Breakthroughs in Tx of AD likely to be positive news for many patients


Patients with atopic dermatitis (AD) can look forward to therapeutic options that are producing significant progress in the management of the condition.

“From studies and work done at the benchside, we understand the pathophysiology of the disease and that certain cytokines play a much more significant role in the disease, specifically IL-4 and IL-13,” said Dr. David Adam, past-president of the Dermatology Association of Ontario, assistant professor at the University of Toronto in Toronto, and medical director of Baywood Dermatology in Ajax, Ont.

“Having a biologic that specifically targets these molecules allows us to effectively abrogate the inflammation while minimizing the off-target effects.

“Until the advent of biologics, we were largely using small molecules that affected a wide range of cytokines, some of which affect the pathogenesis of the disease and some do not,” said Dr. Adam.

Breakthrough drug status granted

The U.S. Food and Drug Administration has granted dupilumab breakthrough drug status, accelerating the regulatory path of the medication. Granting the biologic breakthrough drug status means than it will become available to the pediatric as well as the adult population without a significant

lag in time, noted Dr. Melinda Gooderham, a dermatologist and medical director of Skin Centre for Dermatology in Peterborough, Ont.

“Dupilumab injections are giving people their life back,” said Dr. Gooderham in an interview with

THE CHRONICLE.

“Because great results were being seen with such low risk, and there were more infections in the placebo group than in the active drug group, it was felt it was better to study [dupilumab] in the pediatric population sooner rather than later.

Pediatric patients are the ones who will predominantly benefit [from the availability of dupilumab].”

Indeed, AD typically begins in early childhood with adult onset being less common. A 2007 National Survey of Children’s Health, which looked at a sample of more than 90,000 children and found 6% had empirically defined AD with peak onset being in those aged five years and under (Dermatitis 2007; 18(2):82–91).

Various estimates place AD prevalence as high as 20% in the pediatric population. While many children do not continue to have AD as they reach adulthood, a proportion do.

Because dupilumab involves cytokines IL-4 and IL-13 that are not essential for fighting infection, the safety assessments of the agent have been very impressive, said Dr. Gooderham. “It is not like when you block tumour necrosis factor-alpha [to treat] psoriasis,” she explained, contrasting the AD biologics under study to the biologics that arrived commercially more than a decade ago to treat psoriasis.

Data presented earlier this year at the annual meeting of the American Academy of Dermatology in San Francisco highlighted that dupilumab produced significant improvement in the pruritus numeric rating scale as well as in SCORing Atopic Dermatitis (SCORAD) score. Adverse events that were reported were generally well tolerated and included nasopharyngitis, headache, and upper respiratory tract infections.

Other treatments are also being examined for their therapeutic value in AD. The activity of apremilast has shown some promise in the treatment of AD because it works on a pathway that affects the Th2 aspect of inflammation. A pilot study showed improvements in pruritus as well as decreases in Eczema Area and Severity Index at several points in time (Arch Dermatol 2012; 148(8):890–897).

Topical tofacitinib under study

The Janus kinase inhibitor tofacitinib has also demonstrated efficacy in the treatment of AD, according to data presented at the 23rd World Congress of Dermatology held in Vancouver.

Results of a Phase 2a, multi-site, randomized, double-blind study of 2% tofacitinib, where patients applied ointment twice daily for four weeks, in patients with mild-to-moderate AD showed significantly better outcomes according to the Eczema Area and Severity Index Score.

“There will always be a role for topical steroids [in AD],” said Dr. Gooderham. “They work well, and

they work fast. They are not good for chronic disease, however, because of the side effect profile. We need other options.”

Clearly, a proportion of adult patients and many parents of children with AD do not embrace topical

steroid therapy. Calcineurin inhibitors such as pimecrolimus and tacrolimus became available more than a decade ago for the treatment of AD.

Like topical steroids, side effects can be a concern, particularly in young children, said Dr. Gooderham. “There is burning with application [of calcineurin inhibitors],” Dr. Gooderham said.

Another novel topical compound being explored for the treatment of AD is AN2728, a boron-based molecule that is designed to treat less severe disease than the biologic dupilumab. A study of 34 pediatric patients, aged two to 17 years, showed that 65% of subjects had an Investigator’s Static Global Assessment score of clear or almost clear.

An advantage of the defective skin barrier that is characteristic of subjects with AD is that it presents an opportunity to use topical therapies that are adequately taken in, explained Dr. Adam.

“We know that because of the impaired [skin] barrier function [in AD patients], topical medications are

more readily absorbed because the skin is more porous,” he said.

The impressive results with dupilumab is opening the door to biologics as therapeutic possibilities for

AD, according to Dr. Afsaneh Alavi, a dermatologist at Women’s College Hospital and assistant professor of medicine at the University of Toronto in Toronto.

“The response [to dupilumab] has been impressive,” said Dr. Alavi. “We need more data to see the overall results, but it appears very promising.”

There is a “big gap” in the treatment of AD, so the emergence of new therapies, delivered by infusion or topically, are certainly welcome, said Dr. Alavi. “It is a challenge to treat severe forms of the disease.”

Another subcutaneously-delivered therapy that is under study is lebrikizumab, a biologic therapy being examined for its efficacy in managing moderate-to-severe AD that is poorly controlled with topical corticosteroids.

Control of disease, prevention of flares are dual goals of therapy

Dr. Alavi explained the long-term use of biologics such as dupilumab and lebrikizumab needs to be studied further.

“The treatment of AD has two parts,” said Dr. Alavi. “Control of the disease is one aspect and prevention of flares is another aspect. “

Open-label extension investigations will supply more data regarding the use of biologic agents as maintenance therapies in AD, she said. Dr. Miriam Weinstein, a staff dermatologist at the Hospital for Sick Children in Toronto and associate professor, Faculty of Medicine, University of Toronto, said prudence should govern the adoption of biologic agents like dupilumab once they become commercially available.

“The data accumulated to date are very promising and exciting, but I would temper this with a bit of caution,” said Dr. Weinstein.

“One issue is that we do not have long-term safety data on these medications. The majority of patients with AD are young children, and another issue is if we put young children on immunemodulating medication, will we buy them trouble down the road? It does not mean they should not be offered a medication that might make a difference, but I think we need to be very thoughtful [about prescribing biologic agents],” Dr. Weinstein added.

For patients with truly severe AD that is refractory to the current available therapies, dupilumab and other biologics will be well-received, said Dr. Weinstein. Many pediatric patients, however, may have mild-tomoderate disease that presents as severe because therapies are not used optimally.

“There are patients who should be managed with the medications we currently have,” said Dr. Weinstein.

“Many factors contribute to undertreatment, including steroidphobia, where there is fear of using topical steroids. [Parents] may be using insufficient quantities [of topical steroids] for their children.

Compliance may be an issue. It’s a challenge to manage a chronic disease. The compliance of using products like moisturizers daily may be poor. Children may end up being labelled with worse disease than what they really have.”

If a first-line therapy has been used optimally to manage AD, and children are still not well-controlled,

then second-line therapies should be considered, and dupilumab will likely be one of those potential second-line therapies, said Dr. Weinstein.

Note: This article was previsiously published in The Chronicle of Skin & Allergy.


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