New Frontiers Open for AD, Eczema Solutions

The ongoing promise that the outpouring of new atopic dermatitis (AD) drugs brings to younger patients in particular may one day extend to additional subpopulations with AD. For now, knowledge continues to grow around topical steroid withdrawal (TSW) and complementary approaches ranging from dietary supplements to topical cosmeceuticals. Innovation on these topics and other key issues in combating AD and eczema took center stage at the National Eczema Association (NEA)’s annual patient conference, the Eczema Expo, held August 27 to 29, 2021. 

Therapeutic Revolution

With more than 100 therapies in the eczema pipeline, physicians and patients are witnessing a therapeutic revolution, said Raj Chovatiya MD, PhD, who spoke on a panel convened by the NEA,¹ He is an assistant professor of dermatology at Northwestern University Feinberg School of Medicine in Chicago.

Pediatric patients could be major beneficiaries of this robust pipeline. “To date, we have a huge issue with children and babies,” said Peter Lio, MD, a clinical assistant professor of dermatology and pediatrics at Northwestern University Feinberg School of Medicine, who led the Eczema Expo panel. “Trials of new eczema agents have focused largely on adults, and occasionally teenagers.”

Because approximately 85% of patients develop AD before the age of 5,² children not only represent the largest group of AD patients, but physicians also have the fewest FDA approved treatments for them, he said. Fortunately, Lio explained, the FDA is working to reduce this disparity.

“Numerous clinical trials are underway in various phases, examining the efficacy and safety of topical, biologic, and oral medications for dermatitis across all age groups,” Chovatiya added. “Early results are encouraging and suggest that these newer treatments are equally efficacious and safe across all ages.”

Pivotal trials of dupilumab (Dupixent; Sanofi and Regeneron Pharmaceuticals) led to its approval for adults, adolescents, and, most recently, children down to age 6 months.^3-6 Crisaborole was initially approved in 2016 for ages 2 years and older, and in 2020 was expanded down to 3 months. 

Additionally, the topical JAK inhibitors abrocitinib (Pfizer) and upadacitinib (Rinvoq; AbbVie) have met primary and secondary phase 3 endpoints for patients aged 12 years and up.^7-9 However, getting these drugs to market has a new challenge.

Oral JAK inhibitors abrocitinib, baricitinib (Olumiant; Eli Lilly and Company), and upadacitinib, a biologic agent that targets interleukin (IL)-13 (tralokinumab) were awaiting FDA approval and labeling. However, a September 1 FDA decision to require warnings of serious health risks on JAK inhibitor tofacitinib (Xeljanz; Pfizer), which is used to treat rheumatoid arthritis among other conditions, delivered a setback. The decision was expanded to include baricitinib, and upadacitinib in the warning mandate.

"We eagerly await these new additions to the armamentarium for AD as we continue to have unmet needs and patients who have, quite literally, run out of options,” Lio said. “Although there are significant safety concerns with the JAK inhibitor class, I hope that we will be able to carefully review the specific safety data in the AD population so that we can better guide our patients in a shared decision-making process.”

The FDA added a new treatment option with its September 21 approval of Opzelura. This novel cream formulation for Incyte’s selective JAK1/JAK2 inhibitor ruxolitinib is “the first and only topical JAK inhibitor approved for short-term use in the United States for the topical short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis (AD) in non-immunocompromised patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies, or when those therapies are not advisable,” according to a company press statement.¹⁰

Incyte noted that the approval was based on data from the TRuE-AD (Topical Ruxolitinib Evaluation in Atopic Dermatitis) clinical trial program. Results of the 2 randomized, double-blind, vehicle-controlled Phase 3 studies (TRuE-AD1 and TRuE-AD 2) showed significant improvement from baseline in Investigator’s Global Assessment scores and reduction in itch.¹¹

Although the most common (≥1%) treatment-emergent adverse reactions in patients treated with Opzelura were nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increased, urticaria, folliculitis, tonsillitis and rhinorrhea¹¹, the statement added that Opzelura will carry a box warning regarding increased risk of major cardiovascular events, blood clots, low blood cell counts and cholesterol increases.

Tackling TSW

“Although topical corticosteroids [TCS] are first-line therapy for many patients with AD,” said Chovatiya, “special care should be taken with patients who require constant, ongoing use of these agents.” TSW remains poorly understood, he noted. The starting point is grasping the idea that the term denotes a collection of cutaneous findings that occur with long-term, continuous use of mid- to high-potency TCS, advised Chovatiya.

