Santina Conte, MD1 and Monica K. Li, MD, FRCPC, FAAD2

1Faculty of Medicine and Health Sciences, McGill University, Montréal, QC, Canada
2Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest: Monica K. Li is a consultant and speaker for Galderma Canada. Santina Conte has no relevant conflicts of interest.
Funding sources: None.

Abstract: Acne vulgaris is a common, often chronic inflammatory disease that can affect all ages and skin tones. Beyond acute lesions, the sequelae of acne – specifically scarring and dyspigmentation – can be long-lasting, challenging to treat and have substantial psychosocial impact on affected individuals. For acne scarring, treatment modalities include topical, physical, and laser and light therapies, with combination approaches typically yielding optimal outcomes. Trifarotene is a novel fourth generation retinoid with targeted action towards retinoid acid receptor gamma (RAR-γ), the most common isotype found in the epidermis, that has previously been approved for the management of moderate-to-severe facial and truncal acne in individuals over the age of 12 years. Recently, data on trifarotene supports its application in acne scarring. Herein, we provide a succinct review on various treatments for acne scarring and explore how trifarotene and its mechanism of action present an additional topical approach to target atrophic acne scarring.

Keywords: acne, atrophic scar, retinoid, scar, trifarotene

Introduction

Pathophysiological processes at the pilosebaceous unit, including increased sebum production, follicular hyperkeratinization, Cutibacterium acnes proliferation and augmented localized immune responses, contribute to the development of acne vulgaris (AV).1 While its estimated global prevalence is almost 10%, AV most commonly affects adolescents, with 9 in 10 Canadian adolescents impacted by the disease.2,3 However, AV commonly persists into adulthood, affecting 50% of women in their 20s and over 35% of women in their 30s.4

AV plays an important role on an individual’s self-perception, with patients expressing how acne-related concerns affect their social, personal and professional lives.4 Moreover, patient distress is not only linked to active AV lesions, but also to subsequent scarring, irritation and hyperpigmentation.5 Early, effective management of AV is therefore key to reduce the risk of irreversible scarring and long-term disfigurement, given that clinically relevant scars occur in roughly 50% of individuals.6 The majority of AV-induced scars are atrophic in nature, thought to be secondary to collagen loss, while approximately 10% are hypertrophic.7 Notably, acne scars, particularly atrophic ones, have proven to be surgically and cosmetically challenging to treat, reinforcing the importance of prevention.8

Current clinical treatments for atrophic acne scars include chemical peels, dermabrasion, punch techniques, laser and light-based devices, tissue-augmenting agents, needling, subcision, fat transplantation and combinations thereof – modalities typically requiring considerable out-of-pocket expenses and lengthy commitment for the patient.9 This underscores the importance of a proactive, preventative approach. Retinol products have long been established and recognized to promote skin resurfacing secondary to their capacity to increase cell turnover and re-epithelialize tissues.10 Recently, a phase 4 controlled study by Schleicher et al. demonstrated that trifarotene, a selective fourth generation retinoid, was effective and well-tolerated in reducing atrophic acne scarring.11-13 The new data supports the utility of this topical retinoid as an evidence-based, adjunctive measure to manage a highly prevalent acne sequela.

Background

Trifarotene (Aklief®) is a fourth generation topical retinoid with activity selective for retinoid acid receptor gamma (RAR-γ), the most predominant RAR isotype in the epidermis.9,10 Similar to other retinoids, trifarotene works by regulating epidermal keratinization, differentiation, maturation, and proliferation through the activation of specific genes, but its unique capacity to affect inflammation, cellular movement, immune cell trafficking and tissue remodelling, as well as to downregulate pro-fibrotic macrophages, lends to its efficacy and desirability as a molecule for acne treatment.9,11 Moreover, an in vitro study that aimed to characterize trifarotene’s metabolism and pharmacology found that the product was an efficient comedolytic agent and demonstrated anti-inflammatory, depigmenting and anti-pigmenting properties, while having a favorable safety profile.12

The medication is sold as a 0.005% or 50 mcg/g cream in 75 g pumps, and 1 pump is directed for once daily application to affected skin.13 Other clinically relevant ingredients in the product include allantoin, copolymer of acrylamide and sodium acryloyldimethyltaurate with isohexadecane, polysorbate 80, sorbitan oleate, cyclomethicone 5, ethanol, phenoxyethanol, propylene glycol, purified water and medium-chain triglycerides.14 Some benefits of the aforementioned ingredients include increased proliferation of healthy tissue, wound healing, emulsification, improved moisturizing benefits and enhanced stratum corneum penetration.15-18 Trifarotene has been approved by Health Canada and the United States Food and Drug Administration for the treatment of AV of the face and/or trunk in patients aged 12 years and older.14

