Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review

Jonathan I. Silverberg; Mark Boguniewicz; Francisco J. Quintana; Rachael A. Clark; Lara Gross; Ikuo Hirano; Anna M. Tallman; Philip M. Brown; Doral Fredericks; David S. Rubenstein; Kimberly A. McHale

doi:10.1016/j.jaci.2023.12.013

Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review

Jonathan I. Silverberg, Mark Boguniewicz, Francisco J. Quintana, Rachael A. Clark, Lara Gross, Ikuo Hirano, Anna M. Tallman, Philip M. Brown, Doral Fredericks, David S. Rubenstein, Kimberly A. McHale^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

3 Scopus citations

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases.

Original language	English (US)
Pages (from-to)	1-10
Number of pages	10
Journal	Journal of Allergy and Clinical Immunology
Volume	154
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2023.12.013
State	Published - Jul 2024

Funding

Disclosure of potential conflict of interest: J. I. Silverberg has received honoraria as a consultant and/or advisory board member for AbbVie , Alamar, Aldena, Amgen , AObiome, Arcutis, Arena, Asana, Aslan, BioMX, Biosion, Bodewell, Boehringer Ingelheim , Bristol-Myers Squibb , Cara, Castle Biosciences, Celgene, Connect Biopharma, Corevitas, Dermavant Sciences, Inc, Dermira, Dermtech, Eli Lilly, Galderma , GlaxoSmithKline , Incyte, Kiniksa , LEO Pharma, Menlo, Novartis , Optum, Pfizer, RAPT, Recludix, Regeneron, Sanofi-Genzyme, Shaperon, TARGET-RWE, Union, and UpToDate and has served as a speaker for AbbVie, Eli Lilly, LEO Pharma, Pfizer, Regeneron, and Sanofi-Genzyme; in addition, his institution has received grants from Galderma, Incyte, and Pfizer. F. J. Quintana is a cofounder of AnTolRx. R. A. Clark has received research sponsorship from Dermavant Sciences, Inc, to carry out scientific studies on the mechanism of action of tapinarof. L. Gross has served as a consultant and/or advisory board member for AstraZeneca, Dermavant Sciences, Inc, Intrommune Therapeutics, Optinose, and Sanofi and has been a subinvestigator for AstraZeneca, Bellus Health, Inc., Genentech, and Teva. I. Hirano is a consultant for AbbVie , Allakos, AstraZeneca , Calyx/Parexel, Dermavant Sciences, Inc, Eli Lilly, Ellodi/Adare Pharma, EsoCap, Gossamer Bio, GSK, Nexstone, Pfizer/Arena Pharmaceuticals, Phathom, Receptos/BMS, Regeneron Pharmaceuticals, Inc, and Shire/Takada and has received research funding from Adare/Ellodi, Allakos, Arena, AstraZeneca, Meritage, Celgene/Receptos/BMS, Regeneron, and Shire/Takeda. M. Boguniewicz has been an investigator for Regeneron, Sanofi and Incyte, and served as a consultant and/or advisory board member for AbbVie, Amgen, Dermavant Sciences, Inc, Eli Lilly, Incyte, Janssen, LEO Pharma, Pfizer, Regeneron, and Sanofi Genzyme. A. M. Tallman, P. M. Brown, D. Fredericks, D. S. Rubenstein, and K. A. McHale are employees of Dermavant Sciences, Inc, with stock options. Editorial and medical writing support under the guidance of the authors was provided by ApotheCom, UK, and funded by Dermavant Sciences, Inc, in accordance with Good Publication Practice guidelines (Ann Intern Med 2022;175:1298-1304). Supported by Dermavant Sciences, Inc.

Keywords

Aryl hydrocarbon receptor
atopic dermatitis
inflammatory disorders
psoriasis
tapinarof cream

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2023.12.013

Cite this

Silverberg, J. I., Boguniewicz, M., Quintana, F. J., Clark, R. A., Gross, L., Hirano, I., Tallman, A. M., Brown, P. M., Fredericks, D., Rubenstein, D. S., & McHale, K. A. (2024). Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review. Journal of Allergy and Clinical Immunology, 154(1), 1-10. https://doi.org/10.1016/j.jaci.2023.12.013

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Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review

Abstract

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Keywords

ASJC Scopus subject areas

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