Novel Aryl Hydrocarbon Receptor Agonist Vtama® (tapinarof) Cream 1% for Treatment of Atopic Dermatitis

Atopic dermatitis (AD) is a chronic relapsing and remitting inflammatory skin disease that affects both children and adults and, even when mild, can have a significant negative impact on quality of life.¹ The multifactorial pathophysiology of the disease involves elements of barrier dysfunction, alterations in cell-mediated immune responses and IgE-mediated hypersensitivity related to an imbalance in Th2 to Th1 cytokines.^2,3 The trajectory of the disease is variable with intermittent flares, an inherent feature of its course.^2,3

Treatment for mild-to-moderate AD is most often initiated with topical therapy. Despite advances in topical steroidal and nonsteroidal formulations, however, limitations among conventional and newer classes leave significant treatment gaps: many are formulated as ointments rather than preferred creams;⁴ twice-daily dosing regimens may compromise treatment adherence;^5,6 and available nonsteroidal alternatives have shown suboptimal efficacy.⁷ Well-recognized adverse effects may also affect preference and limit adherence, including steroid-induced skin atrophy, application-site discomfort with calcineurin inhibitors and the phosphodiesterase 4 inhibitor crisaborole, and safety restrictions with ruxolitinib cream.^2,3,7,8

Tapinarof cream 1%, a nonsteroidal, topical aryl hydrocarbon receptor (AhR) agonist is approved by the FDA for the topical treatment of AD in adults and pediatric patients 2 years of age and older. It is applied to affected areas in a “thin layer” once daily.⁹

The mechanism of action and formulation of tapinarof cream provide an alternative therapeutic approach that has the potential to address important gaps in the current array of AD treatment options.^1-3

Novel Mechanism of Action

The AhR, a ligand-dependent transcription factor, serves as a master regulator and communication node for multiple pathways involved in the pathophysiology of AD, including skin homeostasis, immune response, and epithelial barrier function.⁷ Tapinarof reduces the production of pro-inflammatory cytokines (interleukin-17, IL-22, IL-23) while increasing anti-inflammatory IL-10 production.^{1-3, 7,8} Upregulation of filaggrin expression and other proteins essential for skin barrier integrity facilitate restoration of the barrier. Tapinarof also reduces oxidative stress in AD, through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and by direct scavenging of reactive oxygen species.^{1-3, 7,8} 

Clinical Efficacy

Phase 3 Trials

The ADORING-1 and ADORING-2 clinical trials were identical phase 3, randomized, double-blind, vehicle-controlled, multicenter studies (n = 813) conducted in the US and Canada that evaluated the efficacy and safety of tapinarof cream 1% or vehicle cream applied once daily in individuals with AD as young as age 2 years.³ Following a 30-day screening period, eligible participants were randomly assigned 2:1 to apply tapinarof or vehicle cream to any lesion, regardless of anatomic location, once-a-day for 8 weeks. A majority of participants had moderate disease at baseline, ie, a Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 3, and at least 10% had severe AD (vIGA-AD of 4). Inclusion also required an Eczema Area and Severity Index (EASI) score of 6 or greater and 5% to 35% body surface area (BSA) BSA involvement at screening and baseline.³ Eighty percent of the final cohort were between 2 and 17 years of age and the median age was 11. The overall cohort was racially diverse, with 51% self-identified as White, 31% as Black, and 12% as Asian. For ethnicity, 78% of subjects identified as non-Hispanic or LatinX.³

The primary efficacy endpoint in both trials was the proportion of patients with a vIGA-AD score of 0 (clear) or 1 (almost clear) and an improvement of 2 grades or more from baseline at week 8.³

Key secondary endpoints included the proportion of participants with an improvement of 75% or more in EASI score from baseline at week 8 (EASI75), and the proportion of participants aged 12 years and older with a baseline Peak Pruritus Numerical Rating Scale (PP-NRS) of 4 or greater who achieved PP-NRS response (4 point or greater reduction in the mean weekly PP-NRS total score from baseline at week 8).³

In both trials, significantly more participants treated with tapinarof 1% than vehicle achieved the primary efficacy endpoint of a vIGA-AD response at week 8: 45.4% in the tapinarof arm compared with 13.9% with vehicle in ADORING 1 (P <.001), and 46.4% vs 18.0% in ADORING 2 (P <.001).³

