In the Pipeline: What to Know About Tapinarof

Patients treated with tapinarof cream, 1% once daily demonstrated improvement in PASI 75 as early as week 2, according to data published in The Journal of the American Academy of Dermatology (JAAD) and reported by drug developer Dermavant. Data come from the Phase 2b randomized clinical trial of tapinarof, a therapeutic aryl hydrocarbon receptor modulating agent (TAMA), for the treatment of plaque psoriasis.

PASI 75 associated with tapinarof was statistically significant starting at week 8 and was maintained for four weeks after treatment discontinuation (through week 16) compared with vehicle. Similarly, PASI 90 response also showed statistically significant efficacy at week 12 and a maintenance of effect at week 16 for tapinarof 1% compared with vehicle.

Total target lesion grading scores improved from week 2 onward for tapinarof cream compared with vehicle and were maintained for four weeks after treatment discontinuation (through week 16) in all tapinarof treatment groups.

A significantly higher proportion (88 percent) of patients treated with tapinarof 1% reported very or moderately improved psoriasis symptoms and psoriasis-related pruritus (76 percent), compared with those receiving vehicle QD (35 percent) at week 12.

Todd Zavodnick, CEO at Dermavant Sciences, spoke with Practical Dermatology® magazine about this investigational treatment.

What is a therapeutic aryl hydrocarbon receptor modulating agent (TAMA)? What is the mechanism of action?

Todd Zavodnick: Tapinarof, a TAMA, inhibits two pro-inflammatory pathways implicated in psoriasis (Th17 cytokines: IL-17A; IL-17F) and atopic dermatitis (Th2 cytokines: IL-4; IL-5; IL-13). It is believed that the AhR modulation by tapinarof also increases antioxidant activity via upregulation of Nrf2 and promotes skin barrier restoration through upregulation of a number of epidermal barrier genes, including filaggrin, hornerin, and involucrin.

How was the molecule discovered? Has it been used in other therapeutic areas?

Mr. Zavodnick: The molecule is a naturally derived compound produced by a bacterium (Photorhabdus luminescens) first identified in the gut of a nematode. It was originally pursued for antibacterial purposes, but did not exhibit adequate potency as an antibiotic and was subsequently observed to possess potent anti-inflammatory activity. Today, the molecule is manufactured synthetically and formulated in a cosmetically elegant, stable cream that is being explored for once-daily dosing.

Due to the physical chemical properties of tapinarof and the subsequent challenges associated with developing a stable, cosmetically elegant commercial formulation, Dermavant has broad patent protection that extends to at least 2036.

Is the MOA the same for atopic dermatitis and psoriasis? Are there other potential applications?

Mr. Zavodnick: As a TAMA, tapinarof is observed to inhibit two pro-inflammatory pathways: one implicated in psoriasis (Th17 pathway with downregulation of the associated cytokines IL17A and F) and one implicated in atopic dermatitis (Th2 pathway with downregulation of the associated cytokines IL4, 5, and 13).

While we are pursuing disease states where data exists (atopic dermatitis and psoriasis), we have interest in exploring tapinarof’s utility across a broad spectrum of inflammatory skin disorders. As a new chemical entity with a highly unique mechanism of action, tapinarof represents a newly emerging investigational medicine with the potential ability to positively impact the lives of patients with either atopic dermatitis or psoriasis.

Most current investigational products lack data suggesting they have adequate potency in multiple distinct disease states; however, the published results in JAAD illustrate tapinarof’s potential utility in both atopic dermatitis and psoriasis and its unique position as an emerging transformative agent for inflammatory skin diseases.