What is the path forward for treating children with severe atopic dermatitis with dupilumab?

By Kathryn Schwarzenberger, MD, March 1, 2021

In this month’s Clinical Applications column, Physician Editor Kathryn Schwarzenberger, MD, talks with Amy Paller, MD, about her recent JAAD article "Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6-11 years old with severe atopic dermatitis: A randomized, double-blinded, placebo-controlled phase 3 trial."

DermWorld: You and your colleagues recently published a study looking at efficacy and safety of dupilumab with topical corticosteroids in 6- to 11-year-old children with severe atopic dermatitis. Can you briefly describe your study and explain what you concluded?

Dr. Paller: The bottom line is that, overall, the 6- to 11-year-old children with severe atopic dermatitis treated in this study with dupilumab responded with no surprises in terms of unrecognized side effects of dupilumab (still limited to injection site reactions and the conjunctivitis in a minority). The study further confirmed that we don't have to perform laboratory testing, which is welcome news to families and affected children. What was interesting is that there was a weight-based difference in the more efficacious dosing regimen — with a higher dose (600 mg loading, 300 mg thereafter) given every four weeks achieving best results in those children under 30 kg and a lower dose (400 mg loading, 200 mg thereafter) given every two weeks achieving best results in those weighing 30 lbs or more. These results correlated with better blood levels with these doses in these populations with pK testing. These became the FDA-approved doses as a result. I am really delighted that we have the flexibility now to give the injection every four weeks (much appreciated by children and families), but it also tells us that even a loading dose of 600 mg is well tolerated in these younger children.

DermWorld: This seems like an important study in that we don’t have many well-studied systemic therapies for treating AD in children. Is this a correct assessment?

Dr. Paller: That’s absolutely true. Dupilumab is the first systemic agent to be so well studied in children with AD (now in ongoing trials of six months to six years), although several other systemic medications for AD are now being tested or even have completed testing in adolescents and have moved to lower age groups. For decades before dupilumab, our choices have been confined to systemic steroids (generally avoided in children), cyclosporine (still used in children as a steroid-sparing agent, at least initially, because it works faster than others), and other immunosuppressants, especially methotrexate. However, none of these were tested in double-blind, placebo-controlled trials, or have undergone rigorous pK and safety testing.

DermWorld: Doing clinical trials in children seems like it could be difficult. Can you share some of the challenges you might have experienced and how you overcame them?

Dr. Paller: Trials in children are challenging. There are elements of inconvenience (especially since one has to juggle both school activities and parental schedules) and discomfort (many trials involve blood draws and sometimes even biopsies). However, what parents (and doctors) worry about most is safety — and the risks of developing a side effect during the trial — or even beyond, given the heightened concern in children about long-term toxicity. When I consider whether to participate in a trial for children, I very carefully review the protocol to ensure that blood draws and any other tests are limited, that the time burden is acceptable, and most importantly, that I think that the trial has merit for helping the child with minimal safety risk. If I am going to present a trial to a parent, I have to feel comfortable that I would consider it for my own child, because that is precisely what they often ask me. It is harder for parents to be enthusiastic about an interventional clinical trial if it is just going to help someone else and not their child. We go out of our way to minimize the time burden for families, find activities to make the child more comfortable (e.g., topical anesthetic for blood draws; distraction techniques), and provide encouragement.

Although it’s frustrating that it can take so long for new medications to be available for children, one good thing is that I often have a pretty good idea of the safety profile and risk from adult studies (as with dupilumab) and can be open and reassuring about risks. The hardest aspect is that most trials have a placebo arm. Especially for a disorder like AD, in which children are suffering, it is really hard to do a “washout,” which often worsens their AD, and then have an often prolonged period (often three to four months) of being on placebo. While we try to encourage families to stay in these trials, I certainly have had situations in which it was so unbearable that patients had to drop out. Techniques like “rescue,” at least with a topical, and guarantees that the child would be on the active medication for a long while after the placebo controlled part, are critical to doing an ethical trial and engaging families in research.

DermWorld: Your study population included children with skin of color, including those identified as Asian and Black/African American. Are you satisfied that these groups were appropriately represented in the study? Did you look for, or observe, any differential responses in your different study populations?

