Management of Acne Vulgaris With Trifarotene

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Management of Acne Vulgaris With Trifarotene (2023)
Jerry Tan, MD, Rajeev Chavda, MD, Hilary Baldwin, MD, and Brigitte Dreno, MD, PhD


Topical retinoids have an essential role in the treatment of acne. Trifarotene, a topical retinoid selective for retinoic acid receptor (RAR) γ, is the most recent retinoid approved for the treatment of acne. RAR-γ is the most common isoform of RARs in skin, and the strong selectivity of trifarotene for RAR-γ translates to efficacy in low concentration. Trifarotene, like other topical retinoids, acts by increasing keratinocyte differentiation and decreasing proliferation, which reduces hyperkeratinization. Retinoids have also been shown to inhibit inflammatory pathways via effects on leukocyte migration, toll-like receptors, and Activator Protein (AP)−1. Large-scale randomized, controlled clinical trials have demonstrated trifarotene to be safe, well tolerated, and efficacious in reducing both comedones and papules/pustules of acne. However, unlike all other retinoids, trifarotene is the first topical retinoid with rigorous clinical data on safety and efficacy in truncal acne. Data supporting the use of trifarotene to manage acne are reviewed in this publication.


Acne vulgaris, a chronic inflammatory disease, is the 8th most prevalent disease worldwide and affects adolescents and adults across the demographic spectrum.1 Acne is also associated with long-lasting, sometimes permanent, sequelae including scarring and low self-esteem, particularly when acne affects highly visible regions such as the face.2 While it can affect any area rich with sebaceous glands - face, chest, shoulders, and back—most research has focused on facial acne.3 However, the impact of truncal acne is becoming increasingly appreciated4,5 as approximately 50% to 66% of individuals with acne have trunk involvement.3,6-9 While almost half of all facial acne patients also have truncal acne, there has been a paucity of high-quality studies on facial and truncal acne.4 In addition, recent studies have shown that facial and truncal acne together has a greater impact on quality of life compared to facial acne alone. Furthermore, the impact on quality of life worsens with increasing severity of truncal acne due to self-consciousness about appearance and reluctance to participate in activities where truncal acne would be revealed.5 Thus, truncal acne is an important and clinically relevant issue to address in the clinic.

Acne is a disease with a complex multifactorial pathogenesis, with four factors given most prominence: abnormal follicular keratinization, increased sebum production, colonization with Cutibacterium acnes, and immune system disturbances.10
Nutritional intake, namely a high glycemic index diet, and dairy intake may also affect acne.11,12 Genetics, the microbiome, and environmental influences additionally contribute.13,14

Clinically, active acne is associated with a morphologic spectrum of lesions, including papules, pustules, comedones, nodules, and cysts. Acne lesions have traditionally been classified as “inflammatory” and “non-inflammatory;” however, inflammation exists at every stage of acne lesion development.15,16 Inflammatory mediators and receptors – including a range of cytokines, defensins, peptidases, and other molecules—are activated during the initiation and propagation of acne.15 Uninvolved skin and early acne lesions show upregulation of E-selectin, vascular adhesion molecule-1, interleukin-1 (IL-1), and integrin.15,17,18 Further, IL-1 bioactivity has been shown in comedones, and upregulation of defensin-2 immunoreactivity and elevation of T cells and macrophages are found in uninvolved skin.15,17-19 Clinically, there has long been evidence that topical retinoids are effective in treating “noninflammatory” lesions, and it is known that retinoid therapy down-regulates toll-like receptor (TLR)−2 and IL-10 expression, thus acting in important pathways against inflammatory lesions.20-23 In addition, a recent transcriptomic study of changes in acne lesions that resolved spontaneously versus those that resolved during trifarotene treatment showed that trifarotene modulated a unique set of 67 genes that were not found in spontaneously resolving lesions.24 The genes affected by trifarotene were primarily involved in cellular migration, inflammation, and extracellular matrix organization and SPP1 +macrophages, a recently discovered proliferative macrophage found in fibrotic tissue.24

