Tarrying for tapinarof
By Warren R. Heymann, MD, FAAD
January 12, 2022
Vol. 4, No. 2
Today we held our first round of interviews for our dermatology residency program for 2023. Meeting dermatology resident applicants is a delight — they are brilliant, engaging, and a source of pride for our discipline. We started our program at Cooper Medical School of Rowan University in 1995, the year most candidates were born. This generation will learn to treat psoriatic patients in ways that were unimaginable when I ran the Psoriasis Day Care Center at the Albert Einstein College of Medicine in 1983. I now experience joyful incredulity about how our most severely afflicted patients who would have failed to respond to the most aggressive treatments of that era have the chance of a PASI 100 with just a few injections of the newest biologics.
While the systemic approach to psoriasis is light years away from my initial experience, what all generations of dermatologists have in common is the use of topical agents, which have been introduced slowly over the years. Despite the miraculous advent of biologics, topical treatments will remain the cornerstone of treatment for psoriatic patients with mild or localized disease. Topical steroids, tars, anthralin, keratolytics, vitamin D3 analogs, calcineurin inhibitors, and tazarotene are standard topical therapies that may be used to advantage, although each has their limitations. The quest for the ideal topical treatment for psoriasis continues unabated.
Considerable research has been devoted to the aryl hydrocarbon receptor (AHR) which is expressed in every skin cell type (keratinocytes, sebocytes, fibroblasts, melanocytes, endothelial cells, Langerhans cells, and lymphocytes), playing a role in skin homeostasis and disorders such as atopic dermatitis (AD) and psoriasis. (1) New evidence has emerged implicating AHR signaling through skin microbiota-derived expression of antimicrobial peptides. (2) I have the honor of writing a column each month in the Journal of the American Academy of Dermatology entitled “A Clinician’s Perspective,” highlighting an article(s) in that issue. In January 2019, I wrote about how current understanding of the oldest therapy for psoriasis — crude coal tar — has led to new formulations that are effective and cosmetically elegant. The focus of that editorial was on the use of tapinarof for AD. This commentary is devoted to its use in psoriasis. The following paragraphs are direct quotations from the JAAD editorial (3):
Recent studies have elucidated the mysteries of coal tar's benefit. Through use of organotypic skin models with primary keratinocytes from patients with AD and controls, it has been demonstrated that coal tar activates the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation, restoration of filaggrin expression, and counteraction of type 2 helper T cell cytokine–mediated downregulation of skin barrier proteins. Coal tar interferes with type 2 helper T cell cytokine signaling via dephosphorylation of signal transducer and activator of transcription 6, most likely as a result of AHR-regulated activation of the nuclear factor, erythroid 2 like 2 antioxidative stress pathway. These findings suggested that the therapeutic effect of AHR activation could lead to the development of new mechanism-based drugs for AD.
Tapinarof is a bacteria-derived polyphenol that acts on the AHR and nuclear factor erythroid 2–related factor 2 (a basic leucine zipper protein) that protect against inflammatory-induced oxidative damage. Tapinarof also has free radical scavenging ability. In a study using a mouse model of imiquimod-induced psoriasiform skin lesions, topical treatment of AHR-sufficient mice with tapinarof led to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. Tapinarof had no impact on imiquimod-induced skin inflammation in AHR-deficient mice. This study clearly demonstrated that the anti-inflammatory properties of tapinarof are due to AHR agonism.
In a phase 2b 12 week double-blind, vehicle-controlled trial of tapinarof, Stein Gold et al demonstrated that the 1% formulation showed statistically significant improvement of psoriasis as early as 2 weeks, significantly by 8 weeks, and maintained at 16 weeks (4 weeks after discontinuation). (4)
Lebwohl et al conducted two identical phase 3 randomized trials of tapinarof in adult patients with mild-to-severe plaque psoriasis. Patients were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a Physician’s Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. In trials 1 and 2, a total of 510 and 515 patients were enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis (23.5% in trial 1 and 17.8% in trial 2), nasopharyngitis, contact dermatitis (5.0% in trial 1 and 5.8% in trial 2), headache (2.4% in trial 1 and 3.8% trial 2), upper respiratory tract infection, and pruritus. The authors concluded that tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (5)
Jett et al performed a multicenter, open-label trial to assess the safety, tolerability, pharmacokinetics (PK), and efficacy of tapinarof cream 1% once daily (QD) under maximal use conditions in extensive plaque psoriasis. Twenty-one adults with a baseline PGA score of ≥ 3 and body surface area (BSA) involvement ≥ 20% received tapinarof cream 1% daily for 29 days. At day 29, 14 patients (73.7%) had a ≥ 1-grade improvement in PGA score and 6 patients (31.6%) had a ≥ 2-grade improvement; 4 patients (21.1%) achieved treatment success (PGA 0 or 1 and ≥ 2-grade improvement). Common adverse reactions were folliculitis (19%), headache (19%), back pain (9.5%), and pruritus (9.5%), none of which caused drug discontinuation. Tapinarof plasma exposure was low, with most concentrations being below detectable limits. The authors concluded that daily application of tapinarof cream 1% was well tolerated, with limited systemic exposure and significant efficacy at 4 weeks in patients with extensive plaque psoriasis. (6)
(The reader should note that these 3 studies were supported by Dermavant Sciences. I have no financial, or any other, conflict of interest).
