and potent binding to AhR.17,20 Tapinarof is now synthetically produced and formulated in a topical cream.21,22
The Aryl Hydrocarbon Receptor Pathway and Tapinarof Mechanism of Action
AhR is a transcription factor expressed by various cell types, including immune cells and epithelial cells in barrier tissues such as skin, gastrointestinal tract, and lungs.23 In the skin, AhR helps maintain homeostasis by mediating responses to chemical and environmental challenges. Transcription factors such as AhR regulate gene expression and directly mediate diverse effects by binding to specific DNA sequences. AhR can be activated by a wide range of molecules (ligands) found in endogenous, dietary, environmental, and microbial sources.23 An important characteristic of AhR is its differential activation by a wide range of ligands, which elicits induction or suppression of various genes resulting in diverse signaling and biologic responses.17 AhR can also signal through other transcription factors, leading to varied biologic effects that are highly dependent on the specific ligand.23,24
AhR has been shown to regulate the expression of T-helper (Th) 17 and Th22 immune cells, and IL-17 and IL-22 cytokines, which are implicated in psoriasis.25 AhR is also implicated in Th2 cell differentiation, and IL-4 and IL-5 production, which are important in the pathogenesis of AD.26 Furthermore, impaired skin barrier function in psoriasis and AD is associated with downregulation of skin barrier proteins (filaggrin, loricrin, and involucrin); these proteins are upregulated by AhR activation and signaling.24
The proposed mechanism of action of tapinarof in psoriasis is shown in Figure 2. Once tapinarof binds to AhR, the tapinarof-AhR complex moves to the nucleus and binds to the AhR nuclear translocator (ARNT), creating a high-affinity DNA-binding transcription factor.17,23,24 The tapinarof-AhR/ARNT complex binds to specific DNA recognition sites of AhR-responsive genes and modulates gene expression.23,24
The unique clinical profile of tapinarof results from specific binding to AhR. Tapinarof binds to and activates AhR to downregulate pro-inflammatory cytokines implicated in psoriasis (IL-17A and IL-17F), which most likely contributes to its rapid therapeutic benefit.20 Additionally, tapinarof-activated AhR decreases oxidative stress through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway; and the tapinarof molecule directly scavenges reactive oxygen species (Figure 2).20 Tapinarof also promotes skin barrier normalization by increasing skin barrier proteins related to keratinocyte differentiation, including filaggrin and loricrin.17,20
Tapinarof Cream for Psoriasis and Atopic Dermatitis
The PSOARING phase 3 trial program that evaluated tapinarof cream to treat plaque psoriasis in adults launched in 2019 with two identical, multicenter, double-blind, vehicle-controlled trials, PSOARING 1 (NCT03956355) and PSOARING 2 (NCT03983980), followed by the long-term extension trial, PSOARING 3 (NCT04053387).22,27 The ADORING phase 3 trial program of tapinarof cream for the treatment of AD in adults and children began in 2021.28
