Tapinarof Cream 1% Once Daily for the Treatment of Moderate to Severe Atopic Dermatitis in Children and Adults: The Pivotal Phase 3 ADORING Clinical Program Lawrence F. Eichenfield,1,2 Jonathan I. Silverberg,3 Robert Bissonnette,4 Anna M. Tallman,5 Philip M. Brown,5 David S. Rubenstein,5 Stephen C. Piscitelli,5 John E. Jett5 1School of Medicine, University of California, San Diego, CA, USA; 2Rady Children’s Hospital, San Diego, CA, USA; 3School of Medicine and Health Sciences, The George Washington University, DC, USA; 4Innovaderm Research Inc., Montreal, QC, Canada; 5Dermavant Sciences, Inc., Morrisville, NC, USA SYNOPSIS ■ Atopic dermatitis (AD) is a chronic, relapsing, and remitting inflammatory skin disease characterized by intense pruritus and eczematous lesions that can substantially impact sleep and quality of life1–4 ■ In the US, approximately 16.5 million adults and 9.6 million children under the age of 18 years have AD5 ■ There is a need for efficacious non-steroidal topical therapies for AD without restrictions on duration, extent or site of use ■ Tapinarof is a novel, first-in-class, small-molecule topical therapeutic aryl hydrocarbon receptor modulating agent (TAMA) in development for the treatment of AD and psoriasis. Tapinarof has demonstrated efficacy and a remittive effect in Phase 3 clinical trials for the treatment of plaque psoriasis: PSOARING 1 (NCT03956355), PSOARING 2 (NCT03983980), and PSOARING 3 (NCT04053387) ■ Tapinarof specifically binds to and activates the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor. This leads to the 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 activity6–10 (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% once daily (QD) demonstrated significant efficacy versus vehicle at 12 weeks and was well tolerated in adolescents and adults with moderate to severe AD in a Phase 2b trial (NCT02564055). Efficacy was generally maintained through the last study visit, 4 weeks after completing treatment, warranting further investigation of a potential remittive effect; this will be defined as the maintenance of disease control (a validated Investigator Global Assessment for Atopic Dermatitis™[vIGA-AD™] score of 0 [clear] or 1 [almost clear]) off therapy11,12 OBJECTIVE ■ To assess the efficacy and safety of tapinarof cream 1% QD in children and adults with moderate to severe AD in the two pivotal Phase 3 studies (ADORING 1 and 2) and a long- term extension Phase 3 trial (ADORING 3) METHODS Trial Design: ADORING 1 and 2 ■ ADORING 1 and ADORING 2 are two identically designed, Phase 3, multicenter (US and Canada), double-blind, vehicle-controlled randomized trials (Figure 2) ■ Following a 30-day screening period, patients aged ≥2 years old with an vIGA-AD score ≥3 (moderate to severe) and a percentage body surface area (%BSA) affected of ≥5–≤35% will be randomized 2:1 to tapinarof cream 1% QD or vehicle QD for 8 weeks Figure 2. Trial Design: ADORING 1 and ADORING 2 Trial Design: ADORING 3 ■ ADORING 3 is a long-term, open-label, multicenter extension trial to evaluate the long-term safety and efficacy of tapinarof 1% QD in patients with AD (Figure 3) ■ Eligible patients completing ADORING 1, ADORING 2, or the Maximal Use Pharmacokinetics trial can enroll in ADORING 3 ■ In addition, approximately 125 pediatric patients (aged 2 to <18 years) can enroll directly in ADORING 3 if they had a vIGA-AD score of ≥3 (moderate) and %BSA affected ≥40% at screening and baseline (pre-randomization), or patients with a vIGA-AD score of 2 (mild) at screening and baseline (pre- randomization) regardless of %BSA affected, and were thus not eligible for participation in the ADORING 1 and 2 