New Topical Agents for Treatment of Plaque Psoriasis

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Bridging the GapsNew Directions and Practice-Impacting Recommendations in Plaque Psoriasis

This publication was developed independently by MJH Life Sciences Global Medical Affairs. Support for the thought leaders meeting and the publication was provided by Arcutis Biotherapeutics, Inc; The Bristol Myers Squibb Company; Janssen Global Services, LLC; and UCB, Inc.

Topicals are the mainstay of treatment for patients with plaque psoriasis (PsO) of any disease severity.1 Since 1997, corticosteroids, retinoids, and vitamin D analogues have been the only active ingredients used in topical therapies for PsO; new formulations introduced since then have featured changes in the vehicle components or in combinations of active ingredients. Many of these formulations have limitations on duration of use and body areas on which they can be applied due to the potential for certain adverse effects (AEs). Patients may need to use multiple different topical agents at a time, which increases the likelihood of medication misuse and nonadherence. The 2022 approvals of the tapinarof cream, 1% (VTAMA®; Dermavant Sciences) (an aryl hydrocarbon receptor agonist) and roflumilast cream, 0.3% (Zoryve®; Arcutis Biotherapeutics), (a phosphodiesterase-4 [PDE4] inhibitor) for treatment of plaque PsO has provided 2 new options for safe, effective, and well-tolerated steroid-free topical therapies with the potential to simplify management for patients.1-4

Tapinarof

As an aryl hydrocarbon receptor agonist, tapinarof uses a novel mechanism of action to downregulate expression of T helper type 17 cytokines that drive inflammation in PsO, normalize skin barrier function, and increase antioxidant activity.1 In the pivotal phase 3 PSOARING 1 (NCT03956355) and PSOARING 2 (NCT03983980) trials, researchers found that a Physician’s Global Assessment (PGA) score of 0 or 1 with a 2-grade reduction was achieved by a considerably greater proportion of groups given once-daily tapinarof compared with the respective vehicle groups at 12 weeks (PSOARING 1: 35.4% vs 6.0%; adjusted difference, 29.4 percentage points; relative rate, 5.8; 95% CI, 2.9-11.6; P < .001; PSOARING 2: 40.2% vs 6.3%; adjusted difference, 33.9 percentage points; relative rate, 6.1; 95% CI, 3.3-11.4; P < .001).1 Among 312 patients who achieved PGA 0 at least once during the vehicle-controlled and/or the open label extension period, the median time to relapse (defined as PGA 2 or greater) was an unprecedented 4 months. Additionally, patients treated with tapinarof, 1%, cream who had a Peak Pruritus Numerical Rating Scale (PP-NRS) score of at least 4 points at baseline experienced at least a 4-point reduction as early as 2 weeks, which continued to increase to 60.7% and 56.9% by 12 weeks, compared to just 43.2% and 29.6% of patients in the vehicle groups, demonstrating rapid and robust itch reduction.1

In the 40-week, open-label safety study (PSOARING 3), participants continued the tapinarof cream until they had complete skin clearance, after which the patients held application of the cream. The duration to symptom recurrence was measured, and a durable remittive effect was observed. On average, the median remittive duration was approximately 4 months, and some remained symptom-free for up to 8 to 9 months. In addition, the trial results showed a durable response out to 52 weeks without evidence of tachyphylaxis.5

Overall, tapinarof demonstrated good local tolerability. In the PSOARING 1 and PSOARING 2 trials, respectively, contact dermatitis was experienced by 5% and 5.8% of the patients who received tapinarof vs 0.6% and no patients who received the vehicle; one of these cases in PSOARING 2 was a severe adverse event. Folliculitis was reported in 23.5% and 17.8% in the tapinarof-treated groups vs 1.2% and 0.6% in the vehicle groups. Most cases of folliculitis were mild to moderate with only 1 grade 3 event that was reported during the PSOARING 1 trial; therapy was discontinued due to folliculitis in 1.8% and 0.9% of patients.1

Folliculitis presentation includes keratotic papules, pustules, and milia and varies among patients; it was generally limited to the site of application. In the authors’ experience, this appears to occur more frequently in hair-bearing areas. Treatments for folliculitis include temporary interruption of tapinarof, antibiotics, urea, retinoids, salicylic acid, or topical corticosteroids; however, many cases resolved even without any treatment. Educating patients about the potential for this AE and how it may be managed is important to ensure patient adherence.

Roflumilast

Unlike other available PDE4 inhibitors, roflumilast has 3 major anchoring points that bind to the PDE4 enzyme, which drastically increases the potency (as assessed in vitro) compared with that of other PDE4 inhibitors. In the phase 3 DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389) trials, considerably greater proportions of patients given roflumilast achieved the primary end point of Investigator’s Global Assessment (IGA) scale (clear or almost clear status and at least a 2-grade improvement from baseline) at 8 weeks compared to those given the vehicle (DERMIS-1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3-46.9]; DERMIS-2: 37.5% vs 6.9%; difference, 28.8% [95% CI, 20.8-36.9]).4 Additionally, significant improvements in IGA success with roflumilast were observed as early as 4 weeks after start of treatment (DERMIS-1: 20.6% vs 2.3%; difference, 19.3% [95% CI, 13.5-25.1]; P < .001; DERMIS-2: 19.1% vs 5.3%; difference, 13.5% [95% CI, 7.2-19.9]; P < .001).4

Additional findings from the DERMIS-1 and -2 trials showed that roflumilast was also beneficial for patients with intertriginous psoriasis. Compared with use of the vehicle treatment, roflumilast treatment significantly improved intertriginous IGA scores at 6 weeks among patients having an intertriginous IGA score of 2 or more at baseline (DERMIS-1: 56.6% vs 22.2%; difference, 41.0% [95% CI, 20.1-61.8]; P = .005; DERMIS-2: 57.8% vs 13.8%; difference, 40.5% [95% CI, 18.7-62.2]; P = .004), leading to the inclusion of intertriginous psoriasis in the US prescribing label.4

