madman
Super Moderator
Abstract
Acne vulgaris is a common skin condition of the face and trunk that negatively impacts the quality of life. Trifarotene is a new first-in-class fourth-generation topical retinoid that has been uniquely studied in the treatment of both facial and truncal acne. Through selective agonism of the retinoic acid receptor (RAR)-gamma, the most predominant RAR isotype in the epidermis, trifarotene exerts more targeted, skin-specific effects than earlier generation retinoids. This narrative review summarizes all currently available literature regarding the use of trifarotene in acne vulgaris. We focus on efficacy, safety, and tolerability data and highlight the quality of life outcomes and patient-reported satisfaction. Future clinical trials and the clinical applicability of this novel medication in the treatment of acne are also discussed.
Introduction
Acne vulgaris, or acne, is a common cutaneous disorder that manifests as comedones, papules, pustules, and/or nodules on the face, neck, and trunk. Epidemiologic studies indicate acne affects approximately 9.4% of the global population, ranking it as the eighth most prevalent disease worldwide.1 Up to 85% of adolescents experience acne and while often mistakenly perceived as a disease limited to teenagers, many adults are affected as well.2,3 The psychosocial effects of acne are well documented and include negative impacts on self-perception, social functioning, and mental health.4–6
The pathogenesis of acne involves follicular hyperkeratinization with comedo formation and inflammation of the pilosebaceous unit, which is composed of the hair follicle and accompanying sebaceous gland. Acne lesions are thought to form via a complex dynamic of androgen-mediated sebaceous gland stimulation, microbial dysbiosis, and innate and adaptive immunoreactivity.7 Genetic predisposition and environmental factors such as stress and diet also likely influence the development of acne in susceptible individuals.8
The therapeutic paradigm for acne involves interventions with topical medications in mild-to-moderate disease with the addition of systemic medications as severity increases.9 Each therapy targets one or more pathophysiologic aspects of lesion formation.10 Topical retinoids, azelaic acid, and isotretinoin target follicular hyperproliferation and abnormal desquamation. Oral contraceptives, spironolactone, isotretinoin, and clascoterone diminish androgen-associated sebum production. Benzoyl peroxide, antibiotics, azelaic acid, and to a lesser extent, retinoids, mitigate Cutibacterium acnes proliferation. Topical retinoids, isotretinoin, and antibiotics exert anti-inflammatory properties. Given their targeted action in multiple pathways of disease activity, topical retinoids are critical to the acne treatment armamentarium.
Retinoids are synthetic derivatives of vitamin A and have been first-line therapies for both inflammatory and noninflammatory acne vulgaris for decades.11 They are efficacious as monotherapy and exhibit dose-dependent effects, yielding better responses with higher medication strengths.12 Retinoids also enhance penetration of other topical agents and act synergistically with various medications, such as antimicrobials, for improved efficacy.12 Mechanistically, retinoids mediate their effects by binding to the intranuclear retinoic acid receptor (RAR) or retinoic X receptor (RXR), each of which has three major isotypes (alpha, beta, and gamma). Receptor binding leads to downstream gene transcription and regulation of cellular differentiation, proliferation, and apoptosis.13
Four generations of retinoids have been developed, each with different molecular properties and RAR subtype specificity. All-trans retinoic acid (ATRA) or tretinoin (first generation), adapalene and tazarotene (third-generation), and trifarotene (fourth-generation) are all topical formulations approved by the US Food and Drug Administration (FDA) for the treatment of acne vulgaris. Trifarotene, approved in October 2019,14 is the only topical retinoid that binds selectively to RAR-gamma, which is the most predominant isoform in the epidermis.13 It is the first new topical retinoid approved by the FDA in over 20 years and the only one that has been studied in both facial and truncal acne. In this review, we summarize all published data regarding the safety and efficacy of trifarotene in the treatment of acne vulgaris (Figure 1).
