FormalPara Key Summary Points

Trifarotene is the most recent topical retinoid to receive regulatory approval for treatment of acne; it has a very low systemic absorption, making it well suited for treatment of large skin areas. Clinical trials of trifarotene included evaluations of both facial and truncal acne and showed efficacy in both areas.

In patients at increased risk for atrophic acne scarring, trifarotene cream significantly reduces the development of scars as well as improves appearance of existing atrophic scars.

Introduction

Acne vulgaris is a chronic inflammatory skin disease that affects approximately 85% of the population [1, 2]. Although it often affects adolescents, acne can occur at any age and can persist into adulthood [1, 2]. With a multifactorial pathophysiology that affects pilosebaceous units, acne is a polymorphic disease that frequently presents with several types of lesions simultaneously [3,4,5,6]. Primary acne lesions can be non-inflammatory or inflammatory; secondary lesions that arise from primary lesions include scars and post-inflammatory hyperpigmentation (PIH) [6,7,8]. Approximately half of all acne patients have scarring. While scars are more common in patients with severe acne, they can also accompany mild acne [9]. Both active acne and its sequelae can have significant damaging effects on patients’ quality of life [10]. Currently, a lack of efficacious medical treatments for atrophic acne scarring exists. In addition, a time delay after the onset of acne before patients receive adequate treatment likely translates to increased scarring.

Atrophic acne scarring is speculated to develop from ongoing inflammation in the pilosebaceous unit, since the vast majority of scars originate from papules and pustules and cysts (inflammatory lesions) [11, 12]. Inflammatory lesions that resolve slowly are more likely scar, again highlighting the role of ongoing inflammation [12, 13]. Atrophic acne scars are associated with loss of tissue and dermal matrix [11]. Although the pathogenesis of acne scarring is not completely understood, an intricate cell-mediated immune response is central to both active acne lesions and altered wound healing that leads to scarring [14, 15].

Management of atrophic acne scars is challenging, and many experts recommend early and effective treatment as a preventive strategy [11]. Topical retinoids are well established in active acne treatment, and increasing evidence indicates that these drugs may also improve acne scarring [11, 16,17,18]. Topical retinoids can stimulate dermal fibroblasts to increase procollagen production and can increase epidermal thickness [19, 20]. Trifarotene, the latest topical retinoid to receive FDA and EU approval, has a unique mechanism of action, binding to retinoic acid nuclear receptor gamma (RAR-γ) [21, 22]. Furthermore, a transcriptomic and gene expression analysis by Dreno et al. found that trifarotene uniquely affects genes involved in cellular migration, inflammation, and reorganization of the cellular matrix while downregulating pro-fibrotic macrophages [23]. To date, these effects on epidermal and immune components of acne pathophysiology have only been associated with trifarotene. This controlled clinical study evaluated the effect of trifarotene on facial acne and atrophic scars.

Methods

Study Design

This was a 24-week, double-blind, vehicle-controlled, split-face (randomized right face vs left face) study evaluating the efficacy and safety of once-daily trifarotene cream in patients with moderate to severe facial acne and atrophic acne scarring. The study followed good clinical practice and the Declaration of Helsinki, and was reviewed and approved by independent ethics committees or institutional review boards according to local/national requirements. All patients (aged 18 or older) or their guardians (for patients younger than 18 years) provided written informed consent which included permission to use data and photos for scientific publications purposes. A total of 20 sites in the USA, Canada, and France participated, and the study was sponsored by Galderma. Ethics approval was obtained for the study conduct. Approval for the US and Canada was provided by wcg IRB for protocol RD.06.SPR.202395 and IRB tracking number 20211170. Approval for France was provided by Comite de protection des personnes Sud Mediterranee, Hopital Sainte Margeurite, Marseille, France, Ref CPP 2144, Ref SI 21.04.16.78234, EudraCT 2020–006050-51.

