Tapinarof Cream for Adults and Children with Atopic Dermatitis—Efficacy by Race and Fitzpatrick Skin Type in Two Phase 3 Randomized Clinical Trials

Abstract

Introduction

Patients with atopic dermatitis (AD) and skin of color have heterogeneous presentations and treatment outcomes, however, they are underrepresented in trials. In the ADORING 1 and 2 phase 3, 8-week randomized trials, tapinarof cream 1% once daily (QD) demonstrated superior efficacy versus vehicle in adults and children down to age 2 years with AD. These analyses evaluate efficacy of tapinarof cream 1% QD stratified by race and Fitzpatrick skin type.

Methods

The primary endpoint was a Validated Investigator Global Assessment for Atopic Dermatitis™ (vIGA-AD™) score of 0 (clear) or 1 (almost clear) and ≥ 2-grade improvement from baseline at week 8. Secondary endpoints included achieving ≥ 75% improvement in Eczema Area and Severity Index (EASI75). Efficacy evaluations used race categories of Asian, Black or African American, and white, and Fitzpatrick skin types I–III and IV–VI.

Results

In ADORING 1 and 2, 407 and 406 patients were randomized to tapinarof or vehicle QD (7.3–17.0% Asian; 25.9–35.1% Black/African American 43.0–57.7% white), respectively. Across trials, > 50% had Fitzpatrick skin types IV–VI. Tapinarof demonstrated significant efficacy in adults and children. By race in both trials, the primary endpoint was met by consistently higher proportions treated with tapinarof than vehicle: Asian, 39.5–48.9% versus 3.7–18.5%; Black/African American, 43.1–47.0% versus 17.5–24.1%; white, 49.4–52.1% versus 12.2–14.5%, respectively. Similar, superior responses were reported across Fitzpatrick skin type groups with tapinarof versus vehicle: I–III, 44.8–49.9% versus 13.5–17.7%; IV–VI, 46.8–49.6% versus 15.3–19.5%. EASI75 responses were similarly higher and consistent with tapinarof versus vehicle. Adverse events were mostly mild or moderate, leading to low trial discontinuations (lower with tapinarof than vehicle).

Conclusions

Tapinarof demonstrated consistent efficacy and was well tolerated versus vehicle in a large, diverse population with AD, regardless of race or Fitzpatrick skin type.

Trial registration

Clinicaltrials.gov, NCT05014568, NCT05032859.

Graphical Abstract avaliable for this article.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-025-01489-w.

Key Summary Points

Why carry out this study?

Atopic dermatitis (AD) has heterogeneous presentations and treatment outcomes; patients with skin with skin of color are underrepresented in AD therapy trials.

Tapinarof cream 1% once daily (QD) demonstrated consistent efficacy and was well tolerated compared with vehicle in adults and children down to 2 years of age in two phase 3, 8-week randomized trials that included approximately 50% of patients with skin of color.

Tapinarof efficacy was analyzed by patient self-identified race and investigator-assessed Fitzpatrick skin type.

What was learned from this study?

Tapinarof cream 1% QD was consistently efficacious for the treatment of patients down to 2 years of age with AD regardless of race (Asian, Black or African American, or white) or Fitzpatrick skin type (I–III versus IV–VI).

Tapinarof is a once-daily, nonsteroidal cream that improves AD symptoms in patients down to 2 years of age with AD, regardless of race or skin type.

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by intense pruritus that substantially impacts health-related quality of life [1–3]. There is increasing evidence on variations by race and ethnicity in the prevalence, clinical characteristics, and burden of AD [2, 4–8]. AD is highly prevalent in patients with skin of color, and in the USA, AD affects approximately 19% of Black children and 12% of Asian children, compared with 16% of white children [9, 10]. There is a lack of data on AD treatment in patients with skin of color [11–13].

The term “skin of color” may be used to refer to the skin characteristics of a diverse spectrum of individuals who self-identify with race categories including Asian, Black or African American, American Indian, Alaska Native, or Pacific Islander; a high proportion of these individuals may be classified as having Fitzpatrick skin phototypes IV–VI [11, 12]. The Fitzpatrick skin type scale was originally used to assess reactivity of the skin of white individuals to sunlight or ultraviolet light and was adapted to categorize skin of any color; the scale is widely used in dermatology research and practice for this purpose [12, 14].

