**4.5 AhR agonists**

Tapinarof (also known as WBI-1001, GSK2894512, DMVT-505) is a naturally derived small molecule produced by bacterial symbionts of entomopathogenic nematodes [106]. Broad cellular profiling of tapinatof identified aryl hydrocarbon receptor (AhR) as a primary target [107]. Tapinarof activates the AhR pathway through direct binding. It was reported that AhR activation can modify transcriptional regulation of the immune system and, specifically, affect the differentiation of Th17 and Treg cells [108]. Tapinarof has been shown to inhibit IL-17A message expression by approximately 50% and robustly increase IL-22 levels [107]. Furthermore, 1% tapinarof cream can reduce imiquimod (IMQ )-induced skin inflammation and suppress IMQinduced IL-17A and IL-17F gene expression in AhR-sufficient, but not AhR-deficient mice.

Topical 1.0% tapinarof met its primary endpoint in patients with mild-to-moderate psoriasis from a randomized double-blind placebo-controlled phase II trial [109]. The improvement in PGA at week 12 was 62.8% for patients randomized to tapinarof when compared with 13.0% for patients randomized to placebo (p < 0.0001). The adverse events observed in patients treated with tapinarof were all mild to moderate in intensity.

In 2018, GlaxoSmithKline (GSK) withdrew its phase III trial of tapinarof (GSK2894512) and sold mostly global rights of its Phase III-bound psoriasis candidate tapinarof to Dermavant Sciences [110]. On 9/30/2021, Dermavant Sciences disclosed final results from Phase III PSOARING 3 long-term extension study of tapinarof, a 1.0% once a daily, in patients with plaque psoriasis [111]. 58.2% (302/519) of patients with a PGA score ≥ 2 achieved a PGA score of 0 or 1. Moreover, 40.9% (312/763) of all patients achieved complete disease clearance (PGA score of 0). Those results demonstrate tapinarof's continued improvement in efficacy beyond the 12-week pivotal studies. Treatment-emergent adverse events (TEAEs) were mostly mild to moderate, at application sites, and associated with a low discontinuation rate (5.4%). Incidence and severity of folliculitis and contact dermatitis remained stable with long-term use (up to 52 weeks) and were associated with low discontinuation rates (1.2% and 1.4%, respectively). The FDA accepted the New Drug Application submitted in May 2021, and assigned a Prescription Drug User Fee Act target action date in the second quarter of 2022.