Inclusion/Exclusion Criteria

To be eligible to participate, patients were male or female, aged 17 to 35 years inclusive, and had a diagnosis of facial acne defined as Investigator’s Global Assessment (IGA) score of 3 (moderate) or 4 (severe) with the same score on each side of the face and ≥ 20 inflammatory lesions (at least 10 on each side), no more than 2 nodules, and a minimum of 10 total atrophic scars (≥ 2 mm). Acne and atrophic scar distribution between sides of the face had to be approximately symmetrical. For 1 month prior to screening and during the study, women of childbearing potential had to agree to urine pregnancy tests and to be abstinent or to use effective and approved contraceptive methods. If the woman was using an oral contraceptive that was also approved for acne treatment, a stable dose for 6 months prior to the screening visit was required. Patients were excluded if they had acne conglobate, acne fulminans, secondary acne, nodulocystic acne, or acne requiring systemic treatment; also excluded were those with any facial acne cysts or ≥ 3 excoriated lesions, known active or chronic allergies, or intolerance to trifarotene.

Study Treatment

Patient eligibility was evaluated over a 28-day screening period. Qualified patients completed baseline assessments and were randomized (left or right side face) to apply trifarotene or vehicle over a 24-week period. Prior to study initiation, a randomization list was generated and transmitted to the packaging organization for study drug labeling and assigned trifarotene or vehicle to the right or left side of the face for each study drug kit. Patients applied study medication under site supervision at the baseline visit and videotaped application of study medication to each side of the face to ensure correct application. They were provided skincare products including a gentle skin cleanser, oil absorbing moisturizer with SPF 30, and moisturizing lotion (Cetaphil® products, Galderma, Dallas, TX). Patients were allowed to use equivalent skincare products at their preference, and trifarotene application frequency could be reduced for up to 2 weeks during the first 4 weeks of treatment if dryness or irritation occurred.

Assessments

Patients were evaluated for safety and efficacy at weeks 1, 2, 4, 8, 12, 16, 20, and 24. The primary endpoint was absolute change from baseline in total atrophic acne scar count per half face at week 24. Additional secondary assessments on each half-face included changes in 2–4 mm and > 4 mm and total atrophic scar counts from baseline to week 20, scar global assessment (SGA, 5-point scale with 0 = clear to 4 = severe) and SGA success (proportion of subjects who achieved a score of clear/almost clear and ≥ 2 grade improvement), percent change in acne lesions (total, inflammatory, non-inflammatory), investigator global assessment (IGA, 5-point scale with 0 = clear to 4 = severe), and IGA success rates (clear/almost clear and ≥ 2 grade improvement). Digital photography of the face was also performed.

Patient-reported outcomes included self-assessment of clinical acne-related scars (SCARS) questionnaire at baseline, week 12, and week 24. This questionnaire used a 10-cm visual analog scale for severity and a 5-point Likert-type scale for appearance of scars for each side of the face.

Safety was assessed by collection of adverse events and evaluation of local tolerability parameters (erythema, scaling, dryness, and stinging/burning, 0 = none to 3 = severe) at each visit.

Statistical Methods

A sample size of 118 patients was planned for randomization, and a blinded sample size re-estimation was performed after 40 patients completed/discontinued the study to account for unknown variability. A summary based on observed case was provided for all primary and secondary endpoints and patient-reported outcomes. For these summaries, no data were imputed. Atrophic acne scar counts (and absolute and percent changes from baseline), SGA, IGA, and lesion counts were summarized at each analysis visit using descriptive statistics by treatment side. Differences between the trifarotene and the vehicle sides were also summarized by descriptive statistics. The hypothesis test for the primary endpoint was evaluated at the two-sided significance level 0.05. Student’s t-test was used for paired samples, with point estimate of mean difference and related 95% confidence interval (CI). For analysis of change from baseline in total atrophic acne scar counts to Week 24, missing counts were imputed using multiple imputation (MI) under the missing at random (MAR) assumption. It was expected that the pattern of missing data would be monotonic, with slight deviations being corrected by the Markov Chain Monte Carlo (MCMC) method of the SAS MI procedure. Separate imputations by treatment group were carried out. Linear regression was employed to model the missing acne counts, with the following covariates included in the imputation model: non-missing total atrophic acne scar counts from earlier time points.

