in two identical pivotal phase 3, randomized trials, Mark G. Lebwohl, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
Dr. Mark Lebwohl
“Tapinarof cream has the potential to be a first-in-class topical therapeutic aryl hydrocarbon receptor modulating agent and will provide physicians and patients with a novel nonsteroidal topical treatment option that’s effective and well tolerated,” predicted Dr. Lebwohl, professor and chair of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.
Dermavant Sciences, the company developing topical tapinarof for treatment of atopic dermatitis as well as psoriasis, announced that upon completion of an ongoing long-term extension study the company plans to file for approval of the drug for psoriasis in 2021.
The two pivotal phase 3 trials, PSOARING 1 and PSOARING 2, randomized a total of 1,025 patients with plaque psoriasis to once-daily tapinarof cream 1% or its vehicle. “This was a fairly difficult group of patients,” Dr. Lebwohl said. Roughly 80% had moderate psoriasis as defined by a baseline Physician Global Assessment (PGA) score of 3, with the remainder split evenly between mild and severe disease. Participants averaged 8% body surface area involvement. Body mass index was on average greater than 31 kg/m2.
The primary efficacy endpoint was a PGA score of 0 or 1 – that is, clear or almost clear – plus at least a 2-grade improvement in PGA from baseline at week 12. This was achieved in 35.4% of patients on tapinarof cream once daily in PSOARING 1 and 40.2% in PSOARING 2, compared with 6.0% and 6.3% of vehicle-treated controls, a highly significant difference (both P < .0001).
The prespecified secondary endpoint was a 75% improvement in Psoriasis Area and Severity Index (PASI) score from baseline to week 12. The PASI 75 rates were 36.1% and 47.6% with tapinarof, significantly better than the 10.2% and 6.9% rates in controls.
The most common adverse event associated with tapinarof was folliculitis, which occurred in 20.6% of treated patients in PSOARING 1 and in 15.7% in PSOARING 2. More than 98% of cases were mild or moderate. The folliculitis led to study discontinuation in only 1.8% and 0.9% of subjects in the two trials.
The other noteworthy adverse event was contact dermatitis. It occurred in 3.8% and 4.7% of tapinarof-treated patients, again with low study discontinuation rates of 1.5% and 2.2%.
Dr. Linda Stein Gold
During the audience discussion, Linda Stein Gold, MD, lead investigator for PSOARING 2, was asked about this folliculitis. She said the mechanism is unclear, as is the best management. She encountered it in patients, didn’t treat it, and it went away on its own. It’s not a bacterial folliculitis; when cultured it invariably proved culture negative, she noted.
The comparative efficacy of tapinarof cream versus the potent and superpotent topical corticosteroids commonly used in the treatment of psoriasis hasn’t been evaluated in head-to-head studies. Her experience and that of the other investigators has been that tapinarof’s efficacy is comparably strong, “but we don’t have the steroid side effects,” said Dr. Stein Gold, director of dermatology clinical research at Henry Ford Health System in Detroit.
In an interview, Dr. Lebwohl said tapinarof, if approved, could help meet a major unmet need for new and better topical therapies for psoriasis.
“You keep hearing about all these biologic agents and small-molecule pills coming out, but the majority of patients still only need topical therapy,” he observed.
Moreover, even when patients with more severe disease achieve a PASI 75 or PASI 90 response with systemic therapy, they usually still need supplemental topical therapy to get them closer to the goal of clear skin.
The superpotent steroids that are the current mainstay of topical therapy come with predictable side effects that dictate a 2- to 4-week limit on their approved use. Also, they’re not supposed to be applied to the face or to intertriginous sites, including the groin, axillae, and under the breasts. In contrast, tapinarof has proved safe and effective in these sensitive areas.
Asked to predict how tapinarof is likely to be used in clinical practice, Dr. Lebwohl replied: “The efficacy was equivalent to strong topical steroids, so I think it could be used first line in place of topical steroids. And in particular, in patients with psoriasis at facial and intertriginous sites, I think an argument can be made for insisting that it be first line.”
He also expects that physicians will end up utilizing tapinarof for a varied group of steroid-responsive dermatoses beyond psoriasis and atopic dermatitis.
“It clearly reduces inflammation, which is why I would expect it would work well for those,” the dermatologist said.
The mechanism of action of tapinarof has been worked out. The drug enters the cell and binds to the aryl hydrocarbon receptor, forming a complex that enters the nucleus. There it joins with the aryl hydrocarbon receptor nuclear translocator, which regulates gene expression so as to reduce production of inflammatory cytokines while promoting an increase in skin barrier proteins, which is why tapinarof is also being developed as an atopic dermatitis therapy.
Dr. Lebwohl and Dr. Stein Gold reported receiving research funds from and serving as consultants to Dermavant Sciences as well as numerous other pharmaceutical companies.