The clinical presentation of AD can vary across the spectrum of race or ethnic groups and skin phototypes [1, 2]. Black or African American patients may present more frequently with xerosis, extensor involvement, and prurigo nodularis lesions [8, 9, 15–18], whereas East Asian patients (Japanese or Korean patients in one small study [19]) may be more likely to have well-demarcated and often psoriasiform lesions [17, 19]. Pigment changes, including postinflammatory hypopigmentation and hyperpigmentation, are another distinct feature of AD, and together with diffuse xerosis, can be more prominent in dark skin [4]. Pigment changes and xerosis may be more stigmatizing for these individuals due to greater visibility on dark skin, consequently causing a greater impact on quality of life [4]. Dyspigmentation is also a potential side effect of topical treatments in patients with skin of color, including hypopigmentation from topical corticosteroids, or postinflammatory hyperpigmentation in the context of application site reactions [20–22]. The occurrence of hypopigmentation or hyperpigmentation is rarely assessed in clinical trials, although it is a major concern for patients with skin of color [11]. Notably, the clinical heterogeneity of AD in patients with skin of color can make diagnosis and treatment more challenging, leading to underdiagnosis and underappreciation of disease severity, especially among primary care providers and nondermatologic specialties [20–22].

Potential phenotypic variations have been identified between patient groups with AD; this includes the relative importance of different inflammatory pathways according to race and ethnicity in a small number of studies [7, 9, 15, 23]. Additionally, variations based on race or ethnicity in polymorphisms of genes involved in innate and adaptive immunity have been described [9]. Potential phenotypic, endotypic, and epidemiologic variations across populations underscore the need to include a diverse range of patients in clinical trials to reflect treatment in real-world clinical practice [7, 15]. This is especially important as these factors could influence the effectiveness and safety of treatments for AD [11].

Tapinarof cream 1% (VTAMA; Dermavant Sciences, an Organon Company) is a nonsteroidal, topical aryl hydrocarbon receptor (AhR) agonist approved by the US Food and Drug Administration for the treatment of AD in adults and children down to 2 years of age, and for plaque psoriasis in adults, with no warnings, contraindications, drug–drug interactions, or restrictions on location, extent, or duration of use [24]. Tapinarof is also under investigation for the treatment of plaque psoriasis in children down to 2 years of age. AhR is a transcription factor that acts as a master regulator and plays a role in multiple signaling pathways involved in skin homeostasis, immune responses, and epithelial barrier function [25]. Tapinarof binds to and activates AhR to restore the skin barrier through upregulation of skin barrier components (filaggrin, loricrin, hornerin, involucrin, and ceramide lipids), downregulation of proinflammatory cytokines (interleukin [IL]−4, IL-5, IL-13, and IL-31) that are implicated in AD and itch, and reduction in oxidative stress in the skin through direct free radical scavenging and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway [25–27].

In ADORING 1 and ADORING 2 (NCT05014568, NCT05032859), two pivotal phase 3, randomized, double-blind, vehicle-controlled trials, tapinarof cream 1% once daily (QD) demonstrated statistically significant efficacy and was well tolerated in adults and children down to 2 years of age with AD [28].

Since race has the potential to be a factor in the response to AD therapies, the aim of this analysis was to evaluate the efficacy of tapinarof cream compared with vehicle cream in ADORING 1 and 2, stratified by patient self-identified race and investigator-assessed Fitzpatrick skin type.

Methods

Trial Design

In ADORING 1 and 2, two identically designed, phase 3, double-blind, randomized, vehicle-controlled multicenter (USA and Canada) trials, patients with moderate-to-severe AD were randomized 2:1 to tapinarof cream 1% QD or vehicle QD for 8 weeks (Supplementary Fig. 1) [28]. To address potential confounding factors, randomization was stratified so that the majority in each group had moderate AD (Validated Investigator Global Assessment for Atopic Dermatitis™ [vIGA-AD™] score of 3) at baseline, with at least 10% having severe AD (vIGA-AD™ = 4) [28]. Patients were also stratified by age group with approximately 15% in each age category (2–6 years, 7–11 years, 12–17 years, ≥ 18 years), with no more than 20% of randomized participants being adults. A validated, code-controlled randomization system with pseudo-random number generation was used to generate the allocation sequence, with access to the codes controlled and documented. Participants, their parents or caregivers, investigators and site staff, and the sponsor were blinded to the assigned interventions. Following the double-blind period, eligible patients could enroll in ADORING 3 (NCT05142774), an open-label, long-term trial, for an additional 48 weeks of tapinarof treatment [29].

Fig. 1.

