New medications ‘revolutionary’ for kids with atopic dermatitis

Atopic dermatitis, one of the most common inflammatory skin conditions, begins in many patients by age 1 year, according to the American Academy of Dermatology. Globally, an estimated one in five children is affected by the disease. The prevalence is higher among children in developed countries, including the United States, and it may be increasing, researchers suggest.

Several longstanding therapies have been available for AD, including moisturizers, topical steroids, immunomodulators and even light therapy, according to a review published in Dermatologic Therapy. However, the researchers noted that many patients have been unsatisfied with these options, especially those with more severe forms of the disease. Additionally, steroids and immunosuppressive drugs are associated with long-term side effects.

Newer treatment options began to emerge in late 2016 with the FDA’s approval of Eucrisa (crisaborole, Anacor Pharmaceuticals). This year, the FDA approved Dupixent (dupilumab, Sanofi and Regeneron Pharmaceuticals), an injectable biologic agent, for teenagers with moderate to severe AD.

Some experts, including Infectious Diseases in Children Editorial Board Member Lawrence Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital and vice chair of the department of dermatology at the University of California, San Diego, have called these approvals “revolutionary.”

Infectious Diseases in Children spoke with Eichenfield and other experts at the forefront of pediatric AD treatment to gain a better understanding of the drug pipeline for this condition and how these therapies can potentially transform practice.

Past treatment options

One of the most significant challenges in the treatment of AD in children, according to Jonathan I. Sliverberg, MD, PhD, MPH, an associate professor of dermatology, medical social sciences and preventive medicine at Northwestern University’s Feinberg School of Medicine, is related to the condition’s spectrum of severity and how to treat it for extended periods of time.

“Probably the biggest problem that comes up with treatment is that this is a chronic condition. For many, it’s lifelong,” he said in an interview. “It is important to recognize that when making therapeutic decisions, long-term treatment plans are needed, not just quick fixes and sending patients on their way with follow-up as needed.”

One of those “quick fixes,” Silverberg said, is systemic corticosteroids, which continue to be used in children who do not get relief from topical corticosteroids. Phototherapy or oral systemic immunosuppressants like methotrexate, cyclosporine or mycophenolate are better long-term treatment options for AD.

However, methotrexate has been linked to liver disease, lymphoma and other side effects such as skin sores and gastrointestinal upset. These effects led the FDA to place a black box warning on the drug.

“Although I’ve used a lot of methotrexate to treat eczema in kids, it is not approved and has a litany of side effects,” Douglas Kress, MD, a pediatric dermatologist at UPMC Children’s Hospital of Pittsburgh, told Infectious Diseases in Children. “I had a week recently where I had three kids on methotrexate, and each had to be stopped for different side effects, including oral ulcers, terrible gastrointestinal upset and eczema herpeticum.”

A. Yasmine Kirkorian, MD, interim chief of the department of dermatology and assistant professor of dermatology and pediatrics at Children’s National Health System, told Infectious Diseases in Children that the most common treatment approach for AD is to repair the skin barrier. She said this strategy has not changed and is unlikely to change in the future.

“People with eczema are more likely to have increased transepidermal water loss, reflecting the inadequate skin barrier and is more likely to allow allergens to enter the skin and cause inflammation,” she said. “Barrier repair using moisturizers is critical, and that is going to be the case for anybody with mild, moderate or severe eczema.”

Modernizing AD care

The FDA’s approval of crisaborole and dupilumab have given physicians more options for the treatment of patients with mild to severe AD. Crisaborole, a nonsteroidal topical phosphodiesterase 4 inhibitor, was the first topical molecule to be approved in 15 years at that time, according to Amy S. Paller, MS, MD, and colleagues. In two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies, the drug improved both AD severity and itch in children aged 2 years and older with mild to moderate disease.

“The long-term safety study showed no signals of any significant side effects, and there is no limitation on the duration of use, unlike most of the medicines used for atopic dermatitis,” said Eichenfield, who was involved with the phase 3 studies. However, “there is some stinging and burning that can happen, especially for the first few applications, and especially on the face.”