Topical retinoids are recommended as a foundation of acne treatment since they affect multiple aspects of acne pathophysiology.2
Since the US Food and Drug Administration (FDA) approval of tretinoin in 1971, retinoid molecules have undergone chemical modifications that have resulted in clinical improvements in efficacy and safety.25

Trifarotene 50 µg/g cream, a topical retinoid approved by the US FDA for once-daily treatment of acne, has been studied as a treatment for both facial and truncal areas of involvement. A pharmacokinetic study (n = 19) showed that trifarotene has negligible systemic absorption after 29 days of topical application in doses ranging from 1.5 to 2 g per day to the face, chest, shoulders, and back. As a result, trifarotene did not reduce systemic exposure to oral contraceptives in 24 healthy volunteers participating in a drug-drug interaction study.26 Further, a human trial of 60 healthy adults found no effect on cardiac electrophysiology after 14 days of supra-therapeutic dose trifarotene (12 g of trifarotene 100 µg/g).22 Trifarotene is a selective agonist of retinoic acid receptor (RAR) γ, the most common RAR found in the skin.27

This publication discusses clinical data supporting the use of trifarotene, a novel topical retinoid, in the treatment of acne.

Clinical Data Supporting Use of Trifarotene in Acne

Trifarotene was evaluated in a clinical development program that included two large-scale phase 3 studies and a long-term safety study, among others (Table 1). Unique among modern acne products, the efficacy of trifarotene was rigorously studied on the trunk in addition to the face.28 Recently, recommendations were made about truncal acne by the Personalising Acne: Consensus of Experts (PACE) panel. These included encouraging healthcare professionals to prompt discussion about truncal acne, to grade truncal acne severity separately from facial acne, to individualize treatment based on the impact of acne in different regions, and to consider the risk for scarring.29

*Pivotal Studies

*Combination Therapy: Trifarotene Plus Doxycycline in Severe Acne


Trifarotene is a recently approved retinoid selectively targeting RAR-γ receptors of the skin.24 It has been shown to be efficacious in facial and truncal acne and safe for long-term maintenance with favorable efficacy and tolerability.34 As monotherapy for acne, a continuous improvement over time was reported in the long-term safety study according to both investigators and patients. Trifarotene was recently shown to be efficacious in combination with oral doxycycline, extending its use to patients with severe acne. The trifarotene formulation is reported by patients to be easily spreadable, has an elegant texture suited for face and trunk application, and is associated with low systemic exposure.27 Trifarotene studies showed that some patients treated with trifarotene vehicle alone also had improvements; we feel this is common in acne trials and likely at least partly due to the controlled conditions of a clinical trial and optimization of skin regimens. Overall, trifarotene is an important treatment option for acne vulgaris in patients 9 years or older, and is suitable for monotherapy in moderate acne on both the face and trunk and in combination with oral doxycycline may be considered for severe acne.


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Table 1. Key Results for Pivotal Trifarotene Clinical Trials in Acne.
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Figure 1. Acne vulgaris. Local tolerability in phase 3 clinical trials of trifarotene in acne. The severity scale score indicates 0 (none), 1 (mild), 2 (moderate), and 3 (severe). From Tan et al.
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Figure 2. Acne vulgaris. Reduction in acne lesion counts (absolute numbers) in patients treated with trifarotene plus doxycycline vs vehicle plus placebo. From Del Rosso et al.
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Figure 3. Acne vulgaris. Patient photos (a) trifarotene monotherapy (From Johnson et al) and (b) trifarotene plus doxycycline in severe acne. From Del Rosso et al.
Screenshot (21683).png

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Extremely mild effect on trifarotene by itself.

For severe cases they used trifarotene + doxycycline and it is clear that a large portion of the effect is due to the vehicle. They did not test against vehicle + doxycycline to clarify what portion of the effect is due to doxycycline, which makes me think tirfarotene has almost no contribution.

Low doses oral accutane 5-10mg/day will blow those results out of the water, without any doxycycline that affects the gut flora.
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