Achievement of the primary endpoint^a at week 8 with tapinarof versus vehicle across race categories. ^avIGA-AD™ score of 0 or 1 and ≥ 2-grade improvement from baseline. ^bOther groups includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or multiple races. Patients identifying as a race grouped within other groups were too few to make any meaningful interpretations. Intention-to-treat, multiple imputation. QD once daily, SE standard error of the mean, vIGA-AD™ Validated Investigator Global Assessment for Atopic Dermatitis™

The trials were conducted according to Good Clinical Practice and the Declaration of Helsinki of 1964 and its later amendments. The trials were approved by the Central Institutional Review Board, Advarra IRB, on 4 June 2021 (ADORING 1) and 2 July 2021 (ADORING 2). Advarra IRB is registered with the Office for Human Research Protections (OHRP) and the Food and Drug Administration under IRB#00000971. All patients or parents/legal guardians provided written informed consent, including consent for clinical photography and publication of their clinical images. Consent for the publication of this manuscript was provided by the authors and the sponsor.

Trial Participants

Key inclusion and exclusion criteria for ADORING 1 and 2 have been previously reported [28]. Patients were adults and children down to 2 years of age with a diagnosis of AD by Hanifin and Rajka criteria [30], with a vIGA-AD™ score of ≥ 3 (moderate or severe), an Eczema Area and Severity Index (EASI) score of ≥ 6, and body surface area involvement of 5–35% at screening and baseline.

Patients could provide their self-identified race (white, Asian, Black or African American, or other groups [including American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or multiple races]). Patients could also provide their self-identified ethnicity as Hispanic or Latino, or Not Hispanic or Latino. The investigators at each trial site assessed patients’ Fitzpatrick skin type (I–VI) at the in-person screening visit.

Safety

Safety assessments included incidence and frequency of treatment-emergent adverse events (TEAEs), vital signs, physical examinations, and laboratory tests. The trials were not designed to evaluate safety by race or Fitzpatrick skin type subgroups.

Outcome Measures

The primary endpoint was the vIGA-AD™ response, defined as the proportion of patients with a vIGA-AD™ score of 0 (clear) or 1 (almost clear) and ≥ 2-grade improvement from baseline at week 8. Secondary efficacy endpoints included the proportion with ≥ 75% improvement in EASI score (EASI75) from baseline at week 8. For patients (or parents/legal guardians) providing written consent for clinical photography, target lesions selected by the investigator were serially photographed prior to the first application of investigational product and at intervals during treatment.

Efficacy analyses by self-identified race were prespecified; for these analyses, race categories of Asian, Black or African American, and other categories were categorized as skin of color. In the analyses presented here, efficacy was not evaluated by self-identified ethnicity. Investigator-assessed Fitzpatrick skin types were grouped as I–III and IV–VI (where types IV, V, and VI are generally considered as skin of color [12]), and exploratory efficacy analyses by Fitzpatrick skin type groups were performed post hoc. Exploratory comparisons between race categories and between skin type groups were also performed post hoc.

Statistical Analyses

Enrollment of 400 patients in each trial was estimated to provide 97.2% power to detect a significant difference (two-sided P < 0.05), assuming 45% of patients in the tapinarof arms and 25% in the vehicle arms achieved the primary endpoint on the basis of Fisher’s exact test sample size calculation that assumed 15% of patients receiving tapinarof cream and 30% receiving vehicle cream would be lost to follow-up at week 8. The trials were not powered to evaluate the efficacy of tapinarof versus vehicle by race, ethnicity, or Fitzpatrick skin type groups.

Efficacy was analyzed on the basis of the intention-to-treat population, comprising all randomized patients. The primary efficacy endpoint was analyzed using a Cochran–Mantel–Haenszel test stratified by vIGA-AD™ score at baseline (score of 3 or 4) and age group (2–6 years, 7–11 years, 12–17 years, and ≥ 18 years). Efficacy outcomes based on race categories and Fitzpatrick skin type groups were summarized. Missing data for analyses of vIGA-AD™ and EASI75 were handled using multiple imputation (MI), in which 100 imputations were generated using the PROC MI procedure of SAS software version 9.4. Multiple-imputation standard errors reflect variation both within and across imputations.

Results

Baseline Patient Demographics and Disease Characteristics

In total, 602 and 540 patients were screened and 407 and 406 were randomized in ADORING 1 and 2, respectively (Supplementary Fig. 2). Both trials were conducted in the USA and Canada and started in September 2021; ADORING 1 finished in March 2023 and ADORING 2 finished in February 2023. Disease and demographic characteristics were similar across the arms of each trial at baseline, with 83.7–90.4% of patients having a vIGA-AD™ score of 3 (moderate), mean age of 15.6–16.7 years, and 43.0–48.2% of patients were male. Approximately 50% of patients had skin of color: 7.3–17.0% were Asian, 25.9–35.1% were Black or African American, and 2.6–5.9% were other groups; and 43.0–57.7% were white (Table 1). By Fitzpatrick skin type, 41.7–50.0% of patients were classified as having types I–III and 50.0–58.3% had types IV–VI across trials.