Eichenfield added that the burning sensation appears to be more common in clinical practice than it was in the studies, in which 4% or more of patients reported application site pain.

Although crisaborole demonstrated efficacy in clinical trials, some physicians, including Kress, have not seen a significant impact on AD with its use.

“It is not sufficiently effective to take off the way people thought it might,” Kress said.

Furthermore, some question how the drug is to be used in clinical practice.

“I’m not sure what Eucrisa’s place is in practice,” Kirkorian said. “When it was in the clinical trial, it was shown to be more efficacious than its ointment vehicle, but not head-to-head with topical steroids.

“That being said, it is valuable to have a nonsteroidal option. Many parents have a steroid-phobia or concerns about topical steroids, which are legitimate. It is something we could offer, but I would not consider it a panacea. I explain that Eucrisa is something more like a mild maintenance medication, where if we can get the child’s skin in good shape, we can maintain it with Eucrisa if it’s tolerated.”

First approved for adults in 2017, dupilumab is now available for teenagers aged 12 to 17 years with moderate to severe AD who could not achieve control with other medications.

In a phase 3 trial, Eczema Area and Severity Index (EASI) scores improved approximately 66% from baseline in patients who took dupilumab compared with a 24% improvement in patients who received placebo. Nearly one-quarter of patients who received dupilumab achieved clear or almost clear skin after 16 weeks, and 42% of patients had at least 75% skin improvement compared with only 8% in the placebo group. Furthermore, itch was controlled in 37% of patients who were administered dupilumab vs. 5% who were given placebo.

Silverberg called the approval of dupilumab for adolescent patients “revolutionary in the field.”

“Atopic dermatitis is a chronic disease that requires treatments that will be effective for long-term use,” he said. “Our repertoire pre-Dupixent was just empty. We had nothing really to offer patients, and they were suffering.”

Cost as a barrier

Eichenfield said dermatologists and allergists are pleased to add nonsteroidal agents to their armamentarium, but there are barriers to their routine use.

“Part of our job is to balance efficacy, safety and cost,” he said. “The newer medications are more expensive than traditional topical corticosteroids. That is one of the factors that we have to consider when coming up with appropriate care.”

A JAMA Dermatology study demonstrated that the average copayment for topical corticosteroids ranged from $2.26 to $32.55, depending on the amount of medication in the ointment. In 2018, crisaborole cost $637 for a 60 oz. tube, although most insurance companies cover the drug. Price and insurance coverage can be a more significant barrier for those seeking treatment with dupilumab.

The injectable biologic is covered for approximately 69% of patients with commercial insurance, who pay between $0 and $100 a month, according to the manufacturer. Researchers suggested that those without commercial insurance can be asked to pay up to $37,000 a year for treatment.

Kirkorian, who predominantly works with an underserved population that is either insured through Medicaid or does not have insurance, struggles to get many of her patients on dupilumab after other therapies fail to relieve the problem.

“We get really tough pushback, and that is just for people who are on-label for the medication,” she said. “I have to treat a lot of kids who are young and have failed everything. We treat them with methotrexate or cyclosporine first. If they fail that, we really have to go to bat for them. Our nurses are heroic and easily spend 10 to 20 hours on an individual patient fighting to get this medication approved.”

Although cost is a significant barrier, Silverberg said that many patients have had success with the drug and are satisfied with treatment.

“Patients are happy when two sorts of criteria are met, and it is fairly logical: when the drug works well and they tolerate it well,” he said. “The good news is that the majority of patients will do well with Dupixent efficacy-wise, and they will tolerate it well.”

Silverberg agreed that dupilumab is a welcome option for patients with more severe AD, but there are still unmet needs in this area of medical practice, underscoring the importance of continuous new drug development.

A robust drug pipeline

Several drugs for AD are in the pipeline, many of which are being studied in children and adolescents. One such drug, an oral Janus kinase (JAK) 1 inhibitor known as abrocitinib (Pfizer), demonstrated efficacy and safety in a double-blind, placebo-controlled, parallel-group study in patients aged 12 years and older.

