NEWPORT BEACH, CALIF. – In the clinical opinion of Kelly M. Cordoro, MD, anyone who cares for patients with severe atopic dermatitis understands the sense of misery that can ensue.
“Atopic dermatitis patients don’t sleep well; they have poor school and work performance,” she said at the annual meeting of the Pacific Dermatologic Association. “They have absences. They’re unable to play; they can’t exercise. This leads to social disability; isolation from peers, and it goes on and on. The patients are miserable, the whole family is miserable, and we as physicians trying to sort out how to optimally treat them are miserable trying to figure out what the next best step is.”
Dr. Kelly M. Cordoro
The good news is, several drugs in the pipeline hold promise for atopic dermatitis patients, thanks largely to emerging data on its pathophysiology. In addition, mechanisms of itch, which are not yet fully understood, are also being unraveled. “It’s exciting to read the literature about the interaction of the skin, the immune system, and the nervous system,” said Dr. Cordoro, a pediatric dermatologist at the University of California, San Francisco. “Many of the mediators of itch are being identified. That has allowed for the development of targeted therapies against many of them.”
One of the promising treatments on the horizon for atopic dermatitis patients is phosphodiesterase-4 (PDE4) inhibitors. PDE-4 is a predominant cAMP-degrading enzyme in keratinocytes and inflammatory cells. “It’s really a candidate for not only atopic dermatitis but for psoriasis,” she said.
Oral PDE-4 inhibitors are already approved for psoriasis. Apremilast (Otezla) was approved by the Food and Drug Administration in 2014 for psoriasis and psoriatic arthritis, and a phase II trial of topical apremilast in adults with AD has been completed and the results are pending. “I look forward to seeing if this can help our patients,” Dr. Cordoro said.
Another promising agent for atopic dermatitis is 2% crisaborole topical ointment, a boron-based PDE-4 inhibitor developed by Anacor Pharmaceuticals. Dr. Cordoro described this compound as an anti-inflammatory agent that modifies inflammation by inhibiting the degradation of cAMP by PDE4, resulting in downstream modification of nuclear factor-kB and T-cell signaling pathways.
“Crisaborole has shown promising results from four clinical studies in patients 2 years of age and older, with notable improvements in all atopic dermatitis parameters,” she said (J Am Acad Dermatol. 2016 Sept;75[3]:494-503.e). The FDA review of crisaborole for the treatment of mild to moderate atopic dermatitis in children and adults is currently underway, and is expected to be completed by early January 2017.
An especially favorable drug in development for atopic dermatitis is dupilumab, a fully human monoclonal antibody that targets the interleukin (IL)–4 receptor, and inhibits IL-4 and IL-13 signaling. A published trial of its use in adults with moderate to severe atopic dermatitis showed rapid improvements in all atopic dermatitis clinical indices (N Engl J Med. 2014;371[2]:130-9). The most common side effects were headache and pharyngitis, and skin infections and flares were more common in the placebo group, compared with the treatment group.
Dupilumab “has the potential to shift the treatment landscape of atopic dermatitis, because it can actually change the molecular signature of dermatitic skin, reducing inflammatory and proliferative markers,” Dr. Cordoro said. There are ongoing trials in adult and pediatric populations and FDA approval is anticipated in early 2017.
Published reports also suggest a role for the IL-12/23 pathway inhibitor ustekinumab in severe refractory adult atopic dermatitis (Int J Dermatol. 2012;51[1]:115-6 and JAAD Case Reports 2015;1:25-6). Additional studies are ongoing.
Therapies for itch that have completed phase II trials include the anti-IL31R monoclonal antibody nemolizumab (CIM331); the neurokinin-1R antagonist VLY-686; and the neurokinin-1R antagonist aprepitant gel.
Dr. Cordoro disclosed that she is a consultant for Celgene Corporation, Valeant, and Anacor Pharmaceuticals.