Supporting Evidence from Clinical Trials

Results from a Phase 4 Study

In a phase 4, multi-centre, 24-week, double-blind, vehicle-controlled, split-face study, the efficacy and safety of trifarotene 50 mcg/g applied once daily along with skincare products (Cetaphil® cleanser and Cetaphil® moisturizer/SPF 30) in patients (n=121, aged 17-34 years) with moderate-to-severe facial acne and atrophic acne scarring was assessed.19 Moderate-to-severe facial acne was defined as an Investigator’s Global Assessment (IGA) score of 3 (moderate) or 4 (severe), with equal scores on both sides of the face, as well as at least 10 inflammatory lesions on each side, no more than 2 nodules, and a minimum of 10 total atrophic acne scars at least 2 mm in size on each side. Exclusion criteria included acne conglobata or fulminans, secondary acne, nodulocystic acne or acne requiring systemic treatment, and acne involving facial cysts or 3 or more excoriated lesions. In order to monitor the treatment’s efficacy, absolute and percentage change from baseline in atrophic acne scar counts, acne lesion counts, Scar Global Assessment (SGA) and IGA were followed at weeks 1, 2, 4, 8, 12, 16, 20 and 24, while patient-reported outcomes were evaluated through a self-assessment of clinical acne-related scars (SCARS) questionnaire.

With regards to trifarotene’s effect on AV clearance, the treated half of the face showed statistically significant improvement in comparison to the vehicle-treated side, with marked differences as early as week 1 and progressive improvement through week 24. Both inflammatory and non-inflammatory lesion counts decreased substantially in comparison to placebo from early in the treatment course (weeks 1 or 2), while hemifacial comparison of IGA success rates were significantly different between the two groups by 24 weeks (63.6% in trifarotene, 31.3% in vehicle, p < 0.05). Of note, each of the assessed acne lesion parameters, including mean total (-70.0% vs. -44.9%), inflammatory (-76.3% vs. -48.3%) or noninflammatory (-61.4% vs. -32.1%) lesion counts per half face, were statistically better in the trifarotene group than the control group at 24 weeks (all p < 0.05).

Table 1: Summary of the efficacy of trifarotene in the management of moderate-to-severe facial acne and atrophic acne scars in a phase 4 study. <br> (*) Denotes statistical significance achieved in the difference between the two groups.

Trifarotene achieved similar success with regards to atrophic scarring. In addition to the treated portion of the face demonstrating a statistically significant superior reduction in atrophic scar counts (-5.9) compared to placebo (-2.7) by week 24, improvements were superior throughout the course of treatment and observed as early as week 2. The treated side also yielded significantly better outcomes with regards to reductions in total scar counts (55.2% vs. 29.9%) and mean SGA scores (53.5% vs. 32.3%).

With respect to evaluating patient preference and satisfaction, participants reported a numerically superior impact on atrophic acne scars with trifarotene in comparison to the vehicle (49% vs. 37% reporting that they saw “very few” indents/holes on their face), while the mean severity rating for scars also decreased more substantially on the retinoid-treated side (change of 3.0 for trifarotene vs. 2.3 for vehicle). There were also greater differences in the patients’ perception of their active acne for the trifarotene-treated side (change of 3.2 vs. 2.5 for vehicle).

Additionally, the safety and tolerability of trifarotene were assessed, which found that rates of mild treatment-related adverse events were higher on the treated side (5.8%) compared to the vehicle side (2.5%). The most reported adverse events included skin tightness, pruritus, erythema and rash. No severe adverse events occurred. Moreover, adverse events were found to be transient, with maximal discomfort noted at week 2.

There are two major strengths of this phase 4 study. First, over 30% of subjects were of skin phototypes IV and V, reflecting much greater diversity in recruitment efforts and improving generalizability of results to real-world practice, relative to other studies of prescription topical retinoids performed to date. Further importance of subject racial and ethnic representation is that scarring tends to be more prevalent and severe in skin of color populations.20 Second, the study duration of 6 months provides greater insight into trifarotene’s impact on inflammation underlying active AV lesions, and its subsequent ability to prevent and/or improve secondary scarring. In contrast, pivotal clinical trials evaluating acne treatments typically last 3 months.

Post Hoc Analyses of Phase 4 Study

Additional analyses were performed following the publication of the above-mentioned evidence supporting trifarotene’s efficacy in the management of acne-induced atrophic scarring. First, improvement was assessed according to age quartiles (<18, 18-22, 22-27, and >27 years), which found a statistically significant difference in total atrophic acne scar counts in all age groups with trifarotene treatment as compared to placebo, with the most substantial improvement seen in patients over the age of 27. Comparisons with regards to Fitzpatrick phototypes were also performed, which is highly important given that scarring tends to be more extensive in darker skin tones. All phototypes were noted to have a greater improvement in scar counts with trifarotene, while statistical significance was achieved in Fitzpatrick types II, III and IV. With regards to Investigator and Subjective Global Assessments, trifarotene treatment resulted in statistically significant differences, with the greatest reduction observed in patients with acne severities of 3 (moderate) and 4 (severe), while patients who presented with more severe scarring at baseline tended to experience more substantial improvements in their scarring with trifarotene. Overall, all subgroups analyzed proved to be in favor of trifarotene treatment compared to vehicle for the management of atrophic scarring.

