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    Dupilumab maintains long-term benefits in atopic dermatitis

    Long-term AD data shows continued efficacy, safety


    Patient-reported parameters

    Among results announced at the AAD annual meeting, said Dr. Blauvelt, “Itch was probably the most important patient-reported outcome.” These scores dropped dramatically following the first dupilumab dose, then fell an average of 55% and 58% by week 16 among patients who took dupilumab weekly and every other week, respectively. At week 52, average itch scores had declined 54% and 56% for the two groups, respectively (p<0.0001).2 Sleep scores also showed dramatic improvement, he said. “None of these parameters are captured by physician scores. And the FDA is increasingly trying to include key patient-reported measures in clinical trials.”

    Dr. Eichenfield said, “The improvement in quality-of-life scores and patient outcome measures (the patient-oriented eczema measure/POEM, and the itch numeric rating scale/NRS) were very impressive both at 4 months and one year.” At week 52, 63% of patients who received dupilumab weekly and 80% who received dupilumab every 2 weeks achieved at least a 4-point improvement in Dermatology Life Quality Index (DLQI) scores (p<0.0001).

    Amy Paller, M.D., also noted the speed of dupilumab’s effect on the severity of AD and itch. “Within the first month, the rating of itch was reduced by almost 40%. This is on a par with the effect of cyclosporine without the risk of cyclosporine side effects. And other immunosuppressants, such as methotrexate, mycophenolate and azathioprine, often take 6 to 8 weeks before we see improvement. The combination of rapidity of relief onset and excellent safety profile to date puts dupilumab in a different class from most of the drugs dermatologists have been using for AD.” She is chair, Department of Dermatology; director, Northwestern University Skin Disease Research Center (SDRC); and professor of pediatrics at Northwestern University.

    Over 52 weeks, all 3 patient cohorts experienced similar numbers of adverse events (AEs), including serious AEs. Consistent with prior studies, patients who received dupilumab experienced more injection-site reactions and conjunctivitis (15% and 14%, respectively, in the every-other-week dosing group) than did placebo-treated patients (8% for both side effects).

    Dr. Blauvelt said that in his clinical experience, 10% to 20% of patients using dupilumab develop conjunctivitis. “No one knows why. It is not infective conjunctivitis or pink eye. Most patients have mild or moderate cases.”

    Dr. Guttman-Yassky said that in her experience, conjunctivitis affects 10% to 15% of patients on dupilumab. “We believe it’s allergic in nature. We need more data to understand this phenomenon that is unique to atopic dermatitis and not seen with dupilumab treatment in asthma, for example. However, the majority of patients with conjunctivitis don’t stop treatment because of it. I refer most patients to an ophthalmologist for treatment with topical eyedrops. For most patients, it resolves. It may come back and require retreatment again.” Now that the clinical trials are over, she added, “I recommend that my patients use lubricating drops (artificial tears) before they start dupilumab — for prevention. Patients with atopic dermatitis have dry skin everywhere, including the eyes. It may be that dupilumab has effects on the mucus, because IL-13 is involved in mucus secretion. But we do not know the mechanism yet.”

    The conjunctivitis concern deserves more evaluation, Dr. Paller said. “But that’s a far cry from some of the issues we see with cyclosporine, methotrexate and other drugs” used in adults with AD. Although cyclosporine works fairly well for eczema, it raises concerns for liver toxicity, renal toxicity, hypertension and lymphoma, especially with continuous use. “Methotrexate has fewer problems, but liver toxicity requires close monitoring. Azathioprine also has significant toxicity. These are the kinds of drugs that we’ve been using for affected adults and most of them don’t work very well.”

    CHRONOS patients in the TCS-only group experienced more eczema flares (46%, versus 17% of dupilumab-treated patients). Likewise, 18% of placebo-treated patients experienced non-herpetic skin infections, versus 8% of dupilumab-treated patients. This suggests that the skin of treated patients remained more normal and less susceptible to these infections, said Dr. Blauvelt. “Remarkably, patients did not have any increased incidence of internal infections or side effects with dupilumab.”

    Along with efficacy data, said Dr. Eichenfield, “The safety data are very important in our assessment of the drug. The display of fewer infections in the treated versus placebo group, and no signals of worrisome immunosuppression, differentiate dupilumab from traditional systemic immunosuppressive agents.”

    In phase 2 and 3 extension studies, said Dr. Dr. Guttman-Yassky, “We gave the drug for up to 3 years to more than 35 patients. And they did very well. So my observation from these extension studies is that patients were very well controlled for up to 3 years. This wasn’t reported. But patients were very happy. They didn’t want to switch to another drug.”

    Dr. Guttman-Yassky and colleagues are performing additional research into the Th2 axis targeted by dupilumab. Previously, “We showed that in atopic dermatitis, there are 2 important targets — Th2 and Th22.3 So we did research also targeting the other axes, including Th22. We have an exciting study we have performed with an IL-22 antagonist for atopic dermatitis and are writing up the results.” Her lab is also exploring whether there are different phenotypes of atopic dermatitis patients, which require different treatment approaches.

    “The other area we need to understand is whether the same drug that works for adults will work for children,” said Dr. Guttman-Yassky. To help answer this question, her lab is exploring whether the skin phenotype of children with AD is the same as that of adults (for more information on dupilumab in children, please see sidebar).

    Additionally, she said many new medications are now under study for AD. “Once drug companies understood that they could reverse this disease by targeting specific inflammatory molecules, they are definitely going for it and developing new treatments,” which are expected to begin reaching the market in several years.

    “We are also investigating JAK inhibitors as a means of targeting more than one cytokine axis,” she said. “The future is much brighter for patients with atopic dermatitis. We can target the disease much more safely and effectively than before.”

    For milder AD, “We had one drug, crisaborole ointment, approved in December 2016. There is also a huge unmet need for topical treatments.” Dr. Guttman-Yassky said she also would welcome new nonsteroidal topical agents, some of which are under development.

    She concluded, “We are doing a lot of research on atopic dermatitis, and I believe many new medications will come to market in the next five years. We’re very excited with the approved new medications that showed very good efficacy and safety. And we hope for more to come.”ƒ

    Disclosures: Dr. Blauvelt has been a scientific advisor, clinical investigator and/or speaker for Abbvie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Genentech, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sandoz, Sanofi-Genzyme, Sun Pharma, UCB and Valeant. Dr. Guttman-Yassky is a consultant for Sanofi/Regeneron, and her laboratory did biopsy analyses for dupilumab’s Phase 1 and 2 studies. She also consults with all major companies providing or developing products for atopic dermatitis. Drs. Eichenfield and Paller have served as consultants to Sanofi/Regeneron.


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

    2. Blauvelt A, Gooderham M, Foley P, et al. Long-term management of moderate-to-severe atopic dermatitis (AD) with dupilumab up to one year with concomitant topical corticosteroids (TCS): a randomized, placebo-controlled Phase 3 trial (CHRONOS). American Academy of Dermatology 75th Annual Meeting. March 4, 2017. Orlando.

    3. Czarnowicki T, Gonzalez J, Shemer A, et al. Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population. J Allergy Clin Immunol. 2015;136(1):104-115.e7.

    John Jesitus
    John Jesitus is a medical writer based in Westminster, CO.


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