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.

BACKGROUND: Tapinarof cream 1% once daily (QD), a topical aryl hydrocarbon receptor agonist, downregulates pro-inflammatory Th2 cytokines, upregulates skin-barrier components, and reduces oxidative stress. OBJECTIVE: To assess tapinarof efficacy and safety in adults and children down to 2 years of age with atopic dermatitis (AD). METHODS: 813 patients were randomized to tapinarof or vehicle QD in two 8-week phase 3 trials. RESULTS: The primary efficacy endpoint, Validated Investigator Global Assessment for Atopic DermatitisTM score of 0 or 1 and ≥2-grade improvement from baseline at Week 8, was met with statistical significance in both trials: 45.4% vs 13.9% and 46.4% vs 18.0% (tapinarof versus vehicle; both P<0.0001). Significantly superior EASI75 responses were also observed with tapinarof versus vehicle at Week 8: 55.8% vs 22.9% and 59.1% vs 21.2% (both P<0.0001). Rapid improvements in patient-reported pruritus were also significant with tapinarof versus vehicle. Common adverse events (≥5%) of folliculitis, headache, and nasopharyngitis were mostly mild or moderate, with lower discontinuations due to adverse events in the tapinarof groups than with vehicle. LIMITATIONS: Long-term efficacy was not assessed. CONCLUSION: Tapinarof demonstrated highly significant efficacy and favorable safety and tolerability in a diverse population of patients with AD down to 2 years of age.

Targeting the Aryl Hydrocarbon Receptor to Address the Challenges of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic relapsing–remitting disease with a multifactorial etiology involving epidermal barrier and immunologic dysfunction. Topical therapies form the mainstay of AD treatment, but options are limited by adverse effects and restrictions on application site, duration, and extent of use. Tapinarof (VTAMA; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical aryl hydrocarbon receptor (AhR) agonist approved for the treatment of plaque psoriasis. AhR is a ligand-dependent transcription factor with wide-ranging roles, including regulation of homeostasis and immune response in skin cells. AhR expression and signaling are altered in many inflammatory skin diseases, and clinical trials with tapinarof have validated AhR as a therapeutic target capable of delivering significant efficacy. Tapinarof cream 1% once daily demonstrated efficacy versus vehicle in adults and adolescents with AD and is being investigated in the ADORING trials for the treatment of AD in adults and children down to 2 years of age. J Drugs Dermatol. 2024;23(2):23-28.  doi:10.36849/JDD.8026.

Rapid Improvements in Itch with Tapinarof Cream 1% Once Daily in Two Phase 3 Trials in Adults with Mild to Severe Plaque Psoriasis.

INTRODUCTION: Patients with psoriasis report pruritus as their most bothersome symptom. Tapinarof cream 1% once daily demonstrated significant efficacy versus vehicle and was well tolerated in adults with mild to severe plaque psoriasis in two 12-week trials: PSOARING 1 (NCT03956355) and PSOARING 2 (NCT03983980). Here, we present patient-reported pruritus outcomes from these trials. METHODS: Outcomes included a Peak Pruritus Numerical Rating Scale (PP-NRS) score of 0 or 1 (itch-free state); Dermatology Life Quality Index (DLQI) itch item scores; and Psoriasis Symptom Diary (PSD) itch item scores. RESULTS: Analyses included 683 tapinarof- and 342 vehicle-treated patients. At baseline, mean pruritus scores were similar across trials with only 7-11% of patients reporting an itch-free state. At week 12, the proportion of tapinarof-treated patients achieving an itch-free state was 50% in both trials compared with 32% (P = 0.0007) and 27% (P < 0.0001) in the vehicle groups. Improvements were apparent at the earliest assessments with continued improvement over the course of the trials. There were rapid and statistically significant improvements in the proportion of patients with a ≥ 4-point improvement in PP-NRS for tapinarof-treated patients versus vehicle from week 2 with 68% vs 46% (P = 0.0004) and 60% vs 31% (P = 0.0001) at week 12 achieving a response in each trial. Significantly greater reductions in itch with tapinarof versus vehicle were also demonstrated at week 12 for DLQI itch item 1 (P = 0.0026 and P < 0.0001), PSD item 1 (both P < 0.0001), and PSD item 2 (both P < 0.0001). CONCLUSION: Tapinarof was highly efficacious in reducing pruritus across multiple patient-reported outcome measures, with rapid, statistically significant, and clinically meaningful improvements. The high proportion of patients achieving the treatment target of an itch-free state at week 12 (50%) is a noteworthy clinical outcome for a non-steroidal topical cream in the treatment of mild to severe plaque psoriasis. TRIAL REGISTRATION: Clinical trial registration information: NCT03956355, NCT03983980.

Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases.

