AD drug development driven by symptom and disease control

The evolution in the understanding of the pathogenesis of atopic dermatitis has fueled drug discovery in this arena.

Both T helper cell type 2 (TH2) lymphocyte-driven inflammation and inflammatory mediators have become specific targets for anti-inflammatory therapy, according to Lawrence Eichenfield, M.D., a professor of dermatology and pediatrics at the University of California, San Diego.

Dr. Eichenfield, who is co-author of a comprehensive article in Clinics in Dermatology on current and emerging topical agents for atopic dermatitis (AD), notes that for early intervention, several small studies have demonstrated that emollients decrease the rate of infants at risk for developing atopic dermatitis. Larger studies are underway, he said.

For established atopic dermatitis, rather than solely focusing on managing flares and treatment of acute disease, “we are starting to emphasize long-term disease control,” Dr. Eichenfield says. “Strategies to use topical agents in long-term models have a good evidence basis with either topical corticosteroids, which are generally used two to three times a week, or topical calcineurin inhibitors, which may be used intermittently.”

The goal of such a model is to create topical regimens that will minimize the signs and symptoms of disease, while delivering agents as safely as possible. “This mimics the model for control of asthma, which is not based on simply treating active wheezing, but incorporating a variety of medications to minimize the disease over long periods of time,” Dr. Eichenfield says.

Last December, crisaborole ointment 2 percent (Eucrisa/Pfizer) received FDA approval for the treatment of atopic dermatitis. “This is the first new novel agent since 2001,” Dr. Eichenfield states. The phosphodiesterase (PDE)-4 inhibitor agent “is neither a topical corticosteroid nor a topical calcineurin inhibitor. It targets an inflammatory mediator and has been shown to work topically to decrease signs and symptoms of AD.”

Because crisaborole is not a corticosteroid, “there is no atrophy, telangiectasia or hypopigmentation attributed to the drug’s use,” Dr. Eichenfield says.

Crisaborole was approved in December 2016 to treat mild to moderate eczema in pediatric (two years old or older) and adult patients. It works by inhibiting phosphodiesterase 4 (PDE-4).

Dr. Eichenfield is pleased that crisaborole has been added to his armamentarium of atopic dermatitis therapy, either as monotherapy or along with other topical steroids. “We are using it most commonly in long-term care regimens to minimize patient exposure to topical corticosteroids,” he says. Furthermore, the absence of limitation of duration of use “is highly valuable.” In his practice, crisaborole has been effective in controlling symptoms in his patients in which no significant adverse effects have been observed. 

IN DEVELOPMENT

There are currently other topical PDE-4 agents in development for atopic dermatitis as well as agents that target janus kinase inhibitors. “The janus kinase pathway is one that apparently can be very important in mediating the inflammation of AD,” explains Dr. Eichenfield.

Currently, there are two approved oral janus inhibitors for non-dermatologic indications:  Myelodysplasia and rheumatoid arthritis. One of these inhibitors, tofacitinib (Xeljanz/Pfizer) for rheumatoid arthritis, “has also been studied for AD; however, that drug is not being actively developed at the present time,” Dr. Eichenfield says. “But there are many other janus inhibitors that are in clinical studies for AD.”

Dr. Eichenfield says the development of new topical therapies for AD is happening concurrently with the development and early use of both and other small molecular agents for systemic therapy.

“It is hoped that the heightened awareness about the disease will bring patients into the dermatologist to allow us to improve their AD and minimize the disease process,” Dr. Eichenfield says.

DISCLOSURES

Dr. Eichenfield is a consultant or investigator for Anacor (Pfizer), Medimetriks and Roivant Sciences.

REFERENCES

Udkoff J, Waldman A, Ahluwalia J, et al. “Current and emerging topical therapies for atopic dermatitis,” Clinics in Dermatology. 2017; Volume 35, Issue 4; 375-382. DOI:/10.1016/j.clindermatol.2017.03.010