For the key secondary endpoint of EASI75 response the differences were also statistically superior for tapinarof in both trials at week 8: 55.8% of tapinarof-treated patients vs 22.9% for vehicle in ADORING 1 (P <.001), and 59.1% vs 21.2% in ADORING 2 (P <.001).³

Tapinarof-treated participants also reported greater improvements in itch vs those treated with vehicle across age groups in both trials, with a statistically significant improvement in PP-NRS response in those patients aged 12 and older in ADORING 1 (55.8% vs s 34.2%; P = .037) and ADORING 2 (52.8% vs 24.1%; P =.001); in those aged younger than 12 years (60.7% vs 28.0%; P =.001 and 60.0% vs 40.8%; P =.041); and overall (61.1% vs 34.0%; P <.001 and 57.4% vs 33.0%; P <.001). Many participants and caregivers reported prompt relief of itch, for some within 24 hours after the first application.³

Treatment-free interval. ADORING 3, a 48-week open-label, long-term extension LTE study (n = 728), evaluating the durability of disease control following treatment with tapinarof 1% cream. enrolled eligible participants from ADORING 1 and 2, from a 4-week pharmacokinetics trial, as well as new enrollees aged 2 to 17 years who had vIGA-AD scores of 2 or greater, were tapinarof-naïve and had not met inclusion criteria for the registration trials.^10,11

Participants were followed up to 48 weeks, evaluated for safety and efficacy endpoints that included achieving complete disease clearance (vIGA-AD 0), and achieving clear or almost clear skin (vIGA-AD = 0 or 1). Participants with any disease activity at ADORING 3 entry were treated with tapinarof 1% until achieving vIGA-AD = 0 or study completion. For the 378 participants who entered with or reached vIGA-AD = 0 in the study and discontinued tapinarof treatment, mean duration of the first treatment-free (remittive) interval was approximately 80 consecutive days. Any participants whose AD returned to vIGA-AD of 2 or greater were re-treated with tapinarof until they reached complete disease clearance again or study completion. The safety profile with long term use was generally consistent with the safety profile observed at week 8.^10,11

Tapinarof Safety and Tolerability

The safety profile of tapinarof was favorable across the phase 3 ADORING development program. The most common treatment-emergent adverse events (TEAEs) with an incidence of 1% or greater were upper respiratory tract infection (12%), folliculitis 9%), lower respiratory tract infection (5%), headache (4%), asthma , vomiting, ear infection, pain in extremity (each 2%), and abdominal pain (1%). Most TEAEs were described as mild or moderate and study discontinuation rates were lower among participants treated with tapinarof than vehicle in both ADORING 1 (1.9% vs 3.6% vehicle) and ADORING 2 (1.5% vs 3.0% vehicle). There were no serious TEAEs reported in any of the phase 3 trials.⁹

ADORING 1 and ADORING 2 included 654 pediatric participants aged 2 years and older with moderate to severe atopic dermatitis; 436 were treated withtapinarof cream 1%. Adverse reactions occurring more frequently in pediatric subjects compared to adults were upper respiratory tract infection and ear infection.⁹

Local tolerability was also favorable across the phase 3 trials with no-to-minimal burning/stinging or itching (patient-reported) from first application through week 8, no-to-minimal irritation reported by investigators, with the same assessment holding true for sensitive skin.¹

A survey of patient satisfaction with tapinarof cream 1% administered during the ADORING 3 trial found the majority of participants and caregivers agreed or strongly agreed on the cream’s cosmetic elegance, quick absorption, and application ease.¹²

Tapinarof cream 1% has shown minimal-to-no systemic absorption under maximal usage conditions, including in study participants down to 2 years of age with extensive AD, when applied over a high BSA affected (up to 90%).¹³The pharmacokinetics of tapinarof are consistent with localized skin-targeted effects, a low potential for systemic AEs, and no drug–drug interactions.¹³

Important Safety Information

Use in Specific Populations

Pregnancy and Latation. Data on use of tapinarof cream 1% by pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Similarly, there are no data available regarding the presence of tapinarof in human milk or on the effects of tapinarof on the breastfed infant, or on milk production⁹.

