The U.S. Food and Drug Administration (FDA) has approved the supplemental new drug application (sNDA) for roflumilast cream 0.15% (Zoryve, Arcutis), a next-generation topical phosphodiesterase 4 (PDE4) inhibitor, for the treatment of mild to moderate atopic dermatitis in adults and pediatric patients six years of age and older.
Lawrence F. Eichenfield, MD, Professor of Dermatology and Pediatrics and Vice-chair of the Department of Dermatology at the University of California, San Diego School of Medicine and INTEGUMENT study investigator, discusses the data that led to this approval and what this new steroid-free option will mean for AD patients.
The sNDA is supported by positive results from three Phase 3 studies, a Phase 2 dose-ranging study, and two Phase 1 pharmacokinetic studies. INTEGUMENT-1 and INTEGUMENT-2 (The INterventional Trial EvaluatinG roflUMilast cream for the treatmENt of aTopic dermatitis) were two identical Phase 3, parallel group, double blind, vehicle-controlled trials evaluating the safety and efficacy of roflumilast cream 0.15% or vehicle applied once-daily for four weeks to 1,337 adults and children six years of age and older with mild to moderate atopic dermatitis.
The INTEGUMENT-1 and -2 studies each met their 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); INTEGUMENT-2: 28.9% roflumilast cream cream vs. 12.0% vehicle). 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%), with significant improvement as early as Week 1.
Rapid and significant improvement in itch was observed in individuals treated with roflumilast cream within 24 hours of the first application, as measured by the change from baseline in daily Worst Itch-Numeric Rating Scale (WI-NRS) scores and compared with vehicle (nominal P<0.05). In addition, over 30% of individuals treated with roflumilast cream in each study achieved WI-NRS Success at Week 4 (INTEGUMENT-1: 33.6% vs. 20.7%; INTEGUMENT-2: 30.2% vs. 12.4%), with significant improvements seen as early as Week 1. 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).
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%; INTEGUMENT-2: 42.0% vs. 19.7%). Both studies observed significant improvements based on EASI-75 with roflumilast cream compared to the vehicle as early as Week 1.
Roflumilast cream 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. No adverse reactions in the combined Phase 3 pivotal trials 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%).
In the INTEGUMENT-OLE open-label study (n=658), no new safety signals were observed during treatment up to 56 weeks in duration. Efficacy was maintained and improved over time, with 46.1% and 51.0% of participants who rolled over from the roflumilast cream arm in INTEGUMENT-1 or -2 achieving vIGA-AD Success at Weeks 28 and 56, respectively. Additionally, in the study, 61.5% and 66.2% of participants who rolled over from the roflumilast cream arm in INTEGUMENT-1 or -2 demonstrated EASI-75 after 28 weeks and 56 weeks, respectively.
Starting at Week 4 of INTEGUMENT-OLE, participants who achieved a vIGA-AD score of clear (0) switched to proactive twice-weekly application (130 participants; 19.8% of the study population). For these participants, after their first switch to twice-weekly application, the median duration of “disease control” (maintaining v-IGA-AD of 0 or 1 with adequate control of signs and symptoms on the twice-weekly schedule application) was 281 days.
“Today marks the third FDA approval of a commercial product for Arcutis in just the last two years, and we are thrilled to be able to offer ZORYVE cream 0.15% as a new steroid-free treatment option to children and adults living with atopic dermatitis. With ZORYVE, our goal has been to provide a steroid-free topical that can provide effective and fast results, wherever on the body it’s needed, and long-term disease control through a safe and tolerable formulation,” says Frank Watanabe, president and chief executive officer of Arcutis, in a news release. “ZORYVE is the fastest growing steroid-free topical, relied on to provide effective and safe results in any location on the skin for any duration. With the addition of the new 0.15% strength of ZORYVE cream for atopic dermatitis to the higher strength cream and foam products, the ZORYVE portfolio has the potential to become the preferred topical brand in dermatology.”
Access to Roflumilast Cream
Arcutis intends to make roflumilast cream 0.15% widely available by the end of July. The ZORYVE Direct Program helps patients access their prescribed Arcutis medication. Specifically, this patient support program helps those prescribed ZORYVE navigate the payer process, assists patients with adherence, and includes the ZORYVE Direct Savings Card Program, which can help reduce out-of-pocket costs for eligible commercially insured patients. Arcutis will also continue to offer the Arcutis Cares patient assistance program (PAP) that provides ZORYVE at no cost for financially eligible patients who are uninsured or underinsured.