*Pharmacologic Features of Trifarotene
Mechanism of Action and Downstream Biologic Effects
Trifarotene was developed following detailed characterization of the RAR-gamma ligand-binding domain by Thoreau et al.13 This drug exhibits high selectivity and potency for RAR-gamma, exerting minimal activity on RAR-alpha and RAR-beta (65-fold and 16-fold lower, respectively), and no activity on RXR.15 Activation of specific receptor subtypes influence unique downstream biologic and clinical effects.16 RAR binding leads to receptor dimerization and subsequent activation of retinoic acid receptor response element (RARE) genes. Topical retinoids, including trifarotene, generally confer comedolytic, anti-inflammatory, and antipigmenting properties in the skin, thus contributing to their therapeutic benefit in acne. Murine model data demonstrated that trifarotene yields superior comedolytic effects at lower concentrations than other retinoids such as tazarotene and ATRA, and also exert better antipigmenting effects than adapalene.15
Large-scale translational transcriptomics identified that trifarotene modulates known processes associated with retinoid use, such as epidermal differentiation, proliferation, and response to stress.15 Interestingly, gene expression studies also indicated that trifarotene affects novel pathways not previously associated with other retinoids, including:
1. Cell adhesion: trifarotene downregulates dystonin, weakening hemidesmosomes and intercellular adhesions, which allows keratinocyte migration and comedolysis;
2. Skin hydration: through upregulation of aquaporin 3 and peptidyl arginine deiminase 1, trifarotene influences skin barrier function and enhances cutaneous hydration; and
3. Proteolysis: trifarotene downregulates matrix metalloproteinases, which are proteins that degrade collagen and elastin, thus effectively promoting antiaging benefits in the skin.17
*Pharmacokinetics
Overall, trifarotene had a short half-life (2 to 9 hours) and did not accumulate systemically despite repeat applications. Most adverse events (AEs) were cutaneous in nature (erythema or skin irritation) and were slightly more severe in the 100 μg/g group. No biochemical or hematologic abnormalities were identified. Results from this study confirmed that trifarotene is locally and systemically well-tolerated as well as safe in both children and adults.
*Pivotal Phase III Studies
-12-Week Clinical Trials (PERFECT 1 and PERFECT 2)
-52-Week Clinical Trial
-Ongoing and Future Studies
*Use of Trifarotene in Clinical Practice and Future Directions
Conclusion
Acne vulgaris is a common cutaneous condition that negatively impacts QoL and self-esteem. Trifarotene is a first-in-class fourth-generation topical retinoid approved by the FDA for the treatment of acne vulgaris in patients ≥ 9 years of age. It is the first topical retinoid to be specifically studied in both facial and truncal acne. In clinical studies, trifarotene 50 μg/g cream yielded favorable safety, tolerability, and efficacy data in patients with moderate acne. Continuous improvement over time was observed according to both investigator and patient assessments in a long-term study. Trifarotene exhibits high selectivity for the skin-predominant RAR-gamma, thus theoretically rendering a superior local tolerability profile than the earlier generation retinoids, which bind more nonselectively to the different RAR subtypes. Direct comparison studies will investigate this hypothesis, as well as provide data regarding the efficacy of trifarotene relative to other topical retinoids.
Acne vulgaris is a common skin condition of the face and trunk that negatively impacts the quality of life. Trifarotene is a new first-in-class fourth-generation topical retinoid that has been uniquely studied in the treatment of both facial and truncal acne. Through selective agonism of the retinoic acid receptor (RAR)-gamma, the most predominant RAR isotype in the epidermis, trifarotene exerts more targeted, skin-specific effects than earlier generation retinoids. This narrative review summarizes all currently available literature regarding the use of trifarotene in acne vulgaris. We focus on efficacy, safety, and tolerability data and highlight the quality of life outcomes and patient-reported satisfaction. Future clinical trials and the clinical applicability of this novel medication in the treatment of acne are also discussed.
Introduction
Acne vulgaris, or acne, is a common cutaneous disorder that manifests as comedones, papules, pustules, and/or nodules on the face, neck, and trunk. Epidemiologic studies indicate acne affects approximately 9.4% of the global population, ranking it as the eighth most prevalent disease worldwide.1 Up to 85% of adolescents experience acne and while often mistakenly perceived as a disease limited to teenagers, many adults are affected as well.2,3 The psychosocial effects of acne are well documented and include negative impacts on self-perception, social functioning, and mental health.4–6
The pathogenesis of acne involves follicular hyperkeratinization with comedo formation and inflammation of the pilosebaceous unit, which is composed of the hair follicle and accompanying sebaceous gland. Acne lesions are thought to form via a complex dynamic of androgen-mediated sebaceous gland stimulation, microbial dysbiosis, and innate and adaptive immunoreactivity.7 Genetic predisposition and environmental factors such as stress and diet also likely influence the development of acne in susceptible individuals.8
The therapeutic paradigm for acne involves interventions with topical medications in mild-to-moderate disease with the addition of systemic medications as severity increases.9 Each therapy targets one or more pathophysiologic aspects of lesion formation.10 Topical retinoids, azelaic acid, and isotretinoin target follicular hyperproliferation and abnormal desquamation. Oral contraceptives, spironolactone, isotretinoin, and clascoterone diminish androgen-associated sebum production. Benzoyl peroxide, antibiotics, azelaic acid, and to a lesser extent, retinoids, mitigate Cutibacterium acnes proliferation. Topical retinoids, isotretinoin, and antibiotics exert anti-inflammatory properties. Given their targeted action in multiple pathways of disease activity, topical retinoids are critical to the acne treatment armamentarium.
