RALEIGH, N.C. – Atopic dermatitis is a disease that until now has gone underappreciated by regulatory authorities, the pharmaceutical industry, and the general public, according to thought leaders determined to turn the situation around.
"The first and probably foremost reason atopic dermatitis has been somewhat ignored is that it is perceived as a childhood disease, and that makes development of drugs very, very difficult. First, you have to go through studies in adults and then you have to go through children," Dr. Lisa A. Beck noted during a special plenary session devoted to atopic dermatitis at the conference.
Courtesy Mrs. Emily Boynton, URMC Public Relations Department
Dr. Lisa A. Beck (left) with Dr. Anna De Benedetto, a dermatologist and research scientist at URMC.
Another stumbling block is that researchers haven’t adequately documented the negative effects atopic dermatitis can have on daily life for patients and caregivers. Clinicians who care for atopy patients are aware of it. The outside world is not, observed Dr. Beck, professor of dermatology and medicine at the University of Rochester (N.Y.). Also, better diagnostic criteria for atopic dermatitis are needed. The diagnosis isn’t always as straightforward as in psoriasis, which is "the great comparator in our range of diseases," she said.
A damaging perception that’s particularly entrenched within the regulatory agencies is that atopic dermatitis is not high priority because it lacks serious comorbidities, Dr. Beck continued.
Research Barriers
"That’s something we come up against in atopic dermatitis all the time: the idea that it’s a disease of misery rather than a disease of mortality," agreed Dr. Neil Graham of Regeneron Pharmaceuticals in Tarrytown, N.Y. "However, our view is that human misery is something we should be trying to treat therapeutically, and that this has value both economically and to society. I think we’ve seen this accomplished successfully with psoriasis, which is the template we can use in atopic dermatitis."
Biopharmaceutical companies are interested in applying the psoriasis drug development template to atopic dermatitis. Regeneron is developing a biologic agent that simultaneously blocks interleukins-4 and -13 for the treatment of atopic dermatitis and other diseases whose predominant mechanism involves Th2-driven eosinophilic inflammation, including eosinophilic asthma, chronic sinusitis with nasal polyps, and conjunctival allergic disease. The company wants an agent that can be subcutaneously injected every week or two, noted Dr. Graham.
"We hope eventually to intervene in children and potentially interrupt the atopic march. It will probably take us many years to get there," he said.
Regulatory agencies will almost certainly require that clinical trials involving any biologic agent under development for atopic dermatitis initially be restricted to patients with moderate to severe disease.
That’s a problem, according to Dr. Graham, because the Food and Drug Administration defines the clinical severity of atopic dermatitis using the Investigator’s Global Assessment (IGA) scale: a limited tool that’s not up to the task of capturing the full impact of the disease. Better means of defining the moderate to severely affected patient subset are essential. Also, a standardized, clinically relevant measure of disease severity reduction in response to treatment is needed – something akin to the Psoriasis Area Severity Index (PASI) 50 or -75 as used in psoriasis.
Dr. Eric Simpson agreed that regulatory authorities haven’t devoted sufficient attention to study design requirements or definitions of therapeutic success. For instance, the FDA requires evidence of improvement in the IGA as the bar that must be cleared in order to obtain approval of drugs for atopic dermatitis. Yet the IGA has never been adequately validated, nor has the metric’s definition been standardized. Indeed, the definition changes over time, from one phase-III clinical trial to the next.
Dr. Eric Simpson
"The inter-relater reliability of the IGA is unknown. I think it could be a major issue," said Dr. Simpson of the Oregon Health and Science University, Portland.
He proposed that participants in the SID special session on atopic dermatitis create a position paper recommending better outcome measures to the FDA. "We need to work with the agency to do what’s best for good clinical research," he said.
Identifying Biomarkers
According to Dr. Graham, atopic dermatitis is on the radar of major biotech companies that have biologic agents for psoriasis. They are working to develop biologics for atopic dermatitis, targeting a variety of pathways including interleukins-5, -4, and -13, as well as IgE.
Reliable biomarkers are needed to make drug development in atopic dermatitis go quickly and efficiently. After all, biomarker data are now routinely incorporated into early-phase development of new drugs for psoriasis, and these data are included in support of new drug applications to the FDA. But objective biomarkers have been notably lacking in atopic dermatitis, he noted.