A Different Kind of Mechanism: Agonism, Not Antagonism
Buchi Neita, PA-C, and Shanna Miranti, PA-C, open by tackling a term most in dermatology had never heard until tapinarof arrived: the aryl hydrocarbon receptor (AHR). Miranti, whom Neita calls the subject matter expert on the topic, explains that even clinicians with 20-plus years in the field hadn't encountered a medication built to agonize rather than antagonize a receptor. As she puts it, most anti-inflammatories on the market work by turning something off — shutting down PDE4 or blocking an inflammatory pathway. This one does the opposite.
Miranti describes the AHR as a sensory protein in the cell’s cytoplasm, waiting for the right signal. When a ligand binds, the AHR moves into the nucleus and switches on a set of genes — genes that can decrease oxidative stress, help detoxify the cell, improve immune regulation, and support tissue repair. The point she keeps returning to is that this is 'good activation': the body's own quieting process is being switched on rather than suppressed.
Neita frames it in language he attributes to Dr. Peter Lio — enhancing, restoring, and balancing rather than suppressing — and Miranti agrees that this drug does exactly that by activating a system that already exists within the body.
The Nematode Origin Story
Neita asks where tapinarof was isolated from, and Miranti tells what she calls the true 'tale of the nematode.' Tapinarof is a naturally derived molecule discovered in a bioluminescent bacterium that had infected a nematode—a worm. The molecule prevented the decomposition of that organic material, and when scientists figured out tapinarof was responsible, that discovery helped illuminate the importance of the aryl hydrocarbon receptor.
Miranti is candid that the story gives some people a 'creepy crawly' feeling, and she's careful to note that while the compound was naturally derived, like anything brought to market, it contains additives and preservatives and is not 100% natural. Still, she and Neita agree the natural-origin angle resonates with certain patients. Neita compares it to how patients respond to polypodium leucotomos in the southern U.S. — patients who don't want to squash their immune system, or the 'more granola' patients, tend to accept a naturally derived prescription more easily.
Why the Skin Is a Prime Target: Barrier, Inflammation, and Oxidative Stress
Miranti calls skin a prime target organ for tapinarof because the AHR is abundantly expressed across skin cell types — keratinocytes, melanocytes, Langerhans cells, T cells, and endothelial cells. She emphasizes that future AHR agonists may reach the market for GI and other conditions, but not all AHR activation in the skin is the same, and this is currently the first and only agent with this mechanism.
She breaks the effect into three functions that maintain skin homeostasis. First, AHR activation improves epidermal barrier integrity by upregulating skin barrier proteins — filaggrin, loricrin, involucrin, and ceramides — helping rebuild the patient's 'brick wall.' Second, it inhibits TH2 and TH17 cytokines and downregulates IgE receptors on Langerhans cells to calm inflammation. Third, it supports antioxidant defense by helping neutralize reactive oxygen species and reduce oxidative skin damage.
Neita highlights what he finds most unique: historically, topical AD agents relied on the vehicle for barrier benefit, while the active ingredient handled inflammation. Here, the drug itself repairs and restores the barrier and increases filaggrin production—which matters, Miranti notes, because many AD patients are genetically insufficient in producing these barrier proteins. Miranti shares an analogy from her speaker training: the drug rebuilds the brick wall, calms the inflammation inside it, and acts like a smoke evacuator clearing oxidative stress from the 'house.'
The Remittive Effect and What the Trials Showed
Miranti introduces a concept neither host had heard before tapinarof: the remittive effect, or durable remission—the idea that a medication can be stopped while the disease stays clear. In the trials, patients who reached complete clearance had their medication taken away and were not given it back until they reached a state of mild disease as determined by the investigator, with touchpoints to check in and the ability to come back if itchy.
She cites the data: in the phase 3 psoriasis trials, notable durable remission averaged 130 days off therapy, and in atopic dermatitis there was a mean treatment-free interval of approximately 80 days after clearance — roughly two and a half months without medication while remaining clear. Neita calls this the best part of the drug for compliance, noting Dr. Feldman's observation that patients often aren’t adherent with topicals; telling patients that consistent use until clearance can buy months of remission is a strong motivator.
On dosing and eligibility: tapinarof is a once-daily topical, one strength, one tube for both indications and all ages. Psoriasis approval came in 2022 for adults with plaque psoriasis, with no body-region restriction (studied on face, folds, scalp, and genitalia, but not intraoral, intraocular, or intravaginal). Atopic dermatitis approval came in late 2024 for ages two and up. Miranti praises the AD trial design: more than 50% skin-of-color patients, equal recruitment across pediatric age groups, and over 80% of participants under 18—with every age group performing consistently well.
Adverse Events and Access
The most common adverse event Miranti flags is folliculitis, seen in approximately 12% of AD patients. Importantly, she notes it is not infectious—when cultured, it was often sterile, more like follicular plugging or KP. Her working explanation: as barrier proteins build up, they can get trapped in hair follicles. She often has patients stop, use a keratolytic, and resume, and notes it tends to happen when patients use too much product or apply too often — a reminder that this is QD, not BID, dosing. Contact dermatitis (irritant or allergic) is possible with any topical, and the product contains propylene glycol, so some sensitivities can occur, though rates were relatively low.
On access — where Neita crowns Miranti the 'access queen' — she notes the molecule has changed companies a few times but believes it has landed somewhere that will fight for access. In her state of Florida, it is not currently on Medicaid formulary, which limits use in younger AD patients, but it is very reproducible for commercial patients. She reminds listeners to include the correct ICD-10 code, prior treatments tried and failed, and body surface area, adding that the drug was studied in large BSAs with no BSA restriction, unlike some other topicals.