Fig. 2.

Achievement of the primary endpoint^a at week 8 with across Fitzpatrick skin type group categories. ^avIGA-AD™ score of 0 or 1 and ≥ 2-grade improvement from baseline at week 8 by Fitzpatrick skin type groups, where categories IV–VI indicate patients with skin of color. Intention-to-treat, multiple imputations. QD once daily, SE standard error of the mean, vIGA-AD™ Validated Investigator Global Assessment for Atopic Dermatitis™

Table 1.

Baseline patient demographics and clinical characteristics

Characteristic	ADORING 1		ADORING 2
	Tapinarof cream 1% QD (n = 270)	Vehicle QD (n = 137)	Tapinarof cream 1% QD (n = 271)	Vehicle QD (n = 135)
Age, years, mean (SD)	15.6 (16.6)	15.6 (16.5)	16.4 (16.2)	16.7 (16.1)
Female, n (%)	140 (51.9)	71 (51.8)	154 (56.8)	77 (57.0)
Male, n (%)	130 (48.1)	66 (48.2)	117 (43.2)	58 (43.0)
Race, n (%)
Asian	26 (9.6)	10 (7.3)	39 (14.4)	23 (17.0)
Black or African American	70 (25.9)	38 (27.7)	95 (35.1)	47 (34.8)
White	152 (56.3)	79 (57.7)	124 (45.8)	58 (43.0)
American Indian or Alaska Native	2 (0.7)	0 (0.0)	0 (0.0)	2 (1.5)
Native Hawaiian or other Pacific Islander	0 (0.0)	0 (0.0)	1 (0.4)	0 (0.0)
Multiple races	14 (5.2)	5 (3.6)	6 (2.2)	2 (1.5)
Not reported	6 (2.2)	5 (3.6)	6 (2.2)	3 (2.2)
Fitzpatrick skin type, n (%)
I	9 (3.3)	7 (5.1)	11 (4.1)	4 (3.0)
II	66 (24.4)	22 (16.1)	52 (19.2)	28 (20.7)
III	60 (22.2)	31 (22.6)	50 (18.5)	33 (24.4)
IV	67 (24.8)	30 (21.9)	71 (26.2)	31 (23.0)
V	44 (16.3)	40 (29.2)	63 (23.2)	27 (20.0)
VI	24 (8.9)	7 (5.1)	24 (8.9)	12 (8.9)
Skin types I–III	135 (50.0)	60 (43.8)	113 (41.7)	65 (48.1)
Skin types IV–VI	135 (50.0)	77 (56.2)	158 (58.3)	70 (51.9)
vIGA-AD™ score, n (%)
3 (Moderate)	244 (90.4)	122 (89.1)	228 (84.1)	113 (83.7)
4 (Severe)	26 (9.6)	15 (10.9)	43 (15.9)	22 (16.3)
EASI score, mean (SD)	12.2 (5.0)	12.9 (5.6)	13.5 (5.6)	13.1 (4.7)
BSA affected, mean (SD)	16.5 (8.7)	17.7 (9.5)	17.1 (8.7)	15.8 (7. 9)
PP-NRS total score, mean (SD)
All	6.8 (2.3)	6.5 (2.4)	6.7 (2.4)	6.9 (2.1)
≥ 12 yearsa	6.5 (2.4)	6.3 (2.3)	6.3 (2.4)	6.5 (2.2)
< 12 years	7.0 (2.3)	6.6 (2.5)	7.1 (2.3)	7.4 (1.8)

The vIGA-AD™ scale is copyright ©2017 Eli Lilly and Company—Used with permission under a Creative Commons Attribution—No Derivatives 4.0 International License. https://creativecommons.org/licenses/by-nd/4.0/

^aThe PP-NRS is a well-defined and reliable patient-reported outcome measure for evaluating the intensity of pruritus in the previous 24 h on a scale of 0–10 (with 0 being “no itch” and 10 being “worst itch imaginable”). The PP-NRS is validated for use in patients aged ≥ 12 years with moderate-to-severe AD (Yosipovitch G, et al. Br J Dermatol. 2019;181:761–9) [37]

BSA body surface area, EASI Eczema Area and Severity Index, PP-NRS Peak Pruritus Numerical Rating Scale, QD once daily, SD standard deviation, vIGA-AD™ Validated Investigator Global Assessment for Atopic Dermatitis™

Primary Endpoint of vIGA-AD™ Response at Week 8

As previously reported, the primary efficacy endpoint of a vIGA-AD™ response at week 8 was met for tapinarof versus vehicle with statistical significance in ADORING 1 and 2: 45.4% versus 13.9% and 46.4% versus 18.0% (both P < 0.0001), respectively [28].

