Targeting the aryl hydrocarbon receptor as a strategy to expand the therapeutic armamentarium in atopic dermatitis

Burden of atopic dermatitis

Atopic dermatitis (AD) is an intensely pruritic, chronic, relapsing, inflammatory skin disease that commonly presents in early childhood, but also affects adults, and severely impacts the quality of life of patients and their families (1). The incidence of AD has increased globally and it is one of the most common chronic inflammatory skin diseases in the world, with a US prevalence of 10–20% for children and adolescents and approximately 7% for adults (2–6). In a global burden of disease study, AD was ranked highest among skin diseases and in the top 15 of all non-fatal diseases (7). The economic burden of AD is also considerable, with average annual costs estimated to be more than $5.3 billion in the US in 2015 (8), and annual costs per patient estimated at more than $10,000 in the US (in 2018) (9) and €15,000 in Europe (in 2019) (10).

Most patients with AD are diagnosed in early childhood, but the disease can begin at any age (11). The cardinal and most burdensome symptom of AD is intense pruritus, which has a profound negative influence on sleep, physical and mental development, and the overall quality of life of patients, their families, and caregivers (2,12–14). Sleep impairments in children with AD are associated with increased risk of short stature, metabolic syndrome, mental illness, and neurocognitive dysfunction.

The individual pattern of disease in AD is variable, with acute exacerbations that can affect different areas of the body, including sensitive and intertriginous areas that can be difficult to treat. Symptoms of AD are also influenced by dynamic environmental factors such as temperature, humidity, allergens, irritants, and pollutants (15). Consequently, AD symptoms can be persistent or cycle over time so that a patient can have mild, moderate, or severe symptoms at different times, requiring frequent treatment adjustments to several topical and/or systemic therapies to manage their disease (16).

There is increased recognition that AD presents a broad spectrum of clinical phenotypes, reflective of its underlying pathophysiologic heterogeneity (17–19). Evidence for the clinical relevance of AD endotype variability is also apparent in the widely differing outcomes observed with current therapies and based on a range of factors, such as age, skin type, ethnicity, and disease severity (19). Given the heterogeneity in the natural course of AD, and the unpredictable individual trajectory of the disease, it is perhaps unsurprising that there are significant gaps in available therapies and that no single intervention has proven effective for all patients across the spectrum of disease severity or throughout the disease course.

In addition to treatments that can address the variable signs, symptoms, and needs of patients with AD, there is a gap in the armamentarium for therapeutics that can alter the natural course of disease (20). Disease-modifying therapy for AD could achieve lasting remission and/or prevent progression of the atopic march, because AD increases the risk for the development of other allergic diseases, which is particularly important in children where disease modification may prevent the development of allergies and asthma (21).

Gaps in current treatment

There is no curative therapy for AD and conventional management has relied on corticosteroids (topical and systemic), phototherapy, topical calcineurin inhibitors, topical phosphodiesterase 4 (PDE4) inhibitors, and systemic immunosuppressants such as cyclosporine. Topical corticosteroids are the mainstay of treatment for most patients with AD, regardless of disease severity; however, current options have well-documented limitations and safety concerns, including restrictions on duration, extent, and location of application (22). Furthermore, symptoms can rapidly recur after discontinuation of corticosteroids.

Since 2000, the US Food and Drug Administration has approved four systemic (23–26) and four topical AD medications (27–30) (Table 1). Of the systemic medications, none are approved for mild AD, and all either require injection and/or carry warnings and age restrictions due to safety concerns. Of the topical medications, only one is approved for the treatment of severe AD (tacrolimus), with its use restricted due to safety concerns, to second-line, short-term, non-continuous therapy in non-immunocompromised patients who fail to respond to other topical prescription treatments for AD. The topical AD medications are associated with adverse events of application site pain/burning/stinging (crisaborole, tacrolimus, and pimecrolimus), have restrictions on duration of use (tacrolimus and pimecrolimus), or have warnings and restrictions based on age and maximum body surface area treated (ruxolitinib). Current topical medications also require twice-daily application, which is known to be burdensome and detrimental to patient/caregiver satisfaction and adherence to therapy. Furthermore, as with corticosteroids, signs and symptoms of AD often recur soon after discontinuation of current topical medications.

