Maha Dutil MD MEd FRCPC
Assistant Professor of Medicine, Division of Dermatology, University of Toronto, Toronto, ON, Canada
Topical retinoids have been used for almost half a century and remain a mainstay in the treatment of acne. They target two of the pathogenic processes in acne: The abnormal keratinization in the pilosebaceous apparatus and inflammation. They act on existing acne lesions and prevent new lesions by targeting the microcomedo and by reducing inflammation. Yet they are underutilized in the treatment acne among generalist physicians. A new topical retinoid, trifarotene, the first fourth-generation retinoid, is now available in Canada for the treatment of moderate facial and truncal acne. It selectively binds to the retinoic acid receptor (RAR)-γ making for an efficacious and safe new option and is the only topical acne therapy to have been rigorously studied in truncal acne.
Acne is a chronic inflammatory skin disease that mostly affects teenagers and young adults and can lead to permanent physical and psychological scarring.
50 years after Kligman described the use of tretinoin in the treatment of acne1, a new fourth-generation topical retinoid, trifarotene, is now available in Canada for the treatment of facial and truncal acne. It is a potent and selective RAR gamma agonist.
Though most patients present with facial acne, 50-60% of them are also afflicted with truncal acne.2 Acne severity was found to have a higher correlation between chest and back acne than face/back or face/chest combinations. Recognition of truncal acne can be problematic as patients often fail to report it, making clinical evaluation of the trunk necessary in acne assessment. Despite the fact that patients may not report its presence, most of them are interested in treating it.3
The key pathogenic mechanisms involved in the production of acne include:
- Increased sebum production under androgen control
- Proliferation of Cutibacterium acnes (formerly Propionibacterium acnes)
- Abnormal keratinization in the pilosebaceous apparatus
- Inflammation mostly via innate immunity
Topical retinoids are critical in the treatment of acne. They are recommended by acne guidelines to be used first line and in the maintenance of all forms of acne.4,5 They are the cornerstone of acne treatment because of their comedolytic and anti-comedogenic effects which are brought about by their ability to modify cellular proliferation and differentiation, and because of their anti-inflammatory properties. Some of these anti-inflammatory activities include blocking inflammation via toll-like receptor-2, inhibiting neutrophil chemotaxis and blocking the AP-1 pathway, thus reducing the production of inflammatory cytokines.6 They also have other effects such as the prevention and reduction of acne scarring7,8 and improvement of hyperpigmentation.9,10
Retinoids are a group of compounds that resemble the Vitamin A molecule retinol. Their effects are mediated by two types of nuclear hormone receptors, the retinoid A receptors (RARs: alpha, beta and gamma) and the second receptor system, the retinoid X receptors (RXRs: alpha, beta and gamma).
The first-generation retinoids include tretinoin (retinoic acid) and isotretinoin; they bind all three retinoid A receptors: RAR-α, RAR-β and RAR-γ. The second-generation retinoids are not used in acne. The third-generation retinoids include adapalene and tazarotene; they selectively bind both RAR-β and RAR-γ. The only fourth-generation retinoid is trifarotene; it selectively binds to the retinoic acid receptor (RAR)-γ. RAR-γ is abundantly expressed in the skin11 and is the most important receptor involved in epidermal differentiation.12
The different molecular structures of these retinoids and the different receptors they bind will affect their impact on acne. For instance, the third-generation retinoid adapalene was found to have more potent anti-inflammatory effects in vitro and in animal studies than the first-generation all-trans retinoic acid and 13-cis retinoic acid.13
Trifarotene was designed for metabolic stability in the skin, while being rapidly metabolized in human liver microsomes with a halflife (t ½) of five minutes. It should result in low systemic levels, while retaining strong cutaneous activity. These properties are particularly important when treating large body surface areas such as the face, chest and back. In ex-vivo cultured human skin, trifarotene was three times more potent than tazarotene. In vivo, trifarotene eliminated almost all comedones from the classical retinoid-responsive rhino mouse model, with a dose ten times lower than that required for tazarotene. The rapid in vivo anti-pigmenting activity of trifarotene is another useful advantage of this molecule that may reduce the hyperpigmentation that is seen secondary to acne.14
Two multicentre, double-blind, randomized, vehicle-controlled, 12-week phase 3 trials were undertaken to study trifarotene.15 Of note, these were the first-ever large-scale randomized trials to simultaneously evaluate a topical therapy for facial and truncal acne treatment.
The study subjects, all of whom had moderate acne vulgaris on the face and trunk, ranged in age from 9 to 58 years, with a mean age of 19 years. They were randomized to once-daily application of trifarotene cream or its vehicle in the evening.
The primary efficacy end points on the face were achievement of Investigator Global Assessment (IGA) success as defined by a score of 0 or 1, meaning clear or almost clear, coupled with at least a 2-grade improvement from baseline to week 12. Another primary endpoint was the absolute reduction from baseline in facial inflammatory and non-inflammatory acne lesions. The secondary end points were similar but as applied to truncal acne from baseline to week 12. Safety was assessed through adverse events, local tolerability, vital signs, and routine laboratory testing results.