Consistently high efficacy was also achieved with tapinarof versus vehicle for the primary endpoint across race categories (Fig. 1) and Fitzpatrick skin type groups (Fig. 2) in both trials, except for patients identifying as a race within other groups, who were too few in number to make meaningful interpretations.

EASI75 Response at Week 8

The secondary efficacy endpoint of an EASI75 response was met with statistical significance in the overall population in ADORING 1 and 2: 55.8% versus 22.9% and 59.1% versus 21.2% (both P < 0.0001) for tapinarof versus vehicle, respectively [28]. Similarly, tapinarof demonstrated consistently high achievement of EASI75 response versus vehicle across race categories (Fig. 3) and Fitzpatrick skin type groups (Supplementary Fig. 3) in both trials.

Fig. 3.

Achievement of an EASI75 response^a at week 8 with tapinarof versus vehicle across race categories. ^a ≥ 75% improvement in Eczema Area and Severity Index score from baseline. ^bOther groups includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or multiple races. Patients identifying as a race grouped within other groups were too few to make any meaningful interpretations. Intention-to-treat, multiple imputations. EASI75 ≥ 75% improvement in Eczema Area and Severity Index, QD once daily, SE standard error of the mean

Case Photography

Case 1: The 5-year-old Black or African American patient with Fitzpatrick skin type V in Fig. 4a had moderate AD (vIGA-AD™ = 3) at baseline that improved to achieve the primary and secondary efficacy endpoints as early as week 2, with continued efficacy through week 8. In addition, the patient showed no signs of hypopigmentation or hyperpigmentation through the end of trial at week 8.

Fig. 4.

Achievement of the primary endpoint and EASI75 response in patients treated with tapinarof cream. a Achievement from week 2 through week 8 in a 5-year-old Black or African American patient with Fitzpatrick skin type V. Clinical response of a 5-year-old patient with Fitzpatrick skin type V with moderate AD at baseline who was treated with tapinarof 1% cream QD in ADORING 1. The overall disease burden rapidly improved, with the primary endpoint of vIGA-AD™ response and EASI75 achieved as early as week 2 at the first assessment. Almost complete clearing of the lesions on the leg occurred at week 2, and was maintained through the 8-week endpoint, with no signs of postinflammatory hyperpigmentaiton or hypopigmentation. b Achievement by week 4 through week 8 in a 67-year-old Hispanic patient with Fitzpatrick skin type IV. A 67-year-old patient with Fitzpatrick skin type IV with severe AD and evident xerosis at baseline was treated with tapinarof 1% cream QD in ADORING 2. The overall disease burden was improved as early as week 2, demonstrated by improvements in vIGA-AD™ and achievement of EASI75. At week 4, almost complete clearing occurred, with achievement of the primary endpoint and EASI90, which was maintained at the 8-week endpoint. vIGA-AD™ and EASI scores are global assessments that reflect the burden of disease across the whole body. Clinical photography of target lesions was performed in a subset of patients at selected investigational sites. For individuals who consented to photography, a target lesion was selected by the investigator for serial photography prior to the first application of investigational product. Written informed consent was provided by the patient or their parent/legal guardian. Examples of representative target lesions in tapinarof-treated patients from the ADORING 1 and 2 trials. Individual results may vary. AD atopic dermatitis, EASI Eczema Area and Severity Index score, QD once daily, vIGA-AD™ Validated Investigator Global Assessment for Atopic Dermatitis™

Case 2: The 67-year-old Hispanic patient with Fitzpatrick skin type IV in Fig. 4b had severe AD (vIGA-AD™ = 4), including on the hand, with xerosis, visible cracking, and lichenification at baseline, which improved to achieve the primary and secondary efficacy endpoints at week 8. A rapid EASI75 response was observed as early as week 2, and almost complete skin clearing (vIGA-AD™ = 1) was achieved at week 4, through the end of trial at week 8, with no hypopigmentation or hyperpigmentation. Furthermore, the patient exhibited major improvement in xerosis and lichenification, which are often difficult to treat, at week 8.

