INTRODUCTION ■ Atopic dermatitis (AD) is a chronic, relapsing and remitting inflammatory skin disease, characterized by intense pruritus and eczematous lesions. AD can substantially impact patients’ sleep and quality of life1–4 ■ There is a need for efficacious, non-steroidal topical therapies for AD, without restrictions relating to duration, extent of use, and application sites ■ Tapinarof (VTAMA®; Dermavant Sciences, Inc., USA) is a first-in-class, non-steroidal, topical aryl hydrocarbon receptor (AhR) agonist approved by the Food and Drug Administration for the treatment of plaque psoriasis in adults, and under investigation for the treatment of plaque psoriasis in children down to 2 years of age and for AD in adults and children down to 2 years of age5 ■ Tapinarof cream 1% once daily (QD) demonstrated significant efficacy versus vehicle and was well tolerated in adults with mild to severe plaque psoriasis in two identical, 12-week, phase 3 trials, PSOARING 1 (NCT03956355) and PSOARING 2 (NCT03983980)6 – Efficacy continued to improve beyond the 12-week trials in PSOARING 3 (NCT04053387), the long-term extension trial7 ■ Tapinarof specifically binds to and activates the AhR, a ligand-dependent transcription factor. This leads to downregulation of inflammatory Th2 cytokines (including interleukin [IL]-4, IL-5, and IL-13), increase in expression of skin barrier proteins related to keratinocyte differentiation (including filaggrin, loricrin, and involucrin), and antioxidant activity8–12 (Figure 1) Figure 1. Potential Mechanisms of Action of Tapinarof in Atopic Dermatitis *Demonstrated in vitro. †Demonstrated in mouse models. ‡Demonstrated ex vivo. AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; IL, interleukin; Nrf2, nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen species; TAP, tapinarof. ■ Tapinarof cream 1% QD demonstrated significant efficacy versus vehicle and was well tolerated in adults and adolescents with moderate to severe AD in a 12-week phase 2b trial (NCT02564055)13,14 – Efficacy was generally maintained through the last trial visit, 4 weeks after completing treatment13,14 ■ In a phase 1 pharmacokinetics (PK) evaluation of tapinarof cream 1% in adults (n=6) with moderate to severe AD, there were low levels of systemic absorption that decreased from baseline to Day 21 of assessment (mean 1.2 ng [10–9]/mL [Day 1] and 0.15 ng/mL [Day 21])15 ■ Tapinarof cream 1% has also been assessed in a 4-week, maximal- use PK trial in adults with extensive plaque psoriasis; tapinarof was well tolerated with limited systemic exposure, even in patients with up to 46% body surface area (BSA) affected16 OBJECTIVES ■ To present the 4-week, maximal-use AD trial design and patient baseline characteristics ■ To assess the safety, tolerability, PK, and efficacy of tapinarof cream 1% QD in adolescents and children with extensive AD in the 4-week, maximal-use trial METHODS Trial Design ■ In this phase 2a, multicenter, open-label trial (NCT05186805), adolescents and children with extensive AD will receive tapinarof cream 1% QD for 27 days (Figure 2) ■ Patients or caregivers will be instructed to apply a thin layer of tapinarof cream, sufficient to cover each lesion ■ Tapinarof PK will be assessed at Days 1 (baseline) and 28 – The screening blood sample will be used for baseline pre-dose PK assessment if the patient is enrolled ■ Key inclusion and exclusion criteria are shown in Table 1 ■ Eligible patients completing this trial will have the option to enroll in an open-label, long-term extension trial (NCT05142774) to receive up to an additional 48 weeks of tapinarof treatment Figure 2. Maximal-Use PK Trial Design in Adolescents and Children with AD AD, atopic dermatitis; PK, pharmacokinetics; QD, once daily. Table 1. Key Inclusion and Exclusion Criteria Inclusion Criteria Exclusion Criteria Males and females aged 2–17 years Significant dermatologic or inflammatory