Table 1. Tapinarof cream 1% compared with treatments for atopic dermatitis approved by the US FDA since 2000: Regulatory restrictions, warnings, and common adverse events.

Drug (year approved) Mechanism of action Route of administration	FDA Label Indications
	AD Severity	Age	Boxed Warnings, Restrictions, Common^a Adverse Events (AEs)
SYSTEMIC MEDICATIONS
Dupilumab (2017) Interleukin-4 alpha antagonist SC injection	Moderate to severe	≥6 months	Restrictions: AD that is refractory to topical therapy^b AEs: Injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye
Tralokinumab-ldrm (2021) Interleukin-13 antagonist SC injection	Moderate to severe	≥12 years	Restrictions: AD that is refractory to topical therapy^b AEs: Upper respiratory tract infections, conjunctivitis, injection site reactions, eosinophilia
Abrocitinib (2022) Janus kinase (JAK) inhibitor Oral tablet, once daily	Moderate to severe	≥12 years	Boxed warning: Serious infections, mortality, malignancy, major cardiovascular events, and thrombosis Restrictions: Patients with refractory AD not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants. AEs: Nasopharyngitis, nausea, headache, herpes simplex, increased blood creatine phosphokinase levels, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis, impetigo, hypertension, contact dermatitis, upper abdominal pain, abdominal discomfort, herpes zoster, thrombocytopenia
Upadacitinib (2022) JAK inhibitor Oral tablet, once daily	Moderate to severe	≥12 years	Boxed warning: Serious infections, mortality, malignancy, major cardiovascular events, and thrombosis Restrictions: Patients with refractory AD not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable AEs: Upper respiratory tract infections, acne, herpes simplex, headache, blood creatine phosphokinase levels increased, cough, hypersensitivity, folliculitis, nausea, abdominal pain, pyrexia, increased weight, herpes zoster, influenza, fatigue, neutropenia, myalgia, influenza-like illness
TOPICAL MEDICATIONS
Tacrolimus ointment 0.03% and 0.1% (2000) Calcineurin inhibitor Topical ointment, twice daily	Moderate to severe	≥2 years (0.03%) ≥16 years (0.1%)	Restrictions: Short-term, non-continuous chronic treatment in non-immunocompromised patients who have failed to respond adequately to other topical prescription treatments for AD, or when those treatments are not advisable AEs ≥10%: Burning sensation, pruritus, flu-like symptoms, skin erythema, headache
Pimecrolimus cream 1% (2001) Calcineurin inhibitor Topical cream, twice daily^c	Mild to moderate	≥2 years	Restrictions: Short-term, non-continuous chronic treatment in non-immunocompromised patients who have failed to respond adequately to other topical prescription treatments for AD, or when those treatments are not advisable AEs ≥10%: Burning sensation, headache, fever, nasopharyngitis, cough, bronchitis, upper respiratory tract infection
Crisaborole ointment (2016) Phosphodiesterase-4 inhibitor Topical ointment, twice daily^d	Mild to moderate	≥3 months	AEs: Application site pain
Ruxolitinib cream 1.5% (2021) JAK inhibitor Topical cream, twice daily	Mild to moderate	≥12 years	Boxed warning: Serious infections, mortality, malignancy, major cardiovascular events, and thrombosis Restrictions: Short-term, non-continuous chronic treatment in non-immunocompromised patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable Do not use more than one 60 g tube/week or one 100 g tube/2 weeks. Do not use on >20% body surface area AEs: Nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increased, urticaria, folliculitis, tonsillitis, rhinorrhea
Tapinarof cream 1% Aryl hydrocarbon receptor agonist Topical cream, once daily^e	Mild to severe	≥2 years	Boxed warning: None expected. Restrictions: None expected. AEs ≥5%: Folliculitis, headache, and nasopharyngitis.

^aAEs with incidence ≥1% except where indicated.

^bPatients with AD that is refractory to topical therapy refers to patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

^cPimecrolimus is approved by the FDA for twice-daily application. An evaluation of pimecrolimus twice daily versus once daily in the prevention of relapse of AD in pediatric patients demonstrated that during the double-blind maintenance period, the median time to first disease recurrence was 5 days for pimecrolimus twice daily and 6 days for pimecrolimus once daily (31).