In the trial, 387 patients received either 100 mg or 200 mg of the drug or placebo. According to Pfizer, both doses of the drug were well-tolerated, and no unanticipated safety events occurred during the trial. Detailed results will be presented at a future scientific meeting, the company said.

According to Eichenfield, JAK inhibitors represent a new class of medication that can modulate specific cytokines involved in the pathophysiology of AD.

In addition to abrocitinib, several other JAK inhibitors are in varying stages of development and testing for AD treatment, including Olumiant (baricitinib, Lilly) — which is already approved in the U.S. for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) — upadacitinib (AbbVie), and a topical JAK inhibitor called ruxolitinib (Incyte).

Last year, the results of a phase 2b trial of ruxolitinib were presented at the European Academy of Dermatology and Venerology Congress. When a concentration of 1.5% was used twice daily, patients demonstrated a 71.6% improvement in their EASI scores at week 4 compared with a 15.5% improvement using a placebo (P < .001). Itch was also significantly reduced, with a 1.8-point reduction on the itch numeral rating scale score.

“What I’m hearing is that in high doses, JAK inhibitors seem to be very effective, but they have a lot of side effects like suppressing the immune system, affecting white and red blood cell counts and liver function,” Kress said. “In low doses, they seem to be very safe but much less effective. Within the next year, these companies are going to try and find a balance between safety and efficacy.”

A separate topical product being investigated for psoriasis and AD — called tapinarof (Dermavant Sciences) — has anti-inflammatory properties that are mediated through aryl hydrocarbon receptors, according to researchers. Its efficacy was demonstrated in patients aged 12 to 65 years in a randomized phase 2 study. More than half (58%) of participants had an Investigator Global Assessment score of clear or almost clear after 12 weeks of using a 1% formulation of the topical cream twice daily.

Researchers have even looked at supplementing AD treatment with probiotics — specifically the microbe Lactobacillus pentosus — but results have not been entirely hopeful. A randomized, double-blind, placebo-controlled study presented at this year’s American Academy of Allergy, Asthma and Immunology annual meeting suggested that L. pentosus helped to reduce the severity of AD at 12 weeks, but it was not enough to cause substantial changes in cytokine levels, according to study researcher Young Yoo, MD, PhD, of the department of pediatrics at Korea University in Seoul, South Korea.

Eichenfield estimated that there are at least 40 drugs in early stages of development. Kress suspects that about half will make it to market.

According to Kirkorian, there are several reasons why a condition that did not previously have a booming drug pipeline would suddenly develop so much interest.

“Eczema is one of the most common inflammatory skin conditions on Earth,” she said. “You have a huge market. It is also extremely burdensome to human beings, and its impact on quality of life is huge. I do not think this was necessarily understood before.”

Silverberg also noted that the market share for people with AD is much larger compared with that of other dermatological conditions that have seen more active pipelines, including psoriasis. He said pharmaceutical companies have gone to school on psoriasis and learned their lessons, which are now being applied to AD.

Specifically, immunologic targets were identified for psoriasis much earlier and led to the development of biologic agents like Humira (adalimumab, AbbVie) in 2002, which was later approved for treatment of patients with RA.

Kress described one such target for AD, interleukin-31, as a “master itch cytokine.”

“I think it just took a little longer to figure out the immunology of atopic dermatitis than it did psoriasis and rheumatoid arthritis,” he said. “But now that they have got a beat on it, they have just marched their way through the cytokines.”

No longer tolerating the burden

In a review published in Dermatologic Clinics, Silverberg wrote that AD is associated with increased direct and indirect costs for both payers and patients. This creates a significant public health burden. However, he told Infectious Diseases in Children that heightened interest in the treatment of AD has improved patient care.

“I say half-jokingly that when I got started in atopic dermatitis research over a decade ago — aside from some pediatric dermatologists and a handful of people — no one in the U.S. really cared about this disease,” Silverberg said. “Now, that has completely changed because we have therapies that are working for patients and so much more coming. Among my colleagues, there is just much more interest in working with and managing these patients.”

