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    New treatments on the horizon

    Insights into the role of the skin barrier and immune system drive therapeutic development

    Emerging therapies to treat atopic dermatitis (AD) are showing impressive efficacy and good tolerability, according to Lyn Guenther, M.D., F.R.C.P.C., who spoke at the April 2017 meeting in Toronto of Dermatology Update.

    Dr. Guenther, professor of dermatology at Western University in London, Ontario, Canada, and president of Guenther Research Inc., states that when it comes to advances in medications, AD can be described as the poor cousin to psoriasis.

    “Atopic dermatitis was 10 or 15 years behind psoriasis in terms of opportunities for patients [to manage their AD],” says Dr. Guenther, noting that until recently, there had not been any new AD treatments for over 15 years.

    The treatments that have been available include traditional topical therapies, such as topical steroids and calcineurin inhibitors; systemic therapies, such as methotrexate, cyclosporine, or mycophenolate mofetil; and phototherapy. In the Adelphi study, more than half of the patients on systemic immunosuppressants were uncontrolled.1

    A childhood condition

    In most instances, AD is a condition that appears in childhood; it is generally thought to subside by adulthood. A meta-analysis has shown that fewer than 5% of patients have AD that lasts more than 20 years.2

    The pathogenesis of AD is not completely understood, but investigators have gained insights into the role of the skin barrier and immune system in the development of AD, notes Dr. Guenther. Indeed, AD is a condition that is regarded as a disturbance of skin-barrier function and hyperactive immune response.3

    A straightforward step that parents can take to prevent the development of AD in high-risk neonates is to regularly apply emollients to their babies. One randomized, controlled trial found that emollient therapy employed from birth decreased the cumulative incidence of AD at six months by 50%.4

    "A simple thing that parents can do to is to put moisturizer on a baby,” says Dr. Guenther.

    Since many patients find outcomes of currently available therapies unsatisfactory, there is an unmet need for new AD treatments, she adds.

    New agents

    One of the newest topical agents is crisaborole ointment (Eucrisa, Pfizer), a phosphodiesterase 4 inhibitor approved by the Food and Drug Administration (FDA) in December 2016. The therapy was studied in two placebo-controlled trials that included 1,522 patients, ranging in age from two to 79, with mild-to-moderate AD. Half of those who were exposed to crisaborole had skin that was clear or almost clear after 28 days of therapy as measured by Investigator's Static Global Assessment. After just two days, more patients on crisaborole had no or mild pruritus compared to patients treated with vehicle ointment. Both those measures produced statistically significant differences compared to placebo.5

    Pruritus is a typical feature of AD, so addressing it is critical to sufficient AD management. "Intractable itching is so common [in AD]," says Dr. Guenther.

    One of the advantages of crisaborole is that it works quite rapidly, she notes. Another advantage is the low rate (4.4% vs. 1.2% with vehicle) of associated burning, which resolves within one day in most patients.

    Other topical AD therapies also produce pain at the site of application, according to Dr. Guenther. "We know, with calcineurin inhibitors, that a burning sensation can be a common issue.”

    Biologics

    Biologics are also being explored as possible therapies for AD, she says. Because immunoglobulin E (IgE) is thought to play a role in eczema, the injectable therapy omalizumab (Xolair, Genentech/Novartis) has been studied as a treatment for AD, but it has not shown great success in treatment of AD. "Some studies have shown benefit, and others have not," says Dr. Guenther.

    Cytokines that are seemingly more critical in the pathogenesis of AD are IL-4 and IL-13.6

    Dupilumab (Dupixent, Sanofi/Regeneron), a human monoclonal antibody that inhibits signaling of both IL-4 and IL-13, has been explored in two phase III, randomized trials (SOLO 1 and SOLO 2) for the management of moderate-to-severe AD. Dupilumab not only improved AD and associated pruritus; it also improved anxiety and depression. Side effects included injection-site reactions and ophthalmological adverse events such as conjunctivitis and keratitis.7

    One of the confounding factors in the one-year, placebo-controlled dupilumab trial (CHRONOS), as well as in trials involving other biologics under investigation for treatment of AD, is that concomitant use of topical corticosteroids was permitted, notes Dr. Guenther. "Many [trials with biologics to treat AD] include a topical steroid in the study, and that makes it hard to know how much is due to the biologic and how much is due to the steroid.”

    The inclusion of topical steroids in the AD trials involving biologics is likely to prevent large drop-out rates in these trials, she adds.

    Dupilumab is the first biologic to receive FDA approval for treatment of patients with moderate-to-severe AD that is unresponsive to topical medications, says Dr. Guenther. "If topical agents do not work, you can go directly to using dupilumab.”

     

    Disclosure: Dr. Guenther has been an advisory board member, consultant and speaker for Actelion, Celgene, GSK, Galderma, Janssen, Johnson and Johnson, LaRoche Posay, Leo Pharma Novartis, Pfizer, Pierre Fabre, Sanofi, and Valeant; a speaker for PremPharm; and a clinical investigator for Brasilia, Celgene, Janssen, GSK, Galderma, LaRoche Posay, Leo Pharma, Novartis and Pfizer.

     

    References

    1. Marcus KA. FDA Introductory remarks: Dermatologic and ophthalmic drugs advisory committee meeting. March 9, 2015. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateria.... Data on File (Sanofi and Regeneron), Adelphi study.

    2. Kim JP, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): A systematic review and meta-analysis. J Am Acad Dermatol. 2016 Oct;75(4):681-687.e11.

    3. Wollina U. Microbiome in atopic dermatitis. Clin Cosmet Investig Dermatol. 2017 Feb 22;10:51-56.

    4. Simpson EL, Chalmers JR, Hanafin JM. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014 Oct;134(4):818-823.

    5. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 Sep;75(3):494-503, e4.

    6. Gandhi NA, Pirozzi G, Graham NM. Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol. 2017 May;13(5):425-437.

    7. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 trials of dupilumab vs. placebo in atopic dermatitis. New Engl J Med. 2016 Dec 15;375(24):2335-2348.

     

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