Safety

In ADORING 1 and 2, most TEAEs were mild or moderate in severity and consistent with previous trials [28, 31, 32]. The most frequent TEAEs (≥ 5% in any group) were folliculitis, headache, and nasopharyngitis. While there were fewer patients in the race groups other than white (Table 1), when TEAE numerical data were compared between race groups, no differences were noted that suggested hypotheses for further investigation. Notably, only two patients (0.7%) in ADORING 1 had an event of postinflammatory hyperpigmentation in the tapinarof group, which investigators deemed was not related to treatment; one patient was Black or African American and one patient was Asian (both had Fitzpatrick skin type VI). No events of postinflammatory hypopigmentation occurred in ADORING 1 and no postinflammatory pigmentation changes occurred in ADORING 2. Overall, trial discontinuation rates due to TEAEs were lower with tapinarof cream versus vehicle (ADORING 1: 1.9% versus 3.6%; ADORING 2: 1.5% versus 3.0%, respectively). While these trials were not designed to demonstrate statistical differences by race or Fitzpatrick skin type on safety outcomes, no differences warranting further investigation were noted.

Discussion

The incidence and presentation of AD may differ in individuals of different races and/or ethnicities [2, 5, 8]. There is a paucity of data on potential population variations in response to AD treatment according to self-identified race and ethnicity, or skin phototype, and patients with skin of color are often underrepresented in clinical trials [11]. A comprehensive review of 119 dermatology clinical trials published between 2014 and 2019 found that race and ethnicity were reported in only 22.7% of trials, and when race was reported, white patients were overrepresented by a significant margin [13]. Underrepresentation and underreporting of diversity may limit the utility of clinical trial data to demonstrate whether therapies are effective across all relevant populations.

The ADORING 1 and 2 trials compared AD treatment with tapinarof versus vehicle in a large and diverse population of adults and children down to 2 years of age [28]. Representation of patients with skin of color (considered to be patients who self-identified as Asian, Black or African American, or other race groups, or to be Fitzpatrick skin types IV–VI) in these trials at approximately 50%, is higher than the proportion across eight previously reported clinical trials in AD in the USA, where approximately 38% of participants were races other than white [13, 28]. Tapinarof cream 1% QD demonstrated consistently high efficacy in each of the self-reported race or investigator-assessed Fitzpatrick skin type categories studied. For patients with skin of color, the magnitude of improvement on the primary and secondary efficacy endpoints was similar to the overall population.

Tapinarof demonstrated a predictable safety profile in this population, consistent with previously reported clinical trials of tapinarof in AD and plaque psoriasis [31–34]. Postinflammatory hyperpigmentation, which can be more burdensome in patients with skin of color [4, 5, 9], occurred in only two patients treated with tapinarof (one Black or African American patient and one Asian patient) and was not considered treatment related. No events of postinflammatory hypopigmentation occurred in either trial. The release of inflammatory cytokines and reactive oxygen species in response to inflammation of the skin may cause postinflammatory hyperpigmentation [35]. The mechanism of action of tapinarof has been evaluated in human and mouse models, and includes reduction in proinflammatory cytokines (including IL-4, IL-5, and IL-13), reduction in oxidative stress through direct free radical scavenging and the Nrf2 pathway, and increased expression of skin barrier components [25, 26]. The mechanism of action of tapinarof may, therefore, be beneficial in the context of reducing the risk of pigmentary sequelae of AD in patients with skin of color.

A strength of these trials is the large, diverse patient population representative of general populations, particularly with respect to age and racial diversity, and the use of two separate classification systems to compare treatment across patient subgroups. These trials included approximately 50% of patients with skin of color based on self-identified race or investigator-assessed Fitzpatrick skin type. The prespecified intent to stratify efficacy by self-identified race is another strength of the trial design, as is the concordance of the findings stratified by race with the confirmatory analysis of efficacy stratified by Fitzpatrick skin type groups.

Limitations of the trials include a relatively short duration and lack of head-to-head comparison with other AD treatments; the latter could evaluate whether tapinarof may be more effective than medications that target single pathways or inflammatory markers, due to tapinarof-dependent agonism of AhR-modulating multiple upstream pathways common across endotypes [25]. The present analysis is based on the pivotal, regulatory phase 3 trials that compared tapinarof with vehicle. In addition, the trials were not powered to evaluate differences between tapinarof and vehicle by race, Fitzpatrick skin type, or ethnicity (Hispanic or Latino and Not Hispanic or Latino).