pivotal trials Figure 3. Trial Design: ADORING 3 ■ In ADORING 3, patients will be treated based on their vIGA-AD score: – Patients entering with, or achieving, a vIGA-AD score of 0 (clear) will discontinue treatment and will be monitored for remittive effect, defined as off therapy maintenance of a vIGA-AD score of 0 (clear) or 1 (almost clear) – Patients entering with a vIGA-AD score ≥1 (almost clear) will receive tapinarof 1% QD until they achieve complete disease clearance, defined as a vIGA-AD score of 0 (clear) METHODS (continued) Trial Design: ADORING 3 (continued) – If disease worsening occurs (defined as a vIGA-AD score ≥2 [mild]), tapinarof 1% QD will be started and continued until a vIGA-AD score of 0 (clear) is achieved ■ Treatment and re-treatment will continue until the end of the study Endpoints and Statistical Analysis: ADORING 3 ■ Safety and tolerability endpoints: Adverse events, patient- and investigator-assessed local tolerability, laboratory values, vital signs, and physical exams ■ Efficacy endpoints include: – Complete disease clearance: Proportion of patients achieving vIGA-AD of 0 (clear) – Remittive effect: Duration of efficacy maintenance, vIGA-AD of 0 (clear) or 1 (almost clear) while off therapy, after achieving complete disease clearance (vIGA-AD=0) – Response: Proportion of patients who enter the trial with a vIGA-AD≥2 (mild) and achieve a vIGA-AD of 0 (clear) or almost clear (1) – Durability of response (absence of tachyphylaxis on therapy): Maintenance of efficacy on treatment ■ Efficacy endpoints will be based on the ITT population using observed case and last observation carried forward analyses. Safety endpoint analysis will be based on the ITT population CONCLUSIONS ■ This comprehensive Phase 3 clinical trial program will assess the efficacy, safety, tolerability, durability, and potential remittive effect of tapinarof cream 1% QD for the treatment of moderate to severe AD in patients down to 2 years of age REFERENCES 1. Weidinger S & 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. National Eczema Association. https://nationaleczema.org/research/eczema-facts/. Accessed May 2021; 6. Bissonnette R, et al. J Am Acad Dermatol. 2021;84:1059–1067; 7. Dermavant DOF [DMVT-505 Th2 Polarization; Apr 2015]; 8. Dermavant DOF [DMVT-505 AD Mouse Model; Oct 2016]; 9. Smith SH, et al. J Invest Dermatol. 2017;137:2110–2119; 10. Kim BE, et al. Allergy Asthma Immunol Res. 2018;10:207–215; 11. Peppers J, et al. J Am Acad Dermatol. 2019;80:89–98; 12. Paller A, et al. J Am Acad Dermatol. 2021;84:632–638. ACKNOWLEDGMENTS The ADORING clinical program is funded by Dermavant Sciences, Inc. L.F.E. has served as a consultant/adviser/investigator for Almirall, Amgen, Arcutis, Arena, Dermavant Sciences Inc., Dermira, Eli Lilly, Forté, Galderma, Glenmark/Ichnos, Incyte, LEO Pharma, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme. J.I.S. has received honoraria/grants, and/or has served as a consultant/ advisory board member/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, Sanofi Genzyme. R.B. has served as a consultant/advisory board member/speaker/investigator, and/or receives honoraria/ grant from Almirall, Amgen, AnaptysBio, Arcutis, Arena Pharma, Aristea, Asana BioSciences, Bausch Health, Bellus Health, Bluefin Biomedicine, Boehringer- Ingelheim, Bristol-Myers Squibb, CARA, Dermavant Sciences Inc., Eli Lilly, EMD Serono, Escalier, Evidera, Galderma, GSK, Inmagene Bio, Incyte, Janssen, Kiniksa, Kyowa Kirin, LEO Pharma, Nimbus, Novan, Pfizer, Ralexar, RAPT, Regeneron, Respivant, Sanofi Genzyme, Sienna, Target RWE, UCB. R.B. is an employee and shareholder of Innovaderm Research. A.M.T, P.M.B, D.S.R, S.C.P, and J.E.T. 