Tapinarof Cream 1% Once Daily for the Treatment of Plaque Psoriasis: Case Photography of Clinical Outcomes from Three Phase 3 Trials.

Tapinarof cream 1% (VTAMA®; Dermavant Sciences, Inc.) is a non-steroidal, topical, aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration (FDA) to treat plaque psoriasis in adults and under investigation for the treatment of psoriasis in children down to 2 years of age, and for atopic dermatitis in adults and children down to 2 years of age. The PSOARING phase 3 clinical trial program evaluated tapinarof cream 1% once daily (QD) in adults with mild to severe plaque psoriasis for up to 52 weeks (NCT03956355, NCT03983980, NCT04053387). Here we present case photography documenting outcomes in the PSOARING trials. Cases illustrate various outcomes across different body areas, including responses meeting the formal FDA-mandated regulatory endpoint of a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 points from baseline at week 12, meaningful clinical improvement not meeting this formal endpoint, patient-reported outcomes, and pre-specified adverse events of special interest (AESIs). Tapinarof cream 1% QD demonstrated rapid and highly statistically significant efficacy, with improvements in disease activity and quality of life. In addition, a high rate (40.9%; n = 312/763) of complete disease clearance (PGA = 0) was achieved, and improvements exceeding National Psoriasis Foundation treatment goals were demonstrated. After first achieving complete disease clearance (PGA = 0), patients treated with tapinarof experienced an approximately 4-month remittive effect off therapy. Incidence and severity of folliculitis and contact dermatitis AESIs were generally mild or moderate, localized to the site of application, and associated with low discontinuation rates. Medical images are of importance in trials of dermatologic therapies to inform clinical decision-making and enhance patient assessment. Tapinarof cream 1% QD is efficacious and well tolerated in patients with mild to severe plaque psoriasis, with clinically relevant improvements seen early in the course of treatment.Clinicaltrials.gov numbers: NCT03956355, NCT03983980, NCT04053387.

Tapinarof, a Novel, First-in-Class, Topical Therapeutic Aryl Hydrocarbon Receptor Agonist for the Management of Psoriasis.

Topical treatments remain the foundation of psoriasis management. Tapinarof (VTAMA®; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical, aryl hydrocarbon receptor (AhR) agonist approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults and is under investigation for the treatment of psoriasis in children, and atopic dermatitis in adults and children down to 2 years old. Here, we review the mechanism of action of tapinarof and the PSOARING phase 3 trial program in mild to severe psoriasis. AhR is a ligand-dependent transcription factor involved in maintaining skin homeostasis. Tapinarof specifically binds to AhR to decrease proinflammatory cytokines, decrease oxidative stress, and promote skin barrier normalization. In two identical, randomized, 12-week pivotal phase 3 trials, PSOARING 1 and 2, tapinarof cream 1% once daily (QD) demonstrated significant efficacy versus vehicle and was well tolerated in adults with mild to severe psoriasis. In the PSOARING 3 long-term extension trial of repeated, intermittent tapinarof cream in eligible patients completing the pivotal trials, a high rate of complete disease clearance (40.9%) and a remittive effect of approximately 4 months off therapy were demonstrated over 52 weeks, with no tachyphylaxis. The most common adverse event, folliculitis, was mostly mild or moderate and resulted in a low trial discontinuation rate in PSOARING 1 and 2 (≤1.8%). Tapinarof cream 1% QD provides a novel, non-steroidal, topical treatment option for patients with psoriasis and is highly effective and well tolerated with long-term use including when applied to sensitive and intertriginous skin. Bobonich M, Gorelick J, Aldredge L, et al. Tapinarof, a novel, first-in-class, topical therapeutic aryl hydrocarbon receptor agonist for the management of psoriasis. J Drugs Dermatol. 2023;22(8):779-784. doi:10.36849/JDD.7317.

Tapinarof cream 1% once daily for the treatment of plaque psoriasis: Patient-reported outcomes from the PSOARING 3 trial.

BACKGROUND: Tapinarof cream 1% once daily demonstrated significant efficacy versus vehicle and was well tolerated in two 12-week, phase 3 pivotal trials in adults with mild-to-severe plaque psoriasis. OBJECTIVE: To assess long-term, health-related quality of life and patient satisfaction with tapinarof. METHODS: Patients completing the 12-week trials were eligible for 40 weeks of open-label tapinarof based on Physician Global Assessment score in PSOARING 3, with a 4-week follow-up. Dermatology Life Quality Index was assessed at every visit; Patient Satisfaction Questionnaire responses were assessed at week 40 or early termination. RESULTS: Seven hundred sixty-three (91.6%) eligible patients enrolled; 78.5% completed the Patient Satisfaction Questionnaire. DLQI scores improved and were maintained. By week 40, 68.0% of patients had a DLQI of 0 or 1, indicating no impact of psoriasis on health-related quality of life. Most patients strongly agreed or agreed with all Patient Satisfaction Questionnaire questions assessing confidence in tapinarof and satisfaction with efficacy (62.9%-85.8%), application ease and cosmetic elegance (79.9%-96.3%), and preference for tapinarof versus prior psoriasis therapies (55.3%-81.7%). LIMITATIONS: Open-label; no control; may not be generalizable to all forms of psoriasis. CONCLUSIONS: Continued and durable improvements in health-related quality of life, high rates of patient satisfaction, and positive perceptions of tapinarof cream were demonstrated.