Dr. Paller: It’s very important that trials have diversity, and in this trial about 25% of the patients had skin of color, including about 17% Black. These numbers did not allow for stratification, but certainly showed inclusion of an underrepresented minority group. We all recognize that research that pays attention to skin of color is important as we move forward. For example, Black patients with AD are thought to have more severe, more recalcitrant AD, and have also been found to have differences in skin biomarkers compared to white and Asian patients. Although my own experience has been positive, regardless of the color of skin, formal studies are needed to address the questions of response and toxicity. It is also important to recognize our concerns about scoring AD in individuals with darker skin because of the increasing difficulty with progressively darker skin to appreciate the erythema. I am sure that both the baseline severity and response to therapy are underappreciated through scoring in dark-skinned individuals as a result.

“Parents often tell me that the child has been able to reduce their use of oral or inhaled medications after starting dupilumab. We’ll learn with time the added value of other biologics and oral medications that follow dupilumab in treating AD.”

─ Amy Paller, MD

DermWorld: Many of the children studied had concomitant atopic conditions, and a large number, over 50%, had food allergies. How do you feel we as dermatologists should be addressing these and should this possibly help us decide when we should consider a systemic agent such as dupilumab?

Dr. Paller: Dermatologists should at least be aware of these multimorbid conditions in our patients with AD and make sure that our patients have a holistic approach to their care that includes management by allergy specialists as needed. These often associated allergic disorders can also affect sleep and quality of life. We are fortunate that dupilumab has also shown effectiveness for allergic disorders and is FDA-approved to treat asthma. I certainly like to understand the allergy situation for my patients with more severe AD and track it during the course of dupilumab. Parents often tell me that the child has been able to reduce their use of oral or inhaled medications after starting dupilumab. We’ll learn with time the added value of other biologics and oral medications that follow dupilumab in treating AD.

DermWorld: Do you foresee having access to dupilumab for children in this age group changing our practices, and how can we as individuals, as well as the AAD, advocate to ensure that it is made available to our children who need it?

Dr. Paller: I have seen many children and adolescents have such a change in the quality of life that I am eager to try this if access is not a problem. For children, the fact that the potential toxicity is essentially limited to a minority getting conjunctivitis, largely mild, is so reassuring for me and allows me to feel comfortable in sharing my experience and the literature with parents. The major limitation is its high cost which, for many, leaves too much co-pay to afford, even if insurance covers the medication. In addition, the requirement for injections every two to four weeks is stressful for both the parents and the affected child, although the end result makes it worthwhile in most. I should add that not everyone responds satisfactorily to dupilumab, even with the addition of a topical steroid, so there certainly is a need for additional therapy for pediatric AD. In addition, the “long-term” for children and adolescents is decades and our experience is just a few years with dupilumab, even in adults. So, we need to continue to be vigilant about its use and anything else that follows for years to come.

Regarding advocacy to get access to dupilumab and beyond, this is one of the biggest issues we face. We are so excited about the new therapies coming out, but each one, even topical, involves years of expensive drug development and costs will be high. What I have seen is a worsening of the economic divide and can never predict: who can get a medication like dupilumab (or a biologic for psoriasis) fairly easily; who will have it rejected by insurance again and again (often insisting on step therapy that is inappropriate); and who will have insurance say “yes” but then cover so little that even with defraying of the cost from the manufacturer, it is simply unaffordable. This leads to a huge waste of time for physicians and staff, deflation on the part of hopeful families who ultimately cannot afford the drug, and most importantly a devastating endpoint for the child who ultimately cannot get a medication that could be life-altering. There are no easy answers, but anything that we can do as individuals to make the path easier and that the AAD (perhaps partnering with government and industry) can do to level the playing field and reduce the burden would be much appreciated.

Amy Paller, MD is the chair of the Department of Dermatology and director of the Skin Biology and Diseases Resource-Based Center at Feinberg School of Medicine at Northwestern University. Her paper appeared in JAAD.

Dr. Paller has been an investigator (without compensation) and a consultant (with honorarium) for Regeneron, and has been a consultant for Sanofi-Genzyme, of which Regeneron is a part.

Disclaimer: The views and opinions expressed in this article do not necessarily reflect those of DermWorld.

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