While always cautiously optimistic when I read such studies, the skeptic in me focuses on the adverse reactions. Do I want patients to experience an almost 1 in 4 chance of folliculitis? Bissonette et al discuss this further, (presumably) based on the same cohort of patients in the Lebwohl et al study, stating; “In the most recent, pivotal, phase 3 psoriasis trials in 1025 patients, the adverse event associated with tapinarof was folliculitis, which was mostly mild, resulted in a low incidence of study discontinuation (<1.8%)." (7) What I find most disconcerting is the frequency of headaches. What is the pathomechanism(s)? I cannot find any definitive literature on this topic. The pharmacokinetics suggest that it is unlikely due to systemic effects. This mystery must be solved.
As Bieber asserts, in addition to AHR agonists, other novel compounds such as phosphodiesterase type 4 inhibitors (e.g., roflumilast) and Janus kinase inhibitors (e.g., brepocitinib) are in clinical development and may show promise for topical therapy of psoriasis. Of concern will be the cost-effectiveness of these drugs and if patients will have access to them. (4)
Undoubtedly, an increasing number of topical agents will be available for our psoriatic patients. More research is mandatory. Perhaps our current dermatology residency applicants, who will graduate in 2026, will be able to offer their patients something new.
Point to Remember: Tapinarof, an aryl hydrocarbon receptor-modulating agent, has shown promise for the topical treatment for psoriasis and atopic dermatitis. Questions remain and further study is required before this medication is part of the topical dermatological therapeutic palette.
Our expert’s viewpoint
Mark Lebwohl, MD, FAAD
Dean of Clinical Therapeutics
Professor of Dermatology
Kimberly and Eric J. Waldman Department of Dermatology
Icahn School of Medicine at Mount Sinai
For decades, we have been trying to develop creative protocols to avoid topical steroid side effects such as cutaneous atrophy, striae, perioral dermatitis, and others. Regimens which apply steroids on weekends only or twice a week for maintenance have been popular. (9-11) Non-steroidal agents like calcipotriene and tazarotene have been developed for psoriasis, but they are less effective than our strongest corticosteroids, and they are irritating, particularly on facial and intertriginous skin.
In the coming year, it is likely that we will see two topical non-steroid products approved for psoriasis. (5, 12) Roflumilast is a topical phosphodiesterase 4 (PDE4) inhibitor that is more potent an inhibitor of PDE4 inhibitor than apremilast or crisaborole. Phase 2 results showed highly significant superiority over placebo, and particularly dramatic improvement in intertriginous sites. In the recent New England Journal of Medicine article (5), tapinarof, a topical aryl hydrocarbon receptor modulating agent, showed highly statistically significant improvement in psoriasis over placebo. In patients who cleared completely and discontinued the medication, there was a long period of remission lasting nearly 4 months. In those who improved but did not achieve clearing and continued the therapy, improvement was maintained long-term. No steroid side effects were seen, and the only noteworthy side effect was the development of mild to moderate folliculitis, which did not prevent most patients from continuing in the study.
Both of these agents will be welcome additions to our topical armamentarium against psoriasis.
Dr. Lebwohl had disclosed financial relationships with the following to the AAD at the time of publication: AbbVie, Aditum Bio, Allergan, Inc., Almirall, AltruBio Inc., Amgen, AnaptysBio, Arcutis, Inc., Arena Pharmaceuticals, Aristea Therapeutics, Arrive Technologies, Avotres, Inc., BiomX Ltd., BirchBioMed, BMD Skincare, Inc., Boehringer Ingelheim, Brickell Biotech, Inc., Cara Therapeutics, Castle Biosciences, Inc, Corrona, Inc., Bristol-Myers Squibb, Dermavant Sciences, Dr. Reddy, Eli Lilly and Company, EMD Serono, Evelo Biosciences, Inc., Evommune, Inc., Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research & Education of Dermatology, Helsinn Healthcare, Hexima Ltd., Incyte Corporation, Inozyme Pharma, Janssen Research & Development, LLC, Kyowa Kirin, Leo Pharma Inc, LEO Pharma, US, Meiji Seika Pharma Co., Ltd, Menlo Therapeutics, Mindera, Mitsibushi Pharma, Neuroderm LTD, Ortho Dermatologics, Pfizer Inc., Regeneron, Seanergy Maritime Holdings Corp., Theravance Biopharma, UCB, Verrica Pharmaceuticals Inc. Full disclosure information is available.
Fernández-Gallego N, Sánchez-Madrid F, Cibrian D. Role of AHR Ligands in Skin Homeostasis and Cutaneous Inflammation. Cells. 2021 Nov 15;10(11):3176. doi: 10.3390/cells10113176. PMID: 34831399; PMCID: PMC8622815.
van den Bogaard EH, Esser C, Perdew GH. The aryl hydrocarbon receptor at the forefront of host-microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications. Exp Dermatol. 2021 Oct;30(10):1477-1483. doi: 10.1111/exd.14409. Epub 2021 Jul 8. PMID: 34105853; PMCID: PMC8518783.
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