AD treatments emerging from the drug pipeline may not affect the incidence of AD in the U.S. because none of them are curative, but Kirkorian said the increased awareness of the condition that new treatments are certain to bring will go a long way to address the burden of AD in children and adults.

“We are not going to tolerate the severe atopic dermatitis burden on children and adults as we did before because we did not have good drugs,” Kirkorian said. “You wouldn’t say to a patient with psoriasis who has 80% of their body covered in a rash that they have to deal with it. You have many drugs and you would treat them. I think that is what will happen with atopic dermatitis, too.”

Eichenfield explained that pediatricians should recognize persistent AD as “a sign to step up” treatment.

“It will be increasingly easy to do that as we get newer medicines that allow us to establish long-term control,” he said. – by Katherine Bortz

• References:
• Abbott. Abbott Laboratories’ Humira® (adalimumab) marks successful first year treating patients with rheumatoid arthritis https://www.abbottinvestor.com/news-releases/news-release-details/abbott-laboratories-humirar-adalimumab-marks-successful-first. Accessed July 8, 2019.
• American Academy of Dermatology. Atopic dermatitis. https://www.aad.org/public/diseases/eczema/atopic-dermatitis#overview. Accessed July 8, 2019.
• Castelli G et al. Am Fam Physician. 2018;Sept;98(6):379-380.
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• Dupixent. How much should I expect to pay for Dupixent? https://www.dupixent.com/dupixent-pricing. Accessed July 8, 2019.
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• FDA. Labels – Methotrexate tablets, USP. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/008085s068lbl.pdf. Accessed July 16, 2019.
• Incyte. Incyte announces positive data from phase 2b trial of ruxolitinib cream in patients with atopic dermatitis. https://investor.incyte.com/news-releases/news-release-details/incyte-announces-positive-data-phase-2b-trial-ruxolitinib-cream. Accessed July 17, 2019.
• Kuznik A, et al. Dermatol Ther (Heidelb). 2017;doi:10.1007/s13555-017-0201-6.
• NIH. Clinical trials: A dose-finding study of GSK2894512 cream in subjects with atopic dermatitis (AD). https://clinicaltrials.gov/ct2/show/results/NCT02564055?view=results. Accessed July 8, 2019.
• Paller AS, et al. J Am Acad Dermatol. 2016;doi:10.1016/j.jaad.2016.05.046.
• Pfizer. Pfizer announces positive top-line results from phase 3 study of investigational oral JAK1 candidate, abrocitinib (PF-04965842), in patients with moderate to severe atopic dermatitis. https://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_positive_top_line_results_from_phase_3_study_of_investigational_oral_jak1_candidate_abrocitinib_pf_04965842_in_patients_aged_12_and_older_with_moderate_to_severe_atopic_dermatitis. Accessed July 8, 2019.
• Sanofi. FDA approves Dupixent (dupilumab) for moderate-to-severe atopic dermatitis in adolescents. http://www.news.sanofi.us/2019-03-11-FDA-approves-Dupixent-R-dupilumab-for-moderate-to-severe-atopic-dermatitis-in-adolescents. Accessed July 8, 2019.
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• Yoo Y, et al. Abstract 385. Presented at: American Academy of Allergy, Asthma and Immunology Annual Scientific Meeting; Feb. 22-25, 2019; San Francisco.

• For more information:
• Lawrence Eichenfield, MD, can be reached at leichenfield@rchsd.org.
• A. Yasmine Kirkorian, MD, can be reached through Gabby Little at glittle@childrensnational.org.
• Douglas Kress, MD, can be reached through Andrea Kunicky at andrea.kunicky@chp.edu.
• Jonathan I. Silverberg, MD, can be reached at jonathanisilverberg@gmail.com.

Disclosures: Eichenfield, Kress and Silverberg report numerous ties to industry. Kirkorian reports no relevant financial disclosures.