condition and concurrent skin lesions in the treatment area or pruritus due to conditions other than AD A clinical diagnosis of AD by Hanifin and Rajka criteria17 Patients who would not be considered suitable for topical therapy %BSA involvement ≥25% for adolescents (12–17 years) or ≥35% for children (2–11 years) Use of any prohibited medication or procedure within the indicated period before the baseline visit A vIGA-ADTM score of ≥3 at screening and baseline (pre-dosing) History of sensitivity to the trial medications AD present for ≥6 months for patients aged 6–17 years or 3 months for patients aged 2–5 years Previous known participation in a clinical trial with tapinarof AD, atopic dermatitis; BSA, body surface area; vIGA-ADTM, validated Investigator Global Assessment for Atopic DermatitisTM. Primary Endpoints ■ Incidence, frequency, and nature of adverse events (AEs) and serious AEs ■ Change from baseline in laboratory values and vital signs ■ Mean Investigator-assessed Local Tolerability Scale scores by visit (overall and sensitive areas) ■ Tapinarof plasma PK parameters on Day 1, including: – Area under the plasma concentration versus time curve from baseline to the last quantifiable concentration (AUC 0–last ) – Maximum plasma concentration (C max ) – Time to maximum plasma concentration (t max ) – Time of last quantifiable concentration (t last ) ■ Tapinarof plasma concentration on Day 28 Secondary Endpoints ■ Change in validated Investigator Global Assessment for Atopic DermatitisTM (vIGA-ADTM) score by visit ■ Proportion of patients with a vIGA-ADTM score of clear (0) or almost clear (1) by visit ■ Proportion of patients with ≥50%, ≥75%, and ≥90% improvement in Eczema Area and Severity Index (EASI) score by visit ■ Mean change and percent change in EASI score by visit ■ Mean change and percent change in %BSA affected by visit ■ Proportion of patients with a baseline Peak Pruritus-Numeric Rating Scale (PP-NRS) score of ≥4 who achieve a ≥4-point reduction in PP-NRS score by visit – Proportion of patients ≥12 years old with a baseline PP-NRS score ≥4 who achieve a ≥4-point reduction in PP-NRS score by visit – Proportion of patients 2–12 years old with a baseline PP-NRS score ≥4 who achieve a ≥4-point reduction in PP-NRS score by visit – Mean change in PP-NRS score at each visit by age group Statistical Analyses ■ Safety analyses will include all patients who received at least one application of tapinarof ■ Analyses of efficacy endpoints will be based upon the safety population RESULTS Baseline Patient Demographics and Disease Characteristics ■ Overall, 36 patients were enrolled at nine sites in the US and Canada ■ Patients’ baseline demographics and disease characteristics are shown in Table 2 – Equal proportions of patients (33.3% [12/36]) were young children (2–6 years), children (7–11 years), and adolescents (12–17 years) – Most patients (77.8%) across the three groups had a vIGA-ADTM score of 3 (moderate) – Overall mean (standard deviation [SD]) EASI score was 23.8 (9.2), with a range of 8.2–49.6 indicating moderate to severe AD – Overall mean (SD) %BSA affected was 42.8% (15.1%), with a range of 26%–90% Table 2. Baseline Demographics and Disease Characteristics Tapinarof cream 1% QD Young children 2–6 years (n=12) Children 7–11 years (n=12) Adolescents 12–17 years (n=12) Overall (N=36) Age, years, mean (SD) 3.7 (1.4) 8.2 (1.4) 14.8 (1.8) 8.9 (4.9) Male, n (%) 9 (75.0) 7 (58.3) 8 (66.7) 24 (66.7) vIGA-ADTM of 3 (moderate), n (%) 8 (66.7) 9 (75.0) 11 (91.7) 28 (77.8) vIGA-ADTM of 4 (severe), n (%) 4 (33.3) 3 (25.0) 1 (8.3) 8 (22.2) EASI, mean (SD) 30.2 (8.6) 21.0 (10.0) 20.3 (5.5) 23.8 (9.2) BSA affected, %, mean (SD) 52.4 (19.1) 42.0 (10.0) 33.9 (8.6) 42.8 (15.1) BSA, body surface area; EASI, Eczema Area and Severity Index; QD, once daily; SD, standard deviation; vIGA-ADTM, validated Investigator Global Assessment for Atopic DermatitisTM. CONCLUSIONS ■ In a phase 2b trial, tapinarof cream 1% QD demonstrated significant efficacy versus vehicle and was well tolerated in adolescents and adults with moderate to severe AD13,14 ■ Tapinarof cream 1% has shown minimal systemic absorption in adults with AD or psoriasis, even with extensive BSA affected of up to 46%15,16 ■ This maximal-use PK trial will assess the safety, tolerability, PK, and efficacy of tapinarof cream 1% QD in 36 adolescents and children down to 2 years of age with extensive, moderate to severe AD ■ In addition, tapinarof cream 1% QD is being evaluated for the treatment of AD in adults and children down to 2 years of age in three phase 3 clinical trials (ADORING 1 [NCT05014568], ADORING 2 [NCT05032859], and ADORING 3 [NCT05142774]) REFERENCES 1. Weidinger S and Novak N. Lancet. 2016;387:1109–1122. 2. Bieber T. N Engl J Med. 2008;358:1483– 1494. 3. Carroll CL, et al. Pediatr Dermatol. 2005;22:192–199. 4. Lewis-Jones S. Int J Clin Pract. 2006;60:984–992. 5. Dermavant Sciences. VTAMA (tapinarof) cream, 1%: US prescribing information. 2022. https://www.vtama.com/docs/DMVT_VTAMA_PI.pdf. Accessed July 2022. 6. Lebwohl M, et al. N Engl J Med. 2021;385:2219–2229. 7. Strober B, et al. J Am Acad Dermatol. 2022. https://doi.org/10.1016/j. jaad.2022.06.1171. 8. Bissonnette R, et al. J Am Acad Dermatol. 2021;84:1059–1067. 9. Dermavant DOF [DMVT-505 Th2 Polarization; Apr 2015]. 10. Dermavant DOF [DMVT-505 AD Mouse Model; Oct 2016]. 11. Smith SH, et al. J Invest Dermatol. 2017;137:2110–2119. 12. Kim BE, et al. Allergy Asthma Immunol Res. 2018;10:207–215. 13. Peppers J, et al. J Am Acad Dermatol. 2019;80:89–98. 14. Paller A, et al. J Am Acad Dermatol. 2021;84:632–638. 15. Bissonnette R, et al. Clin Pharmacol Drug Dev. 2018;7:524–531. 16. Jett JE, et al. Am J Clin Dermatol. 2022;23:83–91. 17. Hanifin JM and Rajka G. Acta Dermatovener (Stockholm) Suppl. 1980;92:44–47. ACKNOWLEDGMENTS This trial was funded by Dermavant Sciences, Inc. The authors thank the participating investigators, patients and their families, and colleagues involved in the conduct of the trial. A.P. is an investigator (without personal compensation) for AbbVie, AnaptysBio, Dermavant Sciences Inc., Eli Lilly, Incyte, Janssen, Krystal, Regeneron, and UCB Pharma, a consultant (with honoraria) for AbbVie, Acrotech, Almirall, Amgen, Amryt, Arcutis, Arena, Azitra, BioCryst, BiomX, Boehringer Ingelheim, Botanix, Bridgebio, Castle Biosciences, Catawba, Eli Lilly, Exicure, Gilead, Incyte, Janssen, Kamari, Leo, Novartis, Pfizer, Pierre Fabre, RAPT, Regeneron, Sanofi/Genzyme, Seanergy, UCB Pharma, Union, and on the Data Safety Monitoring Board for AbbVie, Abeona, Bausch, Bristol Myers Squibb, Galderma, Inmed, and Novan. A.A.H. has received grants/honoraria/ research support from AbbVie, Almirall, Arcutis, Dermavant Sciences Inc., GSK (as part of a Data Safety Monitoring Board), Incyte, LEO Pharma, Mayne, Novan, and Verrica. J.E.J., P.M.B., D.S.R., and S.C.P. are employees of Dermavant Sciences, Inc., with stock options. Editorial and medical writing support under the guidance of the authors was provided by ApotheCom, UK, and was funded by Dermavant Sciences, Inc. in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med. 2015;163:461–464). Contact Dr Paller at apaller@nm.org with questions or comments. Open-label Treatment (27 days) Adolescents and children�with AD Screening for up to 30 days Tapinarof cream 1% QD Follow-up visit ~7 days after end of treatment Tapinarof Cream 1% Once Daily for the Treatment of Extensive Atopic Dermatitis in Adolescents and Children: 4-Week Maximal-Use Trial Amy Paller,1 Adelaide A. Hebert,2 John E. Jett,3 Philip M. Brown,3 David S. Rubenstein,3 Stephen C. Piscitelli3 1Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2McGovern School of Medicine and Children’s Memorial Hermann Hospital, UTHealth McGovern, Houston, TX, USA; 3Dermavant Sciences, Inc., Morrisville, NC, USA