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 Lawrence F. Eichenfield at leichenfield@rchsd.org with questions or comments. Double-blind treatment (8 weeks) Patients with moderate to severe atopic dermatitis (N≈800) ■ Aged ≥2 years* ■ vIGA-AD™ score ≥3† ■ BSA ≥5%–≤35% 2:1 N≈400 Tapinarof 1% QDADORING 1 Vehicle QD R 2:1 N≈400 Tapinarof 1% QDADORING 2 Vehicle QD R *A minimum of approximately 15% of patients will be enrolled into each of the following age groups: 2–6 years, 7–11 years, 12–17 years, and ≥18 years. Adults (≥18 years) will comprise a maximum of approximately 20% of enrolled patients. †Patients with a vIGA-AD score of 4 (severe) will represent a minimum of approximately 10% of the total randomized population; the remainder of the population will have a vIGA-AD score of 3 (moderate). Prohibited concomitant medications (and washout periods prior to baseline) include monoclonal antibody products approved for AD (4 months), non-topical corticosteroids or immunosuppressants (28 days), and topical PDE4 inhibitors, tacrolimus ointment, pimecrolimus cream, medium- or high-potency topical corticosteroids or coal tar (all 14 days). BSA, body surface area; vIGA-AD, validated Investigator Global Assessment for Atopic Dermatitis™; PDE4, phosphodiesterase-4; QD, once daily; R, randomized. Statistical Analysis ■ Efficacy endpoints analyzed from the intention-to-treat (ITT) population using multiple imputation for missing data. Safety endpoints analyzed based on the safety population, defined as all randomized subjects who receive at least 1 application of study drug ■ For categorical endpoints, P-values for differences between tapinarof cream 1% QD and vehicle calculated using Cochran-Mantel-Haenszel analysis and stratified by baseline vIGA-AD score and age group. P-values for continuous variables calculated using analysis of covariance, with baseline vIGA-AD score and age group as covariates and baseline value as a continuous covariate Efficacy Endpoints ■ Primary efficacy endpoint is 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 from baseline at Week 8: – Proportion who achieve ≥75% improvement in Eczema Area and Severity Index (EASI75) – Mean change in %BSA affected – Proportion who achieve ≥90% improvement in EASI (EASI90) – Proportion of patients aged ≥12 years with a baseline Peak Pruritus – Numeric Rating Scale (PP-NRS) score ≥4, who achieve ≥4-point reduction in the PP-NRS Safety and Tolerability Endpoints ■ Incidence, frequency and nature of treatment-emergent adverse events and serious adverse events ■ Laboratory values, vital signs, and electrocardiograms ■ Patient- and investigator-assessed local tolerability *Patients electing not to participate in ADORING 3 will attend follow-up visit 1 week after completion of the treatment period in ADORING 1 or 2. †Patients with a vIGA-AD score of ≥3 (moderate) and %BSA affected ≥40% at screening and baseline (pre-randomization), or patients with a vIGA-AD score of 2 (mild) at screening and baseline (pre-randomization) regardless of %BSA affected, who were screened for ADORING 1 or 2 but did not meet vIGA-AD and/or BSA requirements. %BSA, percentage body surface area; vIGA-AD, validated Investigator Global Assessment for Atopic Dermatitis™; PK, pharmacokinetics; QD, once daily. ■ Eligible patients from ADORING 1 and ADORING 2* ■ Eligible patients from Maximal Use PK trial ~125 additional patients aged 2 to <18 years enrolling directly into ADORING 3† ADORING 3 Long-term open-label extension (48 weeks) Follow-up (1 week) Off treatment Off treatment vIGA-AD=0 vIGA-AD≥1 vIGA-AD=0 Stop treatment Tapinarof 1% QD vIGA-AD≥2 Re-start treatment N=up to ~960