Results

Demographics and Disease Characteristics

A total of 121 patients participated, with a mean age of 22 years. Most (84.3%) were 18 years or older, female (72.7%), and white (80.2%), 30.6% had darker skin types (Fitzpatrick IV and V), and 21.5% self-identified as Hispanic. Patient demographics and disease characteristics are shown in Table 1. Baseline disease characteristics were similar, with acne scar severity being mostly mild or moderate according to SGA (> 80%) and all acne severity as assessed by IGA being moderate or severe.

Table 1 Patient demographics and disease characteristics
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Efficacy

Scar Results

As shown in Fig. 1, a significantly superior reduction in atrophic scar count occurred on trifarotene-treated sides of the face compared to vehicle-treated sides. At week 24, the mean absolute change from baseline was − 6.2 ± 5.6 on the trifarotene-treated area compared to − 2.8 ± 3.9 on the vehicle area (Δ − 3.2, P < 0.0001). This was primarily due to a greater amount of reduction in 2–4 mm atrophic acne scars. As shown, there was a difference between treated sides as early as week 2 (P = 0.001), which continued at week 4 (P = 0.007) and weeks 8 through 20 (P < 0.0001). The total scar counts were similar between groups at baseline (Table 1), but by week 24, the total scar count was 5.4 ± 5.6 for trifarotene-treated areas and 9.1 ± 8.6 for vehicle-treated areas (percent reductions of 55.2% and 29.9%, respectively).

Fig. 1
figure 1

Mean absolute change from baseline in total atrophic acne scar counts. P values refer to the Student’s t-test for paired samples performed on the intra-subject difference between trifarotene 50 µg/g and vehicle at each analysis visit. *0.01 ≤ P value < 0.05; **0.001 ≤ P value < 0.01; ***0.0001 ≤ P value < 0.001; ****P value < 0.0001

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At baseline, the mean Investigator SGA scores were the same in trifarotene- and vehicle-treated areas (2.6 for each, Table 1). By week 24, trifarotene-treated sides were rated 1.3 ± 0.7 compared to 1.9 ± 0.9 in the vehicle-treated sides. Trifarotene had superior SGA success rates at 53.5% compared to 32.3% in the vehicle sides (P < 0.001). Figures 2 and 3 show clinical photos at baseline and week 24 with appreciable differences between the trifarotene- and vehicle-treated sides.

Fig. 2
figure 2

Clinical photos at baseline and week 24 showing difference between trifarotene- and vehicle-treated sides

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Fig. 3
figure 3

Clinical photos at baseline and week 24 showing difference between trifarotene- and vehicle-treated sides

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Acne Results

As expected, all acne results were statistically significantly superior in trifarotene- vs vehicle-treated sides. Table 2 presents results of the active acne lesion assessments. Total lesion counts separated significantly between group as early as week 1 (P = 0.0097), and differences persisted through week 24 (P < 0.0001). Reductions in inflammatory lesion counts were significantly superior on trifarotene-treated sides compared to vehicle-treated as early as week 2 and persisted superior through week 24 (P < 0.0001). Separation in non-inflammatory lesion counts occurred by week 1 and lasted through week 24 (P < 0.0001). Superior IGA success rate in trifarotene-treated vs vehicle-treated sides (63.6% vs 31.3%, respectively) emerged by week 4.

Table 2 Changes in acne lesion assessments from baseline to week 24
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Patient Preference/Satisfaction

At baseline, a similar number of atrophic acne scars was reported on each side of the face. At week 24, when asked how many indents/holes they saw on their face, 49% reported “very few” on the trifarotene-treated side, as did 37% for the vehicle-treated side. Similarly, the mean severity rating for scars was 4.9 at baseline and 1.9 at week 24 with trifarotene and 4.9 at baseline and 2.6 at week 24 with vehicle. The mean severity rating for active acne was reduced from a mean of 5.1 to 1.9 in the trifarotene side; for vehicle the change was from 5.2 at baseline to 2.7 at week 24.

Safety

Both trifarotene and its vehicle were well tolerated with treatment emergent adverse events (TEAEs) occurring in 5.8% of trifarotene-treated sides of the face and 2.5% of vehicle-treated sides. A summary of adverse events is shown in Table 3. The most common adverse events were local events, such as skin tightness, pruritus, erythema, and rash. Two adverse events of special interest from one patient (burning sensation and erythema) were reported on the trifarotene-treated side; the same patient discontinued the study drug because of adverse events on the trifarotene-treated side of the face. No serious adverse events occurred during the study.

