Tapinarof

Tapinarof is a topical aryl-hydrocarbon receptor modulator of bacterial origin that acts as an agonist of the aryl-hydrocarbon receptor (AhRT). AhRT is expressed in keratinocytes as well as in fibroblasts and cells of the immune system.

Tapinarof effects have been observed in the interaction of the nematode of the genus Heterorhabditis with insects. This nematode carries in its gut gram-negative bacteria with luminescent properties, called Photorhabdus luminescens, which are released when the nematode infects an insect and kills it by producing metabolites (Hu K et al. 1997). With this mode of infection, it was observed that insects infected with this nematode did not decay after death, in contrast to the rapid decay observed without the specific mode of infection (Hu K et al. 1997). In fact, P. luminescens produces metabolites with antibacterial properties that are responsible for the observed biological effect (Li J et al. 1995). One such metabolite is 3,5-dihydroxy-4-isopropylstilbene (tapinarof). It has been isolated and identified.

Tapinarof has an anti-inflammatory effect by inhibiting the gene expression of pro-inflammatory cytokines such as IL-17A, IL17-.
Tapinarof binds directly to the aryl hydrocarbon receptor and leads to its activation, thereby suppressing inflammatory cytokines (IL-17A/F and IL-4,IL-5 and Il-13). In addition, epidermal skin barrier proteins are increasingly expressed. Tapinarof also has an antioxidant effect.

In a Phase I study, the pharmacokinetics (PK) of tapinarof cream 1% and 2% were investigated in 11 participants with atopic dermatitis when applied twice daily. It was shown that a higher concentration of tapinarof cream leads to higher plasma concentrations of the active substance, which, however, tend to decrease over time, demonstrating that there is no accumulation after repeated exposure. The plasma concentration of tapinarof 1% cream reaches 𝑇max on average after 4.49 hours after administration of the first dose (Jett JE et al. 2022). The metabolism of tapinarof takes place in the liver, with cytochrome (CYP) P450 playing a predominant role. The primary enzymes involved are CYP1A2 and CYP3A4. Due to the large number of CYP enzymes involved in the metabolization of tapinarof, it is unlikely that inhibition of one CYP enzyme will result in increased tapinarof exposure. (Jett JE et al. 2022).

Plaque psoriasis: A multicenter, open-label, phase IIa study (NCT04042103) evaluating the efficacy of tapinarof in the treatment of patients with extensive plaque psoriasis included 21 adult patients. Tapinarof cream 1% was applied once daily to all affected areas for 29 days. The mean PASI value at the start of therapy was 65. On day 29, a significant mean change in the PASI value to 15 was demonstrated (Jett JE et al. 2022).

In a long-term study (PSOARING 3 study) with 763 patients, the efficacy, safety, tolerability, durability of the response to therapy (absence of tachyphylaxis) and the duration of remission after discontinuation of therapy with tapinarof cream 1% in plaque psoriasis were investigated. The total duration of remission after discontinuation of therapy averaged 130.1 days (Strober B et al. 2022).

Safety: ADRs: In the Phase IIa study (NCT04042103), the most common adverse reactions reported with tapinarof cream were folliculitis (19%) and headache (19%). Other side effects included back pain and itching. The drug was also well tolerated in sensitive skin areas. No cardiac side effects were reported (Jett JE et al. 2022).

In a Phase II study (NCT02564042), contact dermatitis was also observed in 3% of patients, which led to discontinuation of treatment (Robbins K et al. 2019). In a Phase IIb study, the reported side effects were mild to moderate (Stein Gold L et al. 2021;Lebwohl MG et al. 2021).

With regard to the long-term data, the most common ADRs were folliculitis (22.7 %), contact dermatitis (5.5 %) and upper respiratory tract infections (4.7 %). Most of these adverse events were mild to moderate (Strober B et al. 2022). > 90 % of patients tolerated the preparation well during the 40-week study period.

Tapinarof Cream 1% (GSK-2894512) has the same active ingredient as Benvitimod Cream 1% (WBI-1001). Benvitimod was developed in China as part of a separate clinical trial program. It has been approved in China since 2019 for topical use in patients with mild to moderate plaque psoriasis (Zhang J et al. 2022). Tapinorof has been approved in the USA in a cream base for the treatment of plaque psoriasis since 2022. It was later also approved on the US market for atopic dermatitis.

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6. Haarmann-Stemmann T et al. (2021) The mode of action of tapinarof may not only depend on the activation of cutaneous aryl hydrocarbon receptor signaling but also on its antimicrobial activity. J Am Acad Dermatol 85:e33-e34.
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12. Robbins K et al. (2019) Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis. J Am Acad Dermatol 80:714-721.
13. Smith SH et al. (2017) Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. J Invest Dermatol 137:2110-2119.
14. Stein Gold L et al. (2021) A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: secondary efficacy and patient-reported outcomes. J Am Acad Dermatol 84: 624-631.
15. Strober B et al. (2022) One-year safety and efficacy of Tapinarof cream for the treatment of plaque psoriasis: results from the PSOARING 3 trial. J Am Acad Dermatol 87:800-806.
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