Retinoids are synthetic derivatives of vitamin A and have been first-line therapies for both inflammatory and noninflammatory acne vulgaris for decades.11 They are efficacious as monotherapy and exhibit dose-dependent effects, yielding better responses with higher medication strengths.12 Retinoids also enhance penetration of other topical agents and act synergistically with various medications, such as antimicrobials, for improved efficacy.12 Mechanistically, retinoids mediate their effects by binding to the intranuclear retinoic acid receptor (RAR) or retinoic X receptor (RXR), each of which has three major isotypes (alpha, beta, and gamma). Receptor binding leads to downstream gene transcription and regulation of cellular differentiation, proliferation, and apoptosis.13
Four generations of retinoids have been developed, each with different molecular properties and RAR subtype specificity. All-trans retinoic acid (ATRA) or tretinoin (first generation), adapalene and tazarotene (third-generation), and trifarotene (fourth-generation) are all topical formulations approved by the US Food and Drug Administration (FDA) for the treatment of acne vulgaris. Trifarotene, approved in October 2019,14 is the only topical retinoid that binds selectively to RAR-gamma, which is the most predominant isoform in the epidermis.13 It is the first new topical retinoid approved by the FDA in over 20 years and the only one that has been studied in both facial and truncal acne. In this review, we summarize all published data regarding the safety and efficacy of trifarotene in the treatment of acne vulgaris (Figure 1).
*Pharmacologic Features of Trifarotene
Mechanism of Action and Downstream Biologic Effects
Trifarotene was developed following detailed characterization of the RAR-gamma ligand-binding domain by Thoreau et al.13 This drug exhibits high selectivity and potency for RAR-gamma, exerting minimal activity on RAR-alpha and RAR-beta (65-fold and 16-fold lower, respectively), and no activity on RXR.15 Activation of specific receptor subtypes influence unique downstream biologic and clinical effects.16 RAR binding leads to receptor dimerization and subsequent activation of retinoic acid receptor response element (RARE) genes. Topical retinoids, including trifarotene, generally confer comedolytic, anti-inflammatory, and antipigmenting properties in the skin, thus contributing to their therapeutic benefit in acne. Murine model data demonstrated that trifarotene yields superior comedolytic effects at lower concentrations than other retinoids such as tazarotene and ATRA, and also exert better antipigmenting effects than adapalene.15
Large-scale translational transcriptomics identified that trifarotene modulates known processes associated with retinoid use, such as epidermal differentiation, proliferation, and response to stress.15 Interestingly, gene expression studies also indicated that trifarotene affects novel pathways not previously associated with other retinoids, including:
1. Cell adhesion: trifarotene downregulates dystonin, weakening hemidesmosomes and intercellular adhesions, which allows keratinocyte migration and comedolysis;
2. Skin hydration: through upregulation of aquaporin 3 and peptidyl arginine deiminase 1, trifarotene influences skin barrier function and enhances cutaneous hydration; and
3. Proteolysis: trifarotene downregulates matrix metalloproteinases, which are proteins that degrade collagen and elastin, thus effectively promoting antiaging benefits in the skin.17
*Pharmacokinetics
Overall, trifarotene had a short half-life (2 to 9 hours) and did not accumulate systemically despite repeat applications. Most adverse events (AEs) were cutaneous in nature (erythema or skin irritation) and were slightly more severe in the 100 μg/g group. No biochemical or hematologic abnormalities were identified. Results from this study confirmed that trifarotene is locally and systemically well-tolerated as well as safe in both children and adults.
*Pivotal Phase III Studies
-12-Week Clinical Trials (PERFECT 1 and PERFECT 2)
-52-Week Clinical Trial
-Ongoing and Future Studies
*Use of Trifarotene in Clinical Practice and Future Directions
Conclusion
Acne vulgaris is a common cutaneous condition that negatively impacts QoL and self-esteem. Trifarotene is a first-in-class fourth-generation topical retinoid approved by the FDA for the treatment of acne vulgaris in patients ≥ 9 years of age. It is the first topical retinoid to be specifically studied in both facial and truncal acne. In clinical studies, trifarotene 50 μg/g cream yielded favorable safety, tolerability, and efficacy data in patients with moderate acne. Continuous improvement over time was observed according to both investigator and patient assessments in a long-term study. Trifarotene exhibits high selectivity for the skin-predominant RAR-gamma, thus theoretically rendering a superior local tolerability profile than the earlier generation retinoids, which bind more nonselectively to the different RAR subtypes. Direct comparison studies will investigate this hypothesis, as well as provide data regarding the efficacy of trifarotene relative to other topical retinoids.