Diagnostic criteria are lacking, Lio said, but several important features can help identify TSW.¹² The most sensitive signal, he said, is that when patients who have used long-term TCS discontinue treatment, eczema flares up, often at levels worse than its initial presentation. For established TSW, Lio said, key findings include confluent erythema, burning pain, and edema. “The findings attributed to TSW are most pronounced in areas with sensitive skin, including the face and genital region,” Chovatiya added.

Strategies for preventing TSW include intermittent TCS regimens and regular incorporation of nonsteroidal topical treatments. Accordingly, Chovatiya and Lio said excitement is growing around several emerging nonsteroidal topical therapies in later-stage clinical trials. Along with topical ruxolitinib, such agents include new phosphodiesterase (PDE4) inhibitors such as roflumilast (ARQ-154, Arcutis), and the aryl hydrocarbon receptor (AhR) agonist tapinarof (Dermavant Sciences), for which the FDA accepted a New Drug Application in August 2021. 

In addition to nonsteroidal topical agents, Lio said he typically discusses dupilumab or phototherapy with patients battling long-term disease. Similarly, Chovatiya recommended increased emphasis on appropriate use of advanced therapies for patients with moderate to severe AD who are not achieving optimal results with topical corticosteroids.

Alternative and Complementary Therapies

Presently, Chovatiya said there is insufficient data from well-controlled trials to support broad use of alternative medicine, supplements, cosmeceuticals, or nutraceuticals for treating AD. “However,” he added, “many of these treatments are frequently used by patients alongside their prescription therapies to achieve better control of their AD, highlighting an immense need for safe, effective therapies from both the patient and healthcare provider perspectives.” 

Patients often use coconut oil and sunflower seed oil as adjunctive moisturizers, Chovatiya said. Both have limited data suggesting that they may enhance barrier function and provide anti-inflammatory effects.^13,14 Small trials have also shown utility for oral agents such as L-histidine, hempseed oil, and lactobacillus.^15-17

“Many patients are interested in integrative approaches,” Lio said, “and it is very encouraging that many clinicians are engaging in these areas now.” For several years, Lio has participated in the Integrative Dermatology Symposium. “It has been exciting to see the research, the clinical experiences, and the incredible traditions represented. [AD] is very amenable to such approaches because it is such a multi-faceted disease.”

The Integrated Dermatology Certificate Program for dermatologists, which debuted in 2020, has 21 graduates and 22 current enrollees. “We developed this program because we were frustrated by the fragmented, confusing, and sometimes incorrect information currently available in integrative dermatology,” Lio said. The 9-month immersive program gives graduates tools that allow them to feel comfortable applying integrative dermatology to their practices without being overwhelmed by coursework, he added.

Special Populations

Regarding AD subpopulations such as pregnant people, patients with skin of color (SOC), and transgender patients in transition, dermatologists’ ability to personalize therapy remains in its infancy, Lio said. “But we now realize that the ultimate goal is to understand health and disease to such a degree that we can customize our approach on a truly individual basis.” Presently, he said, dermatologists can distinguish some AD phenotypes—such as nummular eczema, follicular eczema, gestational eczema, and prurigo nodularis—clinically, and they are beginning to identify AD endotypes in research settings.¹⁸

Although dermatologists acknowledge that AD is probably not one disease^,18 and that it can manifest differently across different racial and ethnic groups,¹⁹ Lio added, dermatologists’ therapeutic approach remains relatively static across the spectrum of these manifestations, partly because their armamentarium remains limited.

Fortunately, Chovatiya said, recent analyses suggest that newer AD treatments—specifically dupilumab and ruxolitinib—offer comparable safety and efficacy in patients with SOC and different racial/ethnic backgrounds.^20,21

One group that does require special treatment is pregnant people. These patients can be very difficult to treat, Lio said, because many of today’s more potent therapies are contraindicated due to concerns over their impact on fetal health. “There is no doubt that we need more research in this area and beyond.”

Absent a “one-size-fits-all” AD treatment strategy, Chovatiya recommended shared decision-making with patients to craft unique care plans that balance patient and provider values alongside safety, efficacy, feasibility, and costs in selecting prescription and nonprescription approaches.

Disclosures:

Chovatiya has been an advisor, consultant, and/or speaker for AbbVie, Incyte, Regeneron Pharmaceuticals,and Sanofi Genzyme. 