Eligible patients from ADORING 1 and 2 (n = 624) went on to enroll in the ADORING 3 long-term trial (N = 728) of up to 48 weeks of open-label tapinarof cream [29]; 47.4% of patients in ADORING 3 had skin of color and 83.0% were aged 17 years or younger. At ADORING 3 baseline, patients had AD with clear skin through to severe disease (the majority had almost clear skin, or mild or moderate AD). Overall, 81.6% of participants achieved clear or almost clear skin (vIGA-AD™ = 0 or 1), and 51.9% achieved complete disease clearance at least once during the long-term trial [29]. Tapinarof was well tolerated with no new safety signals..

People with skin of color comprise a diverse range of individuals from a large number of racial and ethnic backgrounds that may be distinct or heterogeneous [36], and more research may be needed on responses to therapy in some of these groups.

Conclusions

Tapinarof cream 1% QD is a nonsteroidal, topical AhR agonist that demonstrates consistently high efficacy in adults and children as young as 2 years of age with AD, including patients with skin of color based on self-identified race and investigator-assessed Fitzpatrick skin type IV–VI. Tapinarof was well tolerated with a predictable safety profile, consistent with previous trials, and did not lead to any treatment-related hyperpigmentation or hypopigmentation. These results strengthen the clinical relevance and generalizability of the previously reported efficacy and safety outcomes with tapinarof to treat AD from the phase 3 randomized, vehicle-controlled trials and the subsequent long-term trial. AD is a heterogeneous disease, and inclusion of patients with skin of color in AD trials is highly relevant. Future trials to compare tapinarof cream with other active agents in adults and children with AD will provide additional clinical data.

Tapinarof cream has demonstrated efficacy across diverse patient populations and is approved for the treatment of AD in adults and children down to 2 years of age, without restrictions on duration, extent, or sites of application.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Dr Andrew Alexis had full access to all data in the trial and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors (Dr Andrew Alexis, Dr Leon Kircik, Dr Raj Chovatiya, Dr Zakiya Rice, Dr Weily Soong, Dr Tina Bhutani, Dr Philip Brown, Mr Stephen Piscitelli, Dr David S. Rubenstein, Ms Anna M. Tallman, and Dr April W. Armstrong) contributed to the critical revision of the manuscript. All authors have read and approved the final version of the manuscript.

Funding

The trials were sponsored by Dermavant Sciences, Inc., Morrisville, NC, USA. The sponsor provided tapinarof 1% and vehicle cream and analyzed the data. Dermavant Sciences, an Organon Company, Jersey City, NJ, USA. supported editorial and writing assistance and funded the Rapid Service Fee.

Data Availability

Data from these trials are proprietary and not publicly available but may be made available from the corresponding author, with conditions, upon reasonable request and with permission from the sponsor.