One-year safety and efficacy of tapinarof cream for the treatment of plaque psoriasis: Results from the PSOARING 3 trial.

BACKGROUND: Tapinarof cream 1% once daily, an aryl hydrocarbon receptor-modulating agent, was significantly more efficacious than vehicle and well tolerated in two 12-week phase 3 trials in adults with mild to severe plaque psoriasis. OBJECTIVE: To assess long-term safety, efficacy, remittive effect, durability of response, and tolerability of tapinarof. METHODS: Patients completing the 12-week trials were eligible for 40-weeks' open-label treatment and 4-weeks' follow-up. Treatment was based on the Physician Global Assessment (PGA) score. Patients entering with PGA≥1 received tapinarof until PGA = 0. Patients with PGA = 0 discontinued tapinarof and were monitored for remittive effect. Patients with PGA≥2 were re-treated until PGA = 0. RESULTS: Overall, 91.6% (n = 763) of eligible patients enrolled; 40.9% of patients achieved complete disease clearance (PGA = 0), and 58.2% entering with PGA≥2 achieved PGA = 0 or 1. Mean duration of off therapy remittive effect for patients achieving PGA = 0 was 130.1 days. No new safety signals were observed. Most frequent adverse events were folliculitis (22.7%), contact dermatitis (5.5%), and upper respiratory tract infection (4.7%). LIMITATIONS: Open-label; no control; may not be generalizable to all forms of psoriasis; remittive effect/response rate potentially underestimated. CONCLUSIONS: Efficacy improved beyond the 12-week trials, with a 40.9% complete disease clearance rate, ∼4-month off therapy remittive effect, durability on therapy, and consistent safety.

Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis.

BACKGROUND: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. METHODS: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. RESULTS: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. CONCLUSIONS: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).

A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: Secondary efficacy and patient-reported outcomes.

BACKGROUND: Tapinarof cream is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for treatment of psoriasis and atopic dermatitis. METHODS: In a phase 2b, double-blind, vehicle-controlled study, adults with plaque psoriasis were randomized to tapinarof cream 0.5% or 1% once or twice daily or vehicle once or twice daily for 12 weeks with 4-week follow-up. Efficacy outcomes included Physician Global Assessment (PGA) scores, change in PGA and total target lesion grading scores, and proportion of patients achieving ≥50%, ≥75%, and ≥90% reductions in the Psoriasis Area and Severity Index scores from baseline (PASI50, PASI75, and PASI90). RESULTS: At week 12, improvements were observed in all tapinarof groups vs vehicle in PGA response, change in PGA and total target lesion grading scores, PASI50 (71%-92% vs 10%-32%), PASI75 (46%-65% vs 5%-16%), and PASI90 (18%-40% vs 0%); all differences were statistically significant with tapinarof 1% once daily. Tapinarof responses were apparent from week 2, with significant efficacy at week 8 maintained through week 16. Most adverse events were mild or moderate. LIMITATIONS: The analyses reported require confirmation in larger prospective studies. CONCLUSIONS: Tapinarof may represent an important advance in the development of topical medicines for treatment of psoriasis.

Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis.

BACKGROUND: Tapinarof is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for atopic dermatitis (AD) and psoriasis treatment. METHODS: A phase 2b, double-blind, vehicle-controlled study randomly assigned adolescents and adults with AD to receive tapinarof cream 0.5%, 1%, or vehicle, once or twice daily, for 12 weeks with a 4-week follow-up. Outcomes included Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), body surface area affected, pruritus numeric rating scale scores, patients' impressions of AD and pruritus symptom severity, and Patient-Oriented Eczema Measure (POEM) scores. RESULTS: Overall, 191 of 247 randomized patients completed the study. Week 12 IGA responses were higher in the tapinarof groups versus the vehicle group, reaching statistical significance with tapinarof 1% twice daily, ≥75%/90% improvement in EASI from baseline were significantly higher in the tapinarof groups (except 0.5% once daily and 0.5% twice daily), EASI scores were significantly improved in all tapinarof groups, and body surface area affected was significantly reduced in the tapinarof groups (except 0.5% twice daily). More patients reported AD and pruritus symptom severity as very/moderately improved in tapinarof groups, and POEM improvements were observed in all groups. Most adverse events were mild or moderate. LIMITATIONS: Larger prospective studies are required to confirm the reported analyses. CONCLUSIONS: Tapinarof is a potential important advance in topical medicine development for AD.