Table 3 Summary of TEAEs related to study medication
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The mean erythema, scaling, dryness, and burning/stinging scores peaked at week 2 and were slightly higher in the trifarotene-treated vs vehicle-tested half faces (5.8% vs 2.5%). Mean scores for tolerability parameters gradually decreased after week 2 through week 24, and the majority of scores (> 60%) were either mild or moderate.

Discussion

The study met its primary endpoint, with reductions in atrophic acne scar counts from baseline to week 24 being greater on trifarotene-treated facial sides compared to vehicle-treated sides. Secondary endpoints also showed that trifarotene was more effective than vehicle in reducing atrophic acne scarring. Trifarotene achieved superior results on all active acne assessments (lesion counts and IGA scoring) despite the small sample size and the study not being powered for acne lesions. Patients also reported better results on trifarotene vs vehicle sides in multiple aspects of their atrophic acne scars and active acne lesions. Trifarotene efficacy was observed as early as week 2 and increased over time until week 24. Furthermore, trifarotene showed a highly favorable risk-benefit ratio, with no new safety signals reported.

Topical retinoids, including trifarotene, inhibit inflammatory pathways that are activated in acne, including leukocyte migration, activation of Toll-like receptors, and the activator protein-1 pathway [15]. Trifarotene has strong and selective activity on RAR-γ and less pronounced effects on RAR-α and RAR-β; RAR-γ is the most prevalent RAR isoform in skin [22]. This selectivity may allow action on keratinocytes while reducing the potential for systemic adverse events [24]. Trifarotene regulates multiple skin functions, including epidermal keratinization, differentiation, maturation, and proliferation [24]; trifarotene downregulates matrix metalloproteinases and may improve skin texture by preserving elastin and collagen [22]. Recently, Dreno et al. found that trifarotene also affects gene expression and reduces profibrotic macrophages [23].

A reduction in atrophic acne scars was also shown with 6 months treatment with adapalene 0.3%/benzoyl peroxide 2.5% gel compared to vehicle [11]. Dreno et al. reported that the change from baseline in total scar counts increased on the vehicle-treated side but significantly decreased on the actively treated side (P < 0.0001) [11]. In addition, a significantly higher percentage of patients were considered to have success with adapalene/BPO on scar global assessment (32.9% vs 16.4% with vehicle, P < 0.01) [11].

Trifarotene has been shown to have excellent efficacy against acne lesions, and experts have long considered that effective treatment of acne inhibits scar formation [9, 25, 26]. With low systemic absorption, trifarotene may be used on large areas of the body, such as the trunk, in addition to the face [22, 25, 27]. According to the phase III studies of trifarotene, the improvements in active acne were similar on the face and the trunk; therefore, it is a reasonable assumption that trifarotene would then reduce truncal scarring [25]. It is not uncommon for truncal acne to cause persistent scarring, including macular atrophic scars and keloidal scars. While early and effective treatment can be used as a preventive strategy, more aggressive treatment should be offered to patients with existing scars. Truncal acne is often undertreated, and we recommend close examination of the trunk of patients with acne to assess current scarring and scarring risk. Currently, there is a lack of efficacious medical treatments for atrophic acne scarring. In addition, there is often a time delay after the onset of acne before patients receive adequate treatment, which likely translates to increased scarring. Scars have a negative impact on quality of life, both when on the face and on the trunk. A multidisciplinary research of truncal acne is needed to understand its pathogenic characteristics and proper management options.

Limitations of this study are the split-face design and potential of inadvertent contamination of trifarotene from one facial half to the other during the 24 weeks of treatment or from patients transferring cream by touching their face during the day. This was mitigated by using e-diaries during patient applications to ensure adherence and monitor correct application. However, consistent differences were observed between active and vehicle sides, with assessments showing continuous reductions in both active acne lesions and atrophic scars during the study.

Conclusions

Overall, trifarotene clearly reduced atrophic acne scars at week 24, with differences between sides noted as early as week 2. Additionally, trifarotene was well tolerated with a good safety profile.