Tapinarof cream 1% QD resulted in minimal-to-no systemic exposure in the phase 3 plaque psoriasis pivotal trials67 and in patients with plaque psoriasis covering up to 46% of their body surface area (BSA).68 This pharmacokinetic profile underlies the low potential for systemic adverse effects and drug interactions with topical tapinarof, no QT interval effects, and no requirement for dose modifications based on renal/hepatic dysfunction.16
Tapinarof activates AhR, resulting in downregulation of Th2 cytokines implicated in the pathogenesis of AD (Figure 2).14,15 AhR activation by tapinarof restores the epidermal barrier by increasing the expression of the skin-barrier proteins filaggrin, loricrin, hornerin, and involucrin, as well as ceramide lipid components.14,15,42 Tapinarof increases antioxidant responses through the Nrf2 pathway and by direct oxygen scavenging.14 In addition to activation of Nrf2 through AhR, tapinarof directly binds to and activates Nrf2.14
Tapinarof cream 1% QD demonstrated significant efficacy and tolerability in adults and adolescents with AD in early clinical trials.17,18 In a phase 2 clinical trial evaluating tapinarof cream 1% QD in adults and adolescents with moderate to severe AD, efficacy was maintained 4 weeks after completing the 12-week treatment period.18 This remittive effect of therapy is in alignment with findings in adult patients with plaque psoriasis treated with tapinarof64 and is being further investigated in the ADORING phase 3 trial program. Moreover, consistent with the pharmacokinetic profile in psoriasis, tapinarof cream 1% QD demonstrated minimal-to-no systemic exposure in adolescents and children down to 2 years of age with extensive AD, with up to 90% BSA affected.69
The ADORING phase 3 program is a year-long evaluation of the efficacy and safety of tapinarof cream 1% QD for the treatment of AD in adults and children down to 2 years of age. The program comprises two 8-week, vehicle-controlled pivotal trials (ADORING 1 [NCT05014568] and 2 [NCT05032859]) and a 48-week open-label long-term extension trial (ADORING 3 [NCT05142774]). In the pivotal trials, patients with AD received tapinarof or vehicle QD. The primary endpoint of a Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) of 0 (clear) or 1 (almost clear) and 2 or greater-grade improvement from baseline at Week 8, was highly statistically significant in the tapinarof cream 1% QD group versus vehicle at Week 8 in both ADORING 1 and 2: 45.4% vs 13.9% and 46.4% vs 18.0% (both P<0.0001), respectively.70