Declarations

Conflict of Interest

Andrew F. Alexis has served as a consultant or advisory board member for AbbVie, Aerolase, Allergan, Almirall, Alphyn, Amgen, Apogee, Arcutis, Bausch Health, Beiersdorf, Bristol Myers Squibb, Boehringer Ingelheim, Canfield, Castle, Dermavant Sciences Inc., Eli Lilly, Galderma, Genentech, Genzyme, Incyte, Janssen, L’Oréal, LEO Pharma, Ortho, Pfizer, Sanofi-Regeneron, Scientis, Swiss American, Symrise, UCB, and VisualDx; as a speaker for Janssen, L’Oréal, Regeneron, and Sanofi-Genzyme; has received grants to his institution from AbbVie, Amgen, Arcutis, Castle, Dermavant Sciences, Inc., Galderma, Incyte, and LEO Pharma; royalties from Elsevier, Springer, Wiley-Blackwell, and Wolters Kluwer Health; and equipment from Aerolase. Leon Kircik has served as a consultant, speaker, investigator, or advisory board member for Abbott Laboratories, AbbVie, Ablynx, Aclaris, Acambis, Allergan, Inc., Almirall, Amgen, Inc., Anacor Pharmaceuticals, AnaptysBio, Arcutis Biotherapeutics, Arena Pharmaceuticals, Assos Pharmaceuticals, Astellas Pharma US, Inc., Asubio Pharmaceuticals, Bausch Health, Berlex Laboratories (Bayer HealthCare Pharmaceuticals), Biogen Idec, BioLife, Biopelle, Bristol Myers Squibb, Boehringer Ingelheim, Breckenridge Pharma, Cassiopea SpA, Centocor, Inc., Cellceutix, Cipher Pharmaceuticals, Coherus BioSciences, ColBar LifeScience, Combinatrix, Connetics Corporation, Coria Laboratories, Dermavant Sciences, Inc., Dermira, Dermik Laboratories, Dow Pharmaceutical Sciences, Inc., Dr. Reddy’s Laboratories, DUSA Pharmaceuticals, Embil Pharmaceutical Co. Ltd., Eli Lilly, EOS, Exeltis, Ferndale Laboratories, Inc., Ferrer, Foamix Pharmaceuticals, Galderma, Genentech, Inc., GlaxoSmithKline, Glenmark Pharmaceuticals, HealthPoint, Ltd, Idera Pharmaceuticals, Incyte, Intendis, Innocutis, Innovail, ISDIN, Johnson & Johnson, Kyowa Kirin, Laboratory Skin Care Inc., LEO Pharma, L’Oréal, 3M, Maruho Co., Ltd., Medical International Technologies, Merck, Medicis Pharmaceutical Corp., Merz Pharma, NanoBio, Novartis AG, Noven Pharmaceuticals, Nucryst Pharmaceuticals Corp., Obagi, Onset Dermatologics, Ortho Neutrogena, Pediapharma, Pfizer, Promius Pharma, PuraCap, Pharmaderm, QLT, Inc., Quinnova Pharmaceuticals, Quatrix, Regeneron, Sanofi, Serono (Merck Serono International SA), SkinMedica, Inc., Stiefel Laboratories, Inc., Sun Pharma, Taro Pharmaceutical Industries, Toler Rx, Triax Pharmaceuticals, UCB Biopharma, Valeant Pharmaceuticals Intl., Warner Chilcott, XenoPort, and ZAGE. Raj Chovatiya has served as an advisory board member, consultant, speaker, and/or investigator for AbbVie, Apogee, Arcutis, Argenx, ASLAN, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Dermavant Sciences, Inc., Eli Lilly, Galderma, Genentech, Incyte, LEO Pharma, L’Oréal, Novan, Inc., Pfizer Inc., Regeneron, Sanofi, and UCB Biopharma. Raj Chovatiya is an Editorial Board member of Dermatology and Therapy. Raj Chovatiya was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Zakiya P. Rice has served as a board member, consultant, speaker, investigator, or advisory board member for AbbVie, Anacor Pharmaceuticals Inc., Atlanta Ballet Center for Dance Education, Atlanta Speech School, Brickell Biotech Inc., Cassiopea Inc., Celgene, Dermavant Sciences, Inc., Dermira, Eli Lilly, Galderma Pharmaceuticals Co., Incyte Pharmaceuticals Co., International Hyperhidrosis Society, LEO Pharma, Merck, Novartis, Pfizer, Pierre Fabre Inc., Princeton Club of Georgia, and Regeneron/Sanofi-Genzyme Pharmaceuticals Inc.; received honorarium from Cable News Network (CNN), PRIME, Reckner, and Stateline Films; and is the founder/chief executive officer or co-owner of Astrop Advisories LLC and Pantones LLC. Weily Soong has served as a consultant, speaker, investigator, or advisory board member for AbbVie, Allakos, Amgen, Aslan, AstraZeneca, Celldex, Dermavant Sciences, Inc., Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Glenmark, Incyte, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi, and UCB Biopharma. Tina Bhutani is a principal investigator for studies being sponsored by AbbVie, Castle, CorEvitas, Dermavant Sciences, Inc., and Pfizer. She has received additional research funding from Novartis and Regeneron. She has served as an advisor for AbbVie, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Janssen, LEO Pharma, Lilly, Pfizer, Novartis, Sun, and UCB Biopharma. Philip M. Brown, Stephen C. Piscitelli, and Anna M. Tallman are former employees of Dermavant Sciences, an Organon Company. David S. Rubenstein is a former employee of Dermavant Sciences, Inc. April W. Armstrong has served as a research investigator and/or scientific advisor for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant Sciences, Inc., Dermira, Eli Lilly, EPI, Incyte, Janssen, LEO Pharma, Modmed, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB Biopharma.

Ethical Approval

The trials were conducted according to Good Clinical Practice and the Declaration of Helsinki of 1964 and its later amendments. The trials were approved by the Central Institutional Review Board, Advarra IRB, on 4 June 2021 (ADORING 1) and 2 July 2021 (ADORING 2). Advarra IRB is registered with the Office for Human Research Protections (OHRP) and the Food and Drug Administration under IRB#00000971. All patients or parents/legal guardians provided written informed consent, including consent for clinical photography and publication of their clinical images. Consent for the publication of this manuscript was provided by the authors and the sponsor.