^dCrisaborole is approved by the FDA for twice-daily application. Once-daily crisaborole ointment, 2%, demonstrated efficacy in reducing the mean number of flares versus vehicle when used as maintenance treatment in patients aged ≥3 months with mild-to-moderate AD in a 52-week trial (32). No effect was observed in maintenance of pruritus response.

^eTapinarof is not FDA approved for the treatment of AD; expected profile based on preliminary phase 3 data in AD and FDA prescribing information for the treatment of plaque psoriasis in adults (33–35).

AD: atopic dermatitis; BSA: body surface area; FDA: Food and Drug Administration; JAK: Janus kinase; SC: subcutaneous. Source: current FDA prescribing information (23–30,33).

To address these gaps, topical medications that meet the diverse needs of patients with AD across the full spectrum of disease severity with mechanisms of action that might significantly alter the course of the disease would be useful. Ideally, improved topical medications would achieve complete disease clearance with once-daily application, rapid control of symptoms such as itch, favorable safety and tolerability, and minimal systemic absorption with no drug-drug interactions; such mediations would be suitable for pediatric patients and for application to sensitive skin areas; and would have a cosmetically elegant formulation. Additional characteristics of improved topical mediations for AD include durable disease control off therapy, an absence of tachyphylaxis on therapy, and restoration of a healthy skin barrier. An ultimate goal is for new topical medications with efficacy that is maintained after treatment discontinuation, allowing treatment to be paused and restarted as needed, with the potential for disease modification to prevent disease progression and the atopic march.

The aryl hydrocarbon receptor

Advances in our understanding of mechanisms that underlie the pathogenesis and phenotypes of AD offer potential new targets for pharmacologic intervention. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that acts as a master regulator and communication node for multiple signaling pathways involved in skin homeostasis, immune responses, and epithelial barrier function (36,37). Targeting a transcription factor such as AhR represents a novel approach to therapy, with the potential to address several gaps in the current treatment armamentarium for AD.

As an aryl hydrocarbon receptor agonist, tapinarof, a nonsteroidal topical medication, has a profile that fundamentally differs from available AD treatments. Tapinarof specifically binds to, and activates, AhR to downregulate proinflammatory cytokines, reduce oxidative stress, and upregulate skin barrier protein expression (Figure 1) (38,39,43). Tapinarof also inhibits the generation, persistence, and cytokine production of resident memory T cells in the skin (42), which may explain the remittive effect demonstrated in patients with psoriasis who maintained clear or almost clear skin for approximately 4 months after cessation of treatment in a long-term phase 3 trial (45). In the context of AD, a mechanism of action with potential disease-modifying effects may be especially important for children, where restoration of the skin barrier could impact allergic sensitization and the atopic march and offer the opportunity for treatment-free periods.

Figure 1. Ligand-specific binding and activation of the aryl hydrocarbon receptor in the treatment of atopic dermatitis (36,38–44). Ligand-specific binding and activation of the aryl hydrocarbon receptor downregulates proinflammatory cytokines, reduces oxidative stress, upregulates expression of skin barrier components and inhibits the generation, persistence, and cytokine production of resident memory T cells in the skin. Some of the proposed downstream effects of tapinarof in AD are distinct from its mechanism of action in psoriasis. The proposed mechanism of action of tapinarof in psoriasis is described by Bissonnette et al. (36). AhR: aryl hydrocarbon receptor; ARNT: aryl hydrocarbon receptor nuclear translocator; DNA: deoxyribonucleic acid. Th2: T helper 2 cell; T_RM: resident memory T cell.

Preliminary results from the ADORING trials (NCT05014568; NCT05032859), presented as late breaking news at the European Academy of Dermatology and Venereology 2023 in Berlin (34,35), indicate that tapinarof cream 1% once daily has a rapid onset of action with robust efficacy and tolerability for both investigator- and patient-assessed outcomes in patients with AD down to 2 years of age. The primary efficacy endpoint of a Validated Investigator Global Assessment for Atopic Dermatitis™ response at Week 8, defined as a score of 0 or 1 and at least a 2-grade improvement from baseline, was achieved with high statistical significance in the tapinarof groups versus vehicle in both trials (approximately 45% versus 14% and 46% versus 18% in each trial, respectively, both p < 0.0001). The trials were vehicle controlled, but comparing outcomes across trials of AD therapies suggests that tapinarof cream is at least similar, if not superior, in efficacy compared with the other topical AD therapies, and even the injectable drugs.