Geriatric Use. In the ADORING 1 and ADORING 2 clinical trials, 20 of the 541 participants (3.7%) who were treated with tapinarof cream 1% were aged 65 years and older; 4 (0.7%) were 75 years of age and older. No overall differences in efficacy, safety, or tolerability were observed between subjects 65 years of age and older and younger adult participants⁹.

References

1. Stein Gold L, Del Rosso J, Ehst BD, et al. Tapinarof cream 1% once daily was well tolerated in adults and children with atopic dermatitis in two phase 3 randomized trials. J Dermatolog Treat. 2025;36(1). doi:10.1080/09546634.2024.2444489

2. Eichenfield LF, Silverberg JI, Hebert AA, et al. Targeting the aryl hydrocarbon receptor as a strategy to expand the therapeutic armamentarium in atopic dermatitis. J Dermatolog Treat. 2024;35(1):2300354. doi:10.1080/09546634.2023.2300354

3. Silverberg JI, Eichenfield LF, Hebert AA, et a. Tapinarof cream 1% once daily: Significant efficacy in the treatment of moderate to severe atopic dermatitis in adults and children down to 2 years of age in the pivotal phase 3 ADORING trials. J Am Acad Dermatol.
2024;91(3):457-465. doi:10.1016/j.jaad.2024.05.023

4. Eastman WJ, Malahias S, Delconte J, DiBenedetti D. Assessing attributes of topical vehicles for the treatment of acne, atopic dermatitis, and plaque psoriasis. Cutis. 2014;94(1):46-53.

5. Hix E, Gustafson CJ, O’Neill JL, et al. Adherence to a five-day treatment course of topical fluocinonide 0.1% cream in atopic dermatitis. Dermatol Online J. 2013;19(10):20029. doi:10.5070/D31910020029

6. Capozza K, Schwartz A. Does it work and is it safe—parents’ perspectives on adherence to medication for atopic dermatitis. Pediatr Dermatol. 2020;37(1):58-61. doi:10.1111/pde.13991

7. Eichenfield LF, Silverberg JI, Hebert AA, et al. Targeting the aryl hydrocarbon receptor as a strategy to expand the therapeutic armamentarium in atopic dermatitis. J Dermatolog Treat. 2024;35(1):2300354. doi:10.1080/09546634.2023.2300354

8. Simpson EL, Eichenfield LF, Alonso-Llamazares J, et al. Roflumilast cream, 0.15%, for atopic dermatitis in adults and children: INTEGUMENT-1 and INTEGUMENT-2 randomized clinical trials. JAMA Dermatol. 2024;160(11):1161-1170. doi:10.1001/jamadermatol.2024.3121

9. Vtama [prescribing information]. Dermavant. Accessed May 22, 2025. https://vtama.com/PI/

10. Silverberg J, Bissonnette R, Stein Gold L, et al. Tapinarof cream 1% once daily: Maintenance of low disease activity including pruritus through end of the treatment-free interval in a long-term extension trial in patients down to 2 years of age with atopic dermatitis. Poster presented at the American Academy of Dermatology Conference 2025. March 7-11, 2025. Orlando, Florida. Accessed May 22, 2025.

11. New analysis of Organon’s VTAMA® (tapinarof) cream, 1% phase 3 data shows atopic dermatitis disease activity remained low after treatment-free interval in adults and children 2 years of age and older. News release. Organon. Published March 8, 2025. Accessed May 22, 2025. https://www.organon.com/news/new-analysis-of-organons-vtama-tapinarof-cream-1-phase-3-data-shows-atopic-dermatitis-disease-activity-remained-low-after-treatment-free-interval-in-adults-and-children-2-years-of-ag/

12. Hebert AA, Del Rosso J Johnson SM, et al. Patient and parent/caregiver satisfaction with efficacy and cosmetic elegance of tapinarof cream, 1% once daily in a long-term extension trial in adults and children down to age 2 years with atopic dermatitis. J Skin. 2024;8(6)s458. doi:10.25251/skin.8.supp.458

13. Paller A, Hebert AA, Jett JE, Brown PM, Rubenstein DS, Piscitelli SC. Tapinarof cream 1% once daily for the treatment of extensive atopic dermatitis in adolescents and children: 4-week maximal use trial. Br J Dermatol. 2023;188(suppl_2). doi:10.1093/bjd/ljac140.005