Tapinarof in the treatment of psoriasis: A review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor-modulating agent.

Tapinarof, a novel, first-in-class, small-molecule topical therapeutic aryl hydrocarbon receptor (AhR)-modulating agent, is in clinical development for the treatment of psoriasis and atopic dermatitis. The efficacy of tapinarof in psoriasis is attributed to its specific binding and activation of AhR, a ligand-dependent transcription factor, leading to the downregulation of proinflammatory cytokines, including interleukin 17, and regulation of skin barrier protein expression to promote skin barrier normalization. AhR signaling regulates gene expression in immune cells and skin cells and has critical roles in the regulation of skin homeostasis. Tapinarof-mediated AhR signaling underlies the mechanistic basis for the significant efficacy and acceptable tolerability observed in early-phase clinical trials of tapinarof cream in the treatment of psoriasis.

Development and Content Validation of Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) in Adolescents and Adults with Moderate-to-Severe AD.

INTRODUCTION: Most patient-reported outcome (PRO) instruments that measure atopic dermatitis (AD) symptoms do not have sufficient documented evidence of content validity to satisfy regulatory agency guidance for inclusion in product-labelling claims in the USA or Europe. The objective of this study was to develop a PRO instrument in accordance with regulatory agency guidance to assess daily AD symptoms during the course of therapy and to establish its content validity and psychometric properties. METHODS: The Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) daily diary was developed based on qualitative interviews with US adolescents and adults with mild-to-severe AD. Content validity, test-retest reliability, internal consistency reliability, clinically important difference, clinically important responder, convergent validity, and known-group validity were evaluated using correlational and regression methods from phase 2b data from US adults with moderate-to-severe AD who were treated with abrocitinib. RESULTS: Patient interviews conducted with US adolescents and adults with mild-to-severe AD identified 11 relevant symptoms (itch, dryness, redness, flaking, discolouration, pain, bleeding, cracking, bumps, swelling, and weeping/oozing) for inclusion in the PSAAD instrument. All PSAAD psychometric parameters were acceptable based on phase 2b data from US adults with moderate-to-severe AD. Convergent validity and known-group validity were confirmed by significant correlations between PSAAD and six other PRO measures (r = 0.24-0.91, all p ≤ 0.01) and Dermatology Life Quality Index category (p ≤ 0.0001), respectively. CONCLUSIONS: Evidence supports the PSAAD instrument validity, reliability, responsiveness and definitions of clinically important changes/differences for adults with moderate-to-severe AD.

Evaluating the Efficacy of Crisaborole Using the Atopic Dermatitis Severity Index and Percentage of Affected Body Surface Area.

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis pools results from 2 phase 3 studies (ClinicalTrials.gov, NCT02118766 [AD-301]; NCT02118792 [AD-302]) to evaluate crisaborole efficacy in patients ≥ 2 years with mild-to-moderate atopic dermatitis (per Investigator's Static Global Assessment) using the Atopic Dermatitis Severity Index (ADSI) and percentage of treatable body surface area (%BSA). Patients were randomly assigned 2:1 to receive crisaborole (n = 1,016) or vehicle (n = 506) twice daily for 28 days. ADSI scores were the sum of pruritus, erythema, exudation, excoriation, and lichenification severity scores, each graded on a 4-point scale from none (0) to severe (3). Respective mean changes in ADSI score and %BSA at day 29 were (crisaborole vs. vehicle) -3.52 versus -2.42 (p < 0.0001) and -7.43 versus -4.44 (p < 0.0001). Crisaborole was effective in treating mild-to-moderate atopic dermatitis based on ADSI and %BSA.

Topical Agents for the Treatment of Atopic Dermatitis

Approval of the new topical phosphodiesterase 4 inhibitor crisaborole ointment, 2%, to treat mild-to-moderate atopic dermatitis (AD) warrants careful consideration of available efficacy and safety data for topical therapies to contribute to a better understanding of the role of crisaborole in the treatment of mild-to-moderate AD. A literature review was conducted to identify results of randomized, blinded, vehicle-controlled trials of topical agents for the treatment of AD published from January 1, 1997 to April 30, 2018. This review summarizes the efficacy and safety data of topical therapies including corticosteroids, calcineurin inhibitors, and crisaborole and it shows that comparison among available agents is difficult because of differing methodologies used across clinical trials and that there is considerable variability in safety reporting among AD trials. Published clinical studies for crisaborole demonstrate its efficacy and manageable safety profile. J Drugs Dermatol. 2020;19(1):50-64. doi:10.36849/JDD.2020.4508