FDA Approves sNDA for Roflumilast Cream, 0.15%, for Mild-to-Moderate AD


The U.S. Food and Drug Administration (FDA) has approved the supplemental new drug application (sNDA) for ZORYVE (roflumilast) cream, 0.15%, for the treatment of mild-to-moderate atopic dermatitis (AD) in adult and pediatric patients 6 years of age and older, Arcutis Biotherapeutics, Inc. announced in a press release.

A once-daily, steroid-free cream that provides rapid disease clearance and significant reduction in itch, ZORYVE has been specifically developed to be a treatment option for long-term disease control.

“The chronic nature of AD coupled with the disease instability often leaves patients and caregivers feeling that they are constantly chasing their AD flares,” Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics and vice chair of the department of dermatology at UC San Diego School of Medicine and INTEGUMENT study investigator, said in the press release. “ZORYVE rapidly improves and controls disease, including itch, the most bothersome reported symptom. In clinical trials, 9 in 10 patients saw some improvement at 4 weeks, with 69% of patients demonstrating a clinically meaningful improvement of at least an EASI-50. In addition, ZORYVE is a safe and effective steroid-free treatment option. Topical steroids have been the foundation of treatment for AD for the past 50 years. Having a new and effective steroid-free option, without some of the risks associated with topical and systemic steroids, is a welcome advancement for dermatologists, patients, and caregivers.”

Wendy Smith Begolka, chief strategy officer at the National Eczema Association, said in the press release that her organization is pleased to see new advancements and innovation in treatment for the millions of children and adults who are suffering with AD.  “Living with AD, a chronic inflammatory skin disease, and the intense itching associated with it, can have a profound impact on quality of life and family dynamics for both adults and children,” she said.

In clinical trials, ZORYVE cream 0.15% showed rapid, significant, and sustained reduction in itch as soon as 24 hours following the first application. ZORYVE is a next-generation topical phosphodiesterase 4 (PDE4) inhibitor. PDE4 inhibitors can have a direct effect on the itch-signaling nerves of the skin, as well as the inflammatory pathways.

“People suffering from AD experience intense itch, rash, and sensitive skin, which warrant effective, safe, and well-tolerated treatments,”  Jonathan Silverberg, MD, PhD, MPH, professor of dermatology, and the director of clinical research and director of contact dermatitis at The George Washington University School of Medicine and Health Sciences in Washington, D.C., said in the press release. “ZORYVE was developed with the AD patient in mind, to deliver the drug in a moisturizing vehicle that is formulated without common sensitizers or irritants and does not further disrupt the abnormal skin barrier. It’s also important to note that in clinical trials ZORYVE monotherapy provided safe and effective long-term disease control to AD patients.”

“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 AD. 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,” Frank Watanabe, president and chief executive officer of Arcutis, said in the press 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 AD to the higher-strength cream and foam products, the ZORYVE portfolio has the potential to become the preferred topical brand in dermatology.”

Arcutis said it intends to make ZORYVE cream 0.15% widely available via key wholesaler and dermatology pharmacy channels as a new treatment option by the end of July. The company is dedicated to ensuring predictable access for the ZORYVE portfolio of products, with one simple copay and fulfillment process. The ZORYVE® Direct Program helps patients access their prescribed Arcutis medication. Specifically, this patient support program helps those who have been prescribed ZORYVE to 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 CaresTM patient assistance program (PAP) that provides ZORYVE at no cost for financially eligible patients who are uninsured or underinsured.‡

Clinical Data 

The sNDA is supported by positive results from three Phase 3 studies, as well as a Phase 2 dose-ranging study, and two Phase 1 pharmacokinetic studies. INTEGUMENT-1 and INTEGUMENT-2 (The INterventional Trial EvaluatinGroflUMilast 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 ZORYVE cream 0.15% or vehicle applied once daily for four weeks to 1,337 adults and children 6 years of age and older with mild to moderate AD.

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% ZORYVE cream vs. 15.2% vehicle, P<0.0001; INTEGUMENT-2: 28.9% ZORYVE cream vs. 12.0% vehicle, P<0.0001). In both studies, approximately 40% of children and adults treated with ZORYVE 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).

Rapid and significant improvement in itch was observed in individuals treated with ZORYVE 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 ZORYVE cream in each study achieved WI-NRS Success at Week 4 (INTEGUMENT-1: 33.6% vs 20.7% P<0.01; INTEGUMENT-2: 30.2% vs 12.4% P<0.01), 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 ZORYVE 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 based on EASI-75 were observed with ZORYVE cream compared to vehicle as early as Week 1 in both studies (nominal P=0.0006; nominal P=0.0329).

ZORYVE 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 INTEGUMENT-OLE open-label study enrolled 658 participants who rolled over from INTEGUMENT-1 or -2. At any time after 4 weeks, INTEGUMENT-OLE participants who achieved a vIGA-AD score of Clear (0) with once-daily application switched to twice-weekly application (130 participants; 19.8% of study population). All other participants continued once-daily application. After participation in the INTEGUMENT studies for 28 and 56 weeks, 61.3% and 65.7% of participants achieved EASI-75 respectively.

† Subject to eligibility criteria and maximum program limitation. This offer is not valid for patients without commercial drug insurance or whose prescription claims are eligible to be reimbursed, in whole or in part, by any government program.

‡ Subject to financial eligibility requirements. Other terms and restrictions apply.

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