In both studies response rates were significantly better than in the vehicle-treated controls. For the 1214 patients treated with trifarotene and 1206 treated with vehicle, the week 12 facial success rates according to the IGA were 29.4% in the first trial and 42.3% in the second (vs 19.5% and 25.7% for vehicle [p < .001]). Trifarotene treatment also achieved significantly superior reductions in facial acne lesion counts in both studies, with statistical differences apparent as early as weeks one or two. With trifarotene treatment, the mean absolute inflammatory lesion counts were reduced by 19.0 and 24.2 in trial one and two respectively (vs by 15.4 and 18.7 with vehicle [p < .001]) and the mean absolute non-inflammatory lesion counts were reduced by 25.0 and 30.1 (vs by 17.9 and 21.6 with vehicle [p < .001]).
The rates of success with trifarotene at week 12 according to the truncal PGA (Physician’s Global Assessment) were 35.7% in the first trial and 42.6% in the second (vs 25.0% and 29.9%, respectively for vehicle [each p < .001]). In both trials, trifarotene was statistically significantly superior in reducing both inflammatory and non-inflammatory lesions on the trunk starting by week 4 in the first trial and by week 2 in the second. Rates of success on the trunk were statistically significant for trifarotene versus vehicle starting at week 8 in both trials.
Treatment-emergent adverse events leading to study discontinuation were low. They occurred in 1.9% of trifarotene-treated patients in one trial and 1% in the other. The typical adverse effects of retinoids include local skin irritation such as redness, peeling, dryness, stinging and burning.
Retinoid cutaneous reactions are typically dependent on concentration and formulation of the retinoid but more importantly may be related to the sensitivity of the patient’s skin.16 There are various strategies to improve retinoid tolerability. A clinical trial looking at four different regimens showed that adding a moisturizer to the treatment regime improved dryness and scaling while every other night application improved stinging and burning sensations as well as erythema.17
In the long-term safety study (52-week trial) trifarotene was found to be well tolerated and efficacious in moderate facial and truncal acne.18
Retinoids are essential in the treatment of acne, but they are generally under prescribed by physicians.19 There are many ways to improve the tolerability of topical retinoids, allowing the majority of acne sufferers access to this crucial therapy. The practice of altering treatment regimens has been shown to improve local tolerability, which may in turn improve overall adherence to treatment. Using these techniques to help patients tolerate the first 4-6 weeks of retinoid use will help patients stay with this most effective therapy.20 Now Canadians will have a new fourth-generation topical retinoid, trifarotene, for the treatment of moderate facial and truncal acne.
- Kligman AM, Fulton JE Jr, Plewig G. Arch Dermatol. 1969 Apr;99(4):469-76.
- Tan JK, Tang J, Fung K, et al. J Drugs Dermatol. 2008 Jun;7(6):551-6.
- Del Rosso JQ, Bikowski JB, Baum E, et al. J Drugs Dermatol. 2007 Jun;6(6):597-600.
- Asai Y, Baibergenova A, Dutil M, et al. CMAJ. 2016 Feb 2;188(2):118-126.
- Thiboutot D, Gollnick H, Bettoli V, et al. J Am Acad Dermatol. 2009 May;60(5 Suppl):S1-50.
- Czernielewski J, Michel S, Bouclier M, et al. J Eur Acad Dermatol Venereol. 2001;15 Suppl 3:5-12.
- Loss MJ, Leung S, Chien A, et al. Dermatol Ther (Heidelb). 2018 Jun;8(2):245-257.
- Tan J, Tanghetti E, Baldwin H, et al. J Drugs Dermatol. 2019 Mar 1;18(3):255-260.
- Grimes P, Callender V. Cutis. 2006 Jan;77(1):45-50.
- Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. N Engl J Med. 1993 May 20;328(20):1438-43.
- Chen S, Ostrowski J, Whiting G, et al. J Invest Dermatol. 1995 May;104(5):779-83.
- Kroshinsky D, Shalita AR. Topical Retinoids. In: Guy Webster and Anthony Rawlings, editors. Acne and its Therapy. New York: Informa Healthcare p103-12 (2007).
- Hensby C, Cavey D, Bouclier M, et al. Agents Actions. 1990 Jan;29(1-2):56-8.
- Aubert J, Piwnica D, Bertino B, et al. Br J Dermatol. 2018 Aug;179(2):442-456.
- Tan J, Thiboutot D, Popp G, et al. J Am Acad Dermatol. 2019 Jun;80(6):1691-1699.
- Leyden J, Grove G, Zerweck C. J Drugs Dermatol. 2004 Nov-Dec;3(6):641-51.
- Tan J, Bissonnette R, Gratton D, et al. Eur J Dermatol. 2018;28(4):502-508.
- Blume-Peytavi U, Fowler J, Kemény L, et al. J Eur Acad Dermatol Venereol. 2019 Jul 15
- Pena S, Hill D, Feldman SR. J Am Acad Dermatol. 2016 Jun;74(6):1252-4.
- Tan J, Bissonnette R, Gratton D, et al. Eur J Dermatol. 2018 Aug 1;28(4):502-508.