Regarding safety, nonsteroidal options have traditionally been associated with tolerability issues. Findings from the DERMIS-1 and -2 trials indicated that application site pain was infrequent, and nearly 99% of patients reported no signs of irritation at 4 and 8 weeks.4 Additionally, the rates of diarrhea and headache, which are commonly associated with oral PDE4 inhibitors, were low (diarrhea, 2.8%-3.5%; headache, 1.0%-3.8%) and mild or moderate in severity; no events involving diarrhea required interruption or discontinuation of treatment.4

Given the difficult of treating intertriginous PsO, a topical nonsteroidal option that is effective, safe, and well tolerated when used in these areas is particularly valuable. The ability to use roflumilast, 0.3%, cream on multiple areas of the body, including difficult-to-treat areas like the elbows and sensitive areas like the skin folds, can simplify treatment options for appropriate patients.

Roflumilast has a trademarked drug delivery formulation (HydroARQ Technology™) that does not contain propylene glycol, a potential irritant and allergen, and includes a proprietary hydrophilic emulsifier (Crodafos™ CES) found in many other popular cosmeceuticals, resulting in an elegant cream that is well tolerated and compatible with most other skin care products.3 Educating patients about the formulation’s novel mechanism of action and the well-tolerated vehicle may provide reassurance in patients who have had a negative experience with previous PDE4 inhibitors or topical agents.

Use of roflumilast in a foam vehicle has also been studied for scalp and body PsO. In a phase 2b study (NCT04128007), use of this formulation yielded an achievement of scalp-IGA clear or almost clear and a 2-grade or more improvement from baseline to week 8 in 59.1% of patients vs 11.4% of those given vehicle, with significant effects observed as early as week 2.5 Roflumilast foam was also well tolerated; there was no evidence of irritation in 96% or more of patients based on investigator-rated tolerability and mild or no sensation in 94% or more on patient-rated tolerability.6 Due to the anionic nature of the Crodafos CES emulsifying wax, roflumilast foam is repulsed by the natural negative charge of the hair, allowing it to selectively target the scalp skin while avoiding the hair shaft. This is particularly advantageous for patients with tightly coiled hair who may be more susceptible to hair shaft breakage from harsh ingredients.

Incorporating Novel Topical Agents Into Clinical Practice

While topical corticosteroids will continue to be an important option in our topical armamentarium, novel nonsteroidal topicals such as tapinarof and roflumilast can address some of the limitations associated with topical corticosteroids. Furthermore, these agents could simplify the treatment regimen because of both their once-daily application versus the twice-daily frequency required by many other topical agents and their effectiveness, safety, and tolerability across a wide range of body areas. No direct comparative studies have been conducted between tapinarof or roflumilast, yet each of these agents has unique characteristics that should be considered when choosing treatment for a given patient.

Both of the pivotal studies were conducted as monotherapy, yet the product label allows for tapinarof and roflumilast to be used together with other therapeutic agents. Prescribing a topical corticosteroid in addition to tapinarof or roflumilast may benefit patients who want a more rapid response. Patients on a systemic treatment with residual disease may also benefit from adding tapinarof or roflumilast. Educating patients on the mechanism of action and setting specific expectations on the timeline for a therapeutic response is particularly important to improve treatment adherence.

Faculty presenters: Eingun James Song, MD, FAAD; and Kimberly Gutowsy Baker, MSN, FNP-C. This article was reviewed, edited, and approved by Dr Song, Ms Gutowsy Baker, and Dr Stein Gold.

References

  1. Lebwohl MG, Stein Gold L, Strober B, et al. Phase 3 trials of tapinarof cream for plaque psoriasis. N Engl J Med. 2021;385(24):2219-2229. doi:10.1056/NEJMoa2103629
  2. FDA approves Dermavant’s VTAMA (tapinarof) cream, 1% for the treatment of plaque psoriasis in adults: first topical novel chemical entity launched for psoriasis in the U.S. in 25 years. Press release. Dermavant Biosciences. Updated May 24, 2022. Accessed December 14, 2023. https://www.dermavant.com/u-s-fda-approves-our-novel-topical-treatment-for-adults-with-plaque-psoriasis/
  3. FDA approves Arcutis’ ZORYVE (roflumilast) cream 0.3% for the treatment of plaque psoriasis in individuals age 12 and older. Press release. Arcutis Biotherapeutics. Updated July 29, 2022. Accessed December 14, 2023. https://www.arcutis.com/fda-approves-arcutis-zoryve-roflumilast-cream-0-3-for-the-treatment-of-plaque-psoriasis-in-individuals-age-12-and-older/
  4. Lebwohl MG, Kircik LH, Moore AY, et al. Effect of roflumilast cream vs vehicle cream on chronic plaque psoriasis: the DERMIS-1 and DERMIS-2 randomized clinical trials. JAMA. 2022;328(11):1073-1084. doi:10.1001/jama.2022.15632
  5. Strober B, Stein Gold L, Bissonnette R, et al. One-year safety and efficacy of tapinarof cream for the treatment of plaque psoriasis: Results from the PSOARING 3 trial. J Am Acad Dermatol. 2022;87(4):800-806. doi:10.1016/j.jaad.2022.06.1171
  6. Kircik LH, Alonso-Llamazares J, Bhatia N, et al. Once-daily roflumilast foam 0.3% for scalp and body psoriasis: a randomized, double-blind, vehicle-controlled phase IIb study. Br J Dermatol. 2023;189(4):392-399. doi:10.1093/bjd/ljad182
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