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Dupilumab maintains long-term benefits in atopic dermatitis


Long-term data for dupilumab in atopic dermatitis revealed at the American Academy of Dermatology (AAD) 75th Annual Meeting reflect safety, rapid relief of troublesome symptoms and a long-lived response in keeping with the drug’s breakthrough status, experts told Dermatology Times.

Long-term data for dupilumab in atopic dermatitis (AD; ICD 10 code L20) revealed at the American Academy of Dermatology (AAD) 75th Annual Meeting reflect safety, rapid relief of troublesome symptoms and a long-lived response in keeping with the drug’s breakthrough status, experts told Dermatology Times.

Key CHRONOS data

Dr. BlauveltThe 52-week phase 3 randomized, double-blind, placebo-controlled study to demonstrate the efficacy and long-term safety of dupilumab in adult patients with moderate-to-severe atopic dermatitis (CHRONOS ) trial randomized a total of 740 patients to placebo plus topical corticosteroids (TCS), versus weekly or every other week dupilumab 300 mg injections plus TCS.

Before CHRONOS, said principal CHRONOS investigator Andrew Blauvelt, M.D., M.B.A., most previous dupilumab studies in AD involved with monotherapy and lasted only 16 weeks.1 He is president of the Oregon Medical Research Center.

Emma Guttman-Yassky, M.D., Ph.D., says, “Usually you need to do monotherapy trials in atopic dermatitis to see if the drug works compared to placebo. And this has indeed been done with dupilumab. However, what’s important about CHRONOS is that this trial is showing a real-life situation where topical steroids are used together with systemics, and this is the first trial that shows that dupilumab maintains its efficacy and safety long-term.”

She is professor and vice chair, department of dermatology, Icahn School of Medicine at Mount Sinai.

Dr. Blauvelt adds that although prior monotherapeutic studies have shown remarkable efficacy, investigators added TCS because, “we know from prior dupilumab studies that 100% of patients are not 100% clear” after therapy.

Dr. Guttman-Yassky says CHRONOS is “the first study going up to one year, showing that patients did not lose their

Dr. Guttman-Yasskyefficacy, and that adding topical steroids delivers some added benefits. Most importantly, patients did not lose response. That is important with a systemic drug. We’re always afraid with cyclosporine, for example, that it works very well initially. It hits hard. But many patients lose efficacy with cyclosporine after a few months. Here we don’t see that. We see continued efficacy and safety going out to one year.”

Regarding primary endpoints, 39% of CHRONOS patients who received either dupilumab dose achieved clear or almost clear skin (investigator global assessment/IGA 0 or 1) at week 16, versus 12% of placebo-treated patients (p<0.0001).2 Among key secondary endpoints, 40% of patients who received weekly dupilumab and 36% of those who received every other week treatments achieved IGA 0 or 1 at week 52. The corresponding percentage among the placebo group was 12.5% (p<0.0001).

Dr. Blauvelt says, “You can tell by the 39% response rate that IGA 0/1 is a difficult bar to achieve. That doesn’t mean that the drug is only 40% effective. Dupilumab works well and quickly with no loss of efficacy between week 16 and 52.”  The proportions of patients who achieved a 75% reductions in Eczema Area and Severity Index (EASI 75) results at week 16 were 64% and 69% for dupilumab, versus 23% placebo (p<0.0001). The fact that the study delivered better results than previous monotherapeutic trials “makes sense, given that patients had topical steroids in addition to dupilumab.”

Lawrence F. Eichenfield, M.D., added, “The CHRONOS study gives us good data on what to expect in terms of  improvement (around 60% to 70% of patients meeting EASI 75 and around 50% EASI 90) with dupilumab and concurrent topical steroids, as well as consistent efficacy over one year of use.  Week 16 showed peak clinical efficacy, maintained through week 52.” The low levels of improvement achieved by patients on placebo and topical steroids show that “while we believe topical steroids work, they provide more limited benefits than does active systemic therapy.” He is chief of pediatric and adolescent dermatology, professor of dermatology and pediatrics and vice chair, Department of Dermatology, and at the University of California, San Diego School of Medicine.

Drs. Eichenfield and Blauvelt recommended caution when comparing CHRONOS results with previous studies of biologics for psoriasis. “We’re dealing with completely different diseases and scoring systems,” said Dr. Blauvelt.

The fact that dupilumab allowed 65% of treated patients (versus 22% on placebo; p<0.0001) to reduce their EASI scores by 75% does not make dupilumab less effective than biologic drugs that post higher Psoriasis Area and Severity Index (PASI) reductions, said Dr. Blauvelt. “It’s an unfair comparison. The baseline score for these measures is much higher than baseline scores seen in psoriasis biologics studies.” In the 3 CHRONOS cohorts, median body surface area (BSA) affected ranged from 52% to 58.8%. “You never see that in a psoriasis trial,” where average BSA involved is in the 20% range, he said.

Next: Patient-reported parameters


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.

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