Summary of Results from Phase 4 Study

In essence, the above-mentioned phase 4 clinical trial suggests that trifarotene is highly effective and well-tolerated in the management of moderate-to-severe facial and truncal acne and facial acneinduced atrophic scarring, with treated inflamed areas responding as quickly as 2 weeks. Improved parameters included acne lesion and atrophic acne scar counts, Scar and Investigator Global Assessments, as well as patient-reported outcomes, which were all favorable with use of this RAR-γ selective topical retinoid.

Other Available Treatment Modalities for Atrophic Acne Scars

Many studies have assessed the effectiveness of a variety of treatments in the management of acne-induced scars. In real-world clinical practice, the optimal approach may be determined based on the skin phototype, treatment history, personal preferences and financial considerations of the patient, as well as the spectrum of therapeutic options available to the clinician. A 2023 review explored the efficacy of various topical modalities in the management of acne scars, including monotherapy with a range of retinoids (tretinoin, adalapene, adalapene/benzoyl peroxide gel, tazarotene), low strength glycolic acid, vitamin C derivatives and tacrolimus, as well as multimodal management with silicone gel, tranilast, plasma gel, lyophilized growth factors, amniotic fluidderived mesenchymal stem cell products, platelet-rich plasma (delivered via microneedling), insulin, polylactic acid and retinoic acid combined with glycolic acid.21 The authors concluded that despite such an array of available topical interventions, there remains an overall lack of evidence to support their efficacy.21 This contrasts trifarotene’s distinct and demonstrated capacity to improve acne scars.

Furthermore, non-laser and laser interventions have been widely used in acne scar management. For example, a single session of endo-radiofrequency subcision proved to be effective and safe, whereby scores associated with the number and quality of scars both significantly decreased, alongside patient (25-50%) and investigator (25-49%) improvement rates.22 With lasers, a comparison between erbium-doped yttrium-aluminum-garnet (Er:YAG) laser and 20% trichloroacetic acid (TCA), by which the laser was used for a total of 4 sessions and the TCA every 21 days for 3 months, found a statistically significant improvement in qualitative acne scar grading in both groups after 12 weeks (Er:YAG -21.7%, TCA -20.97%) with good tolerability.23 Nd:YAG picosecond laser was also proven to have a similar clinical effect as ablative fractional Er:YAG laser (39.11% vs. 43.33%, p < 0.05), with patient satisfaction being slightly in favor of the Er:YAG laser.24 Fractional carbon dioxide laser resurfacing, for a total of 4 sessions, yielded statistically significant decreases in qualitative scar scales with response seen in almost all patients (96%); results were observed as early as after the first laser session.25 Moreover, varying laser settings have also been assessed, with one study finding that low-fluence neodymium-doped yttrium aluminum garnet (Nd:YAG) laser demonstrated comparable efficacy but superior safety than its high-fluence counterpart (-62.13% vs. -66.73%, p > 0.05) in the management of acne-related scarring.26

Other modalities have also been used in conjunction with laser therapy, such as fractional microneedle radiofrequency (RF), whereby RF energy combined with ablative laser therapy demonstrated significantly superior efficacy in terms of inflammatory acne and acne scar grading, lesion counts, and subjective satisfaction.27 Beyond laser interventions, microneedling with 35% glycolic acid or 15% TCA were found to be equally efficacious, with glycolic acid peels conferring better improvement in skin texture, while microdroplet injections with botulinum toxin type A (e.g., microbotox) and microneedling also showed similar significant results.28,29

Conclusion

Trifarotene 0.005% cream has been shown to be an efficacious treatment modality for moderate-to-severe acne and acne-induced scarring, likely correlating to its novel specificity for RAR-γ, the most common isotype found in the epidermis. In comparison to conventional treatment approaches for acne-induced scars, trifarotene appears to be a relatively cost-effective, safe, well-tolerated and long-term option to improve atrophic acne scars on the face. Based on recent supporting studies, and given that acne scarring often requires multiple treatment modalities over many months, trifarotene can be considered an appropriate, useful and accessible topical adjunct for patients across the skin spectrum. Further studies, particularly with a longer observation period as well as in skin of color populations, evaluating the combined use of trifarotene with currently used interventions, will be valuable to explore its potential synergistic benefits in acne-induced atrophic scarring.


Acknowledgement: We thank Rajeev Chavda, MBBS, MD, DBM for his editorial review and support.

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