundant subtype in skin.3,4 The selectivity of trifarotene for RARγ differentiates it from the existing first- and third-generation topical retinoids, which target both RARβ and RARγ.4 Trifarotene is pharmacokinetically stable in keratinocytes but quickly metabolized in hepatic microsomes, indicating a favorable safety profile. In addition, it has comedolytic, anti-inflammatory, and antipigmenting properties.4,5 In this paper, we review the efficacy, safety, and tolerability of trifarotene 50 μg/g cream, a novel topical retinoid recently approved by the US FDA and Health Canada for the topical treatment of facial and truncal acne.6
Clinical Trials in Acne
The efficacy, safety, and tolerability of Trifarotene 50 μg/g cream was assessed in two large identically designed randomized, double-blind, vehicle-controlled trials of 12-week duration (PERFECT 1 and PERFECT 2 ClinicalTrials.gov: NCT02566369 and NCT02556788).5 Subjects aged 9 years and older with moderate acne vulgaris of the face and trunk were enrolled. Evaluation of acne at the trunk was a unique feature of these trials and required appropriate delineation of truncal sites that could be amenable to self application, repeatable evaluation, and modesty as recruitment would involve males and females. A special T-shirt, with cutouts at the décolletage and upper back, was developed to outline the appropriate regions to fulfill the prior enrollment criteria.
Primary efficacy endpoints for facial acne were based on a composite of global success and absolute change in inflammatory and noninflammatory lesion counts. Secondary efficacy endpoints were for truncal acne and based on corresponding measures. Global success required achievement of clear or almost clear, and at least a 2-grade improvement from baseline of moderate or severe over the course of the 12-week studies (global grading was on a 5 category scale of none, almost clear, mild, moderate, and severe). Standard safety and tolerability assessments were undertaken.
A total of 2420 subjects were randomized 1:1 (1214 to trifarotene 50 μg/g versus 1206 to vehicle) in the two studies with a mean age of 20 years, slight predominance of females, and mainly phototypes II-III. Almost 90% of subjects were white with lesser proportions of black/African-Americans, Asians and others.
Onset of effect, such as reduction in inflammatory and noninflammatory lesions, were seen as early as week 1 for the face and week 2 for the trunk.5 The proportion of subjects achieving facial global success was significantly in favor of trifarotene for both studies, with a treatment difference at week 12 of 9.9% for study 1 and 16.6% for study 2 (p<0.001 for both). Reduction of facial acne lesion count was also in favor of trifarotene in inflammatory and noninflammatory lesion counts in both studies. For inflammatory counts, the difference from baseline to end of study between arms was -3.6 in study 1 and -5.5 in study 2 (p < 0.001 for both). For noninflammatory counts, the corresponding results were -7.1 and -8.5 (p < 0.001 for both).
The proportion of subjects achieving truncal global success was also significantly in favor of trifarotene for both studies with a treatment difference at week 12 of 10.7% for study 1 and 12.7% for study 2 (p<0.001 for both). Truncal acne lesion count reduction was also in favor of trifarotene in inflammatory and noninflammatory lesion counts in both studies. For inflammatory counts, the difference from baseline to end of study between arms was -2.6 in study 1 and -5.7 in study 2 (p<0.001 for both). For noninflammatory counts, the corresponding results were -4.1 and -5.1 (p<0.001 for both).
Cutaneous tolerability assessments showed greater levels of erythema, scaling, dryness, and stinging/burning compared to vehicle, which tended to peak at week 1 for the face and week 2 for the trunk. Mean levels for these parameters were mild or less for the face and trunk.
Overall, truncal mean scores for intolerability were less compared with the face. The proportion discontinuing treatment due to adverse events in the trifarotene arms was 1.5%.
In a 52-week open-label study involving 453 patients with moderate acne on the face and trunk, 13% experienced cutaneous adverse events related to trifarotene 50 μg/g cream.7 The majority of these adverse effects developed in the first 3 months of treatment, were mainly of mild severity and reported as itching (4.6%), irritation (4.2%), and sunburn (1.8%). Severe related adverse events occurred in three different patients and were reported as irritation, pruritus, and erythema. Local intolerability scores (related to erythema, dryness, scaling, stinging/burning) trended higher for facial compared to truncal sites of application. Maximum scores for facial involvement tended to be within the first week compared to trunk, which occurred more frequently in weeks 2-4. Overall, 2.9% of subjects discontinued due to related emergent adverse events. Global success at end of study was 65% for facial and 67% for truncal acne.
In two large randomized vehicle-controlled 12-week trials and in a 52-week open label study of moderate-to-severe acne at the face and trunk in subjects aged 9 years and older, trifarotene 50 μg/g cream demonstrated efficacy, safety, and cutaneous tolerability. As expected with topical retinoids, cutaneous adverse events developed with trifarotene use in an anticipated time for the face. At the trunk, these adverse reactions were of a lesser degree and tended to develop later. Future studies will be required to evaluate the comparative efficacy of this novel agent against current topical incumbents in the treatment of acne.
- Thoreau E, Arlabosse JM, Bouix-Peter C, et al. Structure-based design of Trifarotene (CD5789), a potent and selective RAR gamma agonist for the treatment of acne. Bioorg Med Chem Lett. 2018 Jun 1;28(10):1736-41.
- Chien A. Retinoids in acne management: review of current understanding, future considerations, and focus on topical treatments. J Drugs Dermatol. 2018 Dec 1;17(12):s51-5.
- Kim S, Chen J, Cheng T, et al. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2019 Jan 8;47(D1):D1102-D9.
- Aubert J, Piwnica D, Bertino B, et al. Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene. Br J Dermatol. 2018 Aug;179(2):442-56.
- Tan J, Thiboutot D, Popp G, et al. Randomized phase 3 evaluation of trifarotene 50 mug/g cream treatment of moderate facial and truncal acne. J Am Acad Dermatol. 2019 Jun;80(6):1691-9.
- Drugs.com [Internet]. Trifarotene information from Drugs.com. Updated: September 5, 2019 [cited 2019 Nov 26]. Available from: https://www.drugs.com/ppa/trifarotene.html.
- Blume-Peytavi U, Fowler J, Kemeny L, et al. Long-term safety and efficacy of trifarotene 50 mug/g cream, a first-in-class RAR-gamma selective topical retinoid, in patients with moderate facial and truncal acne. J Eur Acad Dermatol Venereol. 2020 Jan;34(1):166-73.