Emerging Therapies and Future Considerations for Treating Moderate-to-Severe Atopic Dermatitis

The present and future of atopic dermatitis (AD) treatments was the focus of discussion this Saturday at the European Academy of Dermatology and Venereology (EADV) Congress in Vienna, Austria, during a symposium sponsored by Sanofi Genzyme and Regeneron. As a 4-part lecture, “Practical Application of Novel Targeted Strategies in Moderate-to-Severe Atopic Dermatitis” covered the pathogenesis of AD, new insights into the pathophysiology in AD, considerations for change in the treatment of AD, and the latest developments in treatment. Presenters were:

• Georg Stingl, MD, professor and chairman of the Department of Dermatology and Division of Immunology, Allergy, and Infectious Diseases at Medical University of Vienna
• Emma Guttman, MD, PhD, professor of Dermatology and Immunology and director of the Center for Excellence in Eczema and Laboratory for Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai
• Mette Deleuran, MD, DMSc, chairman of the Department of Dermatology at Aarhus University Hospital
• Eric Simpson, MD, MCR, professor of dermatology and director of clinical studies of dermatology at the Oregon Health & Science University

In the opening lecture, “Clinics, Pathogenesis and Treatment of Atopic Dermatitis—Setting the Stage,” Stigl set the focus of the symposium on immune abnormalities in AD. Looking at the pathogenesis of moderate-to-severe AD, Stigl demonstrated that affected patients often exhibit signs of T-cell- and B-cell-driven autoimmunity, and that disease progression is furthered by drivers in the adaptive immune system. Therefore, as Stigl showed, as researchers and practitioners go forward in treating the disease, they must go beyond topical treatments, and consider targeted therapies as new standards of treatment. Such therapies are currently in development and were the focus of subsequent lectures during the symposium.

In “Evolving Understanding of the Pathophysiology in Atopic Dermatitis,” Guttman discussed immune abnormalities in AD, and more specifically, the role of Th2/type 2-mediated inflammation in perpetuating the disease. According to Guttman, while AD is characterized by both barrier and immune abnormalities, the latter are responsible for perpetuating the disease phenotype. Having observed consistent Th2 activation in patients with AD, Guttman and others are convinced that high-level immune activation in both lesional and nonlesional skin and blood necessitates a need for systemic therapies in treating AD.

Deleuran evaluated the current treatment approaches for AD, and discussed considerations for new ones in, “Perspectives for Change in the Treatment of Patients with Moderate-to-Severe Atopic Dermatitis.” Reviewing the established treatment guidelines for treating AD, which identify considerations for toxicity, variable effectiveness, and a requirement for patient monitoring, Deleuran argued that current therapies do not target pathways that drive disease inflation and pathogenesis, echoing Stigl’s call for targeted therapies that lead to change in the molecular signature of AD. As a result, according to Deleuran, there remains a significant unmet need for safe and effective treatments that achieve long-term disease control for patients with moderate-to-severe AD.

Deleuran went on to say that in order for future treatments to meet this unmet need, they should target key drivers of persistent inflammation, be administered systemically, deliver a broad range of efficacy (eg, long-term disease control, reduced inflammation, improved quality-of-life), and provide a positive safety profile. Deleuran was confident that emerging targeted therapies have the potential to meet these recommendations, and better treat moderate-to-severe AD.

In “Latest Developments in the Treatment of Patients with Moderate-to-Severe Atopic Dermatitis,” Simpson continued Deleuran’s coverage of current treatments for AD and new developments in treating the disease. “AD is a complex, heterogeneous disease leading to variable treatment responses … there are broad ranges of symptom burdens and pathobiologies,” Simpson explained.

He first gave a quick overview of established topical treatments and systemic therapies, including phototherapy and oral immunosuppressives. The core of Simpson’s lecture, however, was his discussion about 2 new pathways under investigation.

One such pathway is the use of intracellular target treatments. These are administered through small molecule inhibitors like PDE4 inhibitors, JAX inhibitors, and H4R antagonists.

There are also opportunities in extracellular target treatments, Simpson explained, highlighting biologic agents that target IL receptors. Two such drugs are nemoluzimab and ustekinumab (brand name Stelara), which target IL-31 receptors, and IL- 12 and IL-23 receptors, respectively.

One drug, however, received special attention in Simpson’s lecture. Results from a Phase 3 study, just published in

, substantiate the safety and efficacy of dupilumab (brand name Dupixent) in treating moderate-to-severe AD. Dupilumab is a monoclonal antibody that targets the IL-4 alpha subunit (IL-4Ra). During the LIBERTY AD SOLO 1 and SOLO 2 studies, 2 identical placebo-controlled trials, dupilumab showed clinically significant improvements in overall disease activity compared to placebo at weeks 16 and 52. The drug also demonstrated a positive safety and tolerability profile, and improvements in quality-of-life. The FDA recently accepted Dupixent for priority review with a target action of March 29, 2017.

The New England Journal of Medicine