This marks Arcutis’ third topical roflumilast NDA submission in two years.

Arcutis Biotherapeutics, Inc. submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for roflumilast cream 0.15% for the treatment of mild to moderate atopic dermatitis (AD) in adults and children ages 6 years and older.

Roflumilast cream is a once-daily, steroid-free, topical formulation of a highly potent and selective phosphodiesterase-4 (PDE4) inhibitor. It is formulated with HydroARQ Technology as a non-greasy emollient cream that absorbs quickly and does not disrupt the skin barrier. In addition, roflumilast cream does not include sensitizing excipients or irritants, such as propylene glycol, polyethylene glycol, isopropyl alcohol, ethanol, or fragrances.

The sNDA submission is supported by positive results from the “INterventional Trial EvaluatinG roflUMilast cream for the treatmENt of aTopic dermatitis” (INTEGUMENT-1 and INTEGUMENT-2) trials; two identical Phase 3, parallel group, double blind, vehicle-controlled trials in which roflumilast cream 0.15% or vehicle was applied once-daily for four weeks to individuals 6 years of age and older with mild to moderate AD involving ≥3% body surface area.

Both studies met the primary endpoint of IGA Success, defined as a validated Investigator Global Assessment – Atopic Dermatitis (vIGA-AD) score of ‘clear’ or ‘almost clear’ plus a 2-grade improvement from baseline at Week 4 (INTEGUMENT-1: 32.0% roflumilast cream vs. 15.2% vehicle, P<0.0001; INTEGUMENT-2: 28.9% roflumilast cream vs. 12.0% vehicle, P<0.0001).

More than 30% of individuals treated with roflumilast cream in each study achieved Worst Itch-Numeric Rating Scale (WI-NRS) Success at Week 4. WI-NRS Success is defined as achievement of at least a 4‑point reduction on the WI-NRS 0-10 scale (in individuals 12 and older who had a baseline WI-NRS score of at least 4). Rapid and significant improvement in itch was observed in individuals treated with roflumilast cream compared with vehicle as early as 24 hours following the first application, as measured by the least-squares (LS) mean change from baseline in daily WI-NRS scores between the two groups (nominal P<0.05).

In both studies, approximately 40% of children and adults treated with roflumilast cream achieved a vIGA-AD score of Clear (0) or Almost Clear (1) at Week 4 (INTEGUMENT-1: 41.5% vs. 25.2%, P<0.0001; INTEGUMENT-2: 39% vs. 16.9%, P<0.0001), with significant improvement as early as Week 1 (P< 0.0001).

In addition, more than 40% of children and adults treated with roflumilast cream achieved a 75% reduction in Eczema Area and Severity Index (EASI-75) at Week 4 compared to vehicle (INTEGUMENT-1: 43.2% vs. 22.0%, P<0.0001; INTEGUMENT-2: 42.0% vs. 19.7%, P<0.0001). Significant improvements in EASI-75 were observed with roflumilast cream as early as Week 1 in both studies (nominal P=0.0006; nominal P=0.0329).

Roflumilast cream 0.15% was well tolerated. The incidence of Treatment Emergent Adverse Events (TEAEs) was low in both active treatment and vehicle arms, with most TEAEs assessed as mild to moderate in severity. There were no adverse reactions in the combined Phase 3 pivotal trials that occurred in more than 2.9% of subjects in either arm. The most common adverse reactions included headache (2.9%), nausea (1.9%), application site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

The submission is also supported by data from a Phase 2 dose ranging study, an open label extension study in which patients were treated for up to 52 weeks, and two Phase 1 pharmacokinetic studies.

“Atopic dermatitis is a chronic and relapsing disease that occurs across the lifespan. In clinical studies, once-daily roflumilast cream provided rapid clearance of the disease. In addition, roflumilast cream rapidly reduced itch, one of the most bothersome symptoms to patients, in as little as twenty-four hours,” says Eric Simpson, MD, MCR, Professor of Dermatology at Oregon Health & Science University in Portland, Oregon, and investigator in the Phase 3 INTEGUMENT trials, in a news release. “The INTEGUMENT studies’ novel approach also incorporated assessment of twice weekly proactive treatment in the long-term study, which demonstrated that, once clear, patients could maintain adequate control by staying ahead of the condition rather than chasing flares. Together, these data suggest that roflumilast cream, if approved, could provide a simplified approach to disease control.”

“Atopic dermatitis is a complex disease. Optimal management of the condition requires a complex balance of treatment, efficacy, safety, tolerability, as well as adherence. Atopic dermatitis patients have sensitive skin and increased risk for developing contact dermatitis from their topical medications,” adds Jonathan Silverberg, MD, PhD, MPH, FAAD, Professor, Director of Clinical Research, and Director of Patch Testing at George Washington University School of Medicine and Health Sciences, Washington, DC. “Topical roflumilast cream was intentionally formulated with the atopic dermatitis patient in mind and does not contain excipients that disrupt skin-barrier integrity or are common contact allergens. Overall, once-daily topical roflumilast cream has demonstrated in clinical trials a balance of efficacy and tolerability, along with a long-term safety profile, that could support increased adherence for patients with atopic dermatitis.”

“Topical therapies are foundational therapy for the vast majority of individuals who use pharmaceuticals to treat their atopic dermatitis, but today’s topicals come with limitations. People suffering from atopic dermatitis want fast-acting, steroid-free, topical treatments that are effective and well tolerated,” says Frank Watanabe, President and Chief Executive Officer of Arcutis. “This is particularly important given the prevalence of the disease in children, where safety and tolerability are of particularly great concern when considering which treatment to use. Both healthcare professionals and patients or parents deserve to feel confident in the treatment decisions they make.”