The long-term extension trial, ADORING 3 (ongoing in 2023–24), will confirm if the durability (lack of tachyphylaxis), and potential to achieve complete clearance with disease control maintained while off therapy (i.e., a ‘remittive’ effect), that was observed with tapinarof cream 1% once daily in the phase 3 PSOARING psoriasis long-term extension trial (45), will be replicated in patients with AD. ADORING 3 will also provide further evidence regarding potential long-term use of tapinarof cream 1% once daily in patients down to 2 years of age with AD of any severity, including mild, to achieve consistent efficacy when used continuously or intermittently as needed, based on individual patient responses.

Targeting AhR to modulate multiple upstream actions provides the potential to address the diverse endotypes of AD, and the dynamic and variable individual course of disease, including potential disease-modifying effects (10,20). A remittive effect off therapy, as demonstrated in the treatment of plaque psoriasis with the AhR agonist tapinarof (45), could offer the opportunity for treatment that can be stopped and restarted, as needed, without concerns regarding rebound phenomena. Beyond the above-mentioned attributes, tapinarof has demonstrated no drug-drug interactions and minimal-to-no systemic absorption (33,46). The targeted effect of tapinarof in the skin and minimal systemic exposure confer an intrinsically low potential for drug-drug interactions and systemic side effects. These properties have the potential to improve the treatment of AD by rapidly relieving burdensome symptoms including pruritus, improving quality of life, and reducing reliance on systemic agents.

Discussion and conclusions

AD is a complex disease that encompasses a spectrum of clinical presentations reflective of underlying biologic heterogeneity, resulting in variable outcomes with current therapeutic options. Despite recent developments, key gaps remain in the AD therapeutic armamentarium for topical medications that can provide robust and long-term efficacy, across the spectrum of severity, without restrictions on the duration, location, or extent of application for all patients with AD, regardless of age and disease characteristics. Preliminary results from the ADORING trials indicate that targeting AhR is a valid approach that may address these gaps, with the potential to significantly transform the treatment of AD. Once-daily tapinarof is not associated with application site burning or safety concerns that often restrict the use of current options.

The role of AhR in regulating epidermal barrier function and skin homeostasis underlies the potential of this strategy to address diverse individual patient needs in AD. Long-term data are needed to demonstrate whether this strategy has the potential for disease modification in AD, including reducing the risk of developing atopic comorbidities, such as allergies and asthma.

In view of the clinical effectiveness of tapinarof cream demonstrated in inflammatory skin diseases, targeting AhR may offer a novel therapeutic strategy in other diseases, beyond allergies and asthma, involving homeostasis and immune function of epithelial barrier tissues. New formulations targeting specific tissues may enable the development of targeted AhR therapies for inflammatory gastrointestinal, ophthalmic, and neurological diseases.

Disclosure statement

L.F.E. has served as a consultant, advisor, or investigator for AbbVie, Amgen, Arcutis, Aslan, Dermavant Sciences, Inc., Eli Lilly, Forté, Galderma, Incyte, Janssen, LEO Pharma, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, and UCB Pharma. J.I.S. has received honoraria or grants, and/or has served as a consultant, an advisory board member, or speaker for Afyx, AOBiome, Arena, Asana, BiomX, Bluefin Biomedicine, Bodewell, Boehringer Ingelheim, Celgene, Dermavant Sciences Inc., Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Kiniksa, LEO Pharma, Luna, Menlo, Novartis, Pfizer, RAPT, Regeneron, and Sanofi Genzyme. A.A.H. has received research support paid to the medical school from AbbVie, Arcutis, Dermavant Sciences Inc., and Pfizer; honoraria received from GSK, Sanofi Regeneron, and Ortho Dermatologics (as part of a Data Safety Monitoring Board); honoraria received from Dermavant Sciences, Inc., Incyte, LEO Pharma, Pfizer, Arcutis, Sun Pharma, Galderma, Novan, and Verrica. M.B. has been an investigator for Regeneron, Sanofi, and Incyte, and served as a consultant and/or an advisory board member for AbbVie, Amgen, Dermavant Sciences, Inc., Eli Lilly, Incyte, Janssen, LEO Pharma, Pfizer, Regeneron, and Sanofi Genzyme.

Additional information

Funding

Editorial assistance was funded by Dermavant Sciences, Inc.