Lio has been a speaker for Sanofi Genzyme, Regeneron Pharmaceuticals, Pfizer, Eli Lilly Company, LEO Pharma, Galderma, Incyte, and L'Oréal; an advisory board member for Almirall, ASLAN Pharmaceuticals, Dermavant Sciences, Sanofi Genzyme, Pfizer, LEO Pharmaceuticals, AbbVie, Eli Lilly and Company, Micreos, L'Oréal, Pierre Fabré, Johnson & Johnson, Level Ex, KP Away, Unilever, Menlo Therapeutics, Theraplex, IntraDerm, Exeltis, AOBiome, Realm Therapeutics, Altus Labs, Galderma, Verrica, Arbonne, Amyris, Bodewell, Yobee Care, Burt's Bees, MyOR Diagnostics, and Kimberly-Clark; a researcher for AOBiome, AbbVie, Regeneron Pharmaceuticals, and Sanofi Genzyme; a patent holder for Theraplex AIM (Splashe Brands, patent pending); and a stockholder in LearnSkin, Micreos, Yobee Care, Altus Labs, and KP Away. 

References:

1. Lio P, Chovatiya R, Schoch J. Now hear this: the latest news in prescription treatments for eczema. National Eczema Association Virtual Eczema Expo; August 28, 2021.

2. Kay J, Gawkrodger DJ, Mortimer MJ, et al. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol. 1994;30(1):35-39. doi:10.1016/s0190-9622(94)70004-4

3. 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. doi:10.1056/NEJMoa1610020

4. Simpson EL, Paller AS, Siegfried EC, et al. Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial. JAMA Dermatol. 2020;156(1):44-56. doi:10.1001/jamadermatol.2019.3336

5. Paller AS, Siegfried EC, Thaçi D, et al. Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: a randomized, double-blinded, placebo-controlled phase 3 trial. J Am Acad Dermatol. 2020;83(5):1282-1293. doi:10.1016/j.jaad.2020.06.054

6. Dupixent (dupilumab) pivotal trial meets all primary and secondary endpoints becoming first biologic medicine to significantly reduce signs and symptoms of moderate to severe atopic dermatitis in children as young as six months. Sanofi. August 30, 2021. Accessed September 8, 2021. https://www.sanofi.com/en/media-room/press-releases/2021/2021-08-30-07-00-00-2288011. 

7. Simpson EL, Sinclair R, Forman S, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020;396(10246):255-266. doi:10.1016/S0140-6736(20)30732-7

8. Silverberg JI, Simpson EL, Thyssen JP, et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020;156(8):863-873. doi:10.1001/jamadermatol.2020.1406

9. Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021;397(10290):2151-2168. doi:10.1016/S0140-6736(21)00588-2

10. Incyte announces u. S. Fda approval of opzelura™(Ruxolitinib) cream, a topical jak inhibitor, for the treatment of atopic dermatitis(Ad). Accessed September 23, 2021. https://investor.incyte.com/press-releases/press-releases/2021/Incyte-Announces-U.S.-FDA-Approval-of-Opzelura-ruxolitinib-Cream-a-Topical-JAK-Inhibitor-for-the-Treatment-of-Atopic-Dermatitis-AD/default.aspx

11. Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double-blind studies [published online ahead of print, 2021 May 4]. J Am Acad Dermatol. 2021;S0190-9622(21)00931-2. doi:10.1016/j.jaad.2021.04.085

12. Hwang J, Lio PA. Topical corticosteroid withdrawal ('steroid addiction'): an update of a systematic review [published online ahead of print, 2021 Feb 4]. J Dermatolog Treat. 2021;1-6. doi:10.1080/09546634.2021.1882659

13. Eichenfield LF, McCollum A, Msika P. The benefits of sunflower oleodistillate (SOD) in pediatric dermatology. Pediatr Dermatol. 2009;26(6):669-675. doi:10.1111/j.1525-1470.2009.01042.x

14. Saraogi P, Kaushik V, Chogale R, et al. Virgin coconut oil as prophylactic therapy against alcohol damage on skin in COVID times. J Cosmet Dermatol. 2021;20(8):2396-2408. doi:10.1111/jocd.14258

15. Tan SP, Brown SB, Griffiths CE, et al. Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis. Clin Cosmet Investig Dermatol. 2017;10:403-411.Doi:10.2147/CCID.S146760 

16. Callaway J, Schwab U, Harvima I, et al. Efficacy of dietary hempseed oil in patients with atopic dermatitis. J Dermatolog Treat. 2005;16(2):87-94. doi:10.1080/09546630510035832

17. Rosenfeldt V, Benfeldt E, Valerius NH, et al. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr. 2004;145(5):612-616. doi:10.1016/j.jpeds.2004.06.068

18. Butler DC, Simpson E, Guttman-Yassky E, et al. The atopic dermatitis spectrum disorder. Recognizing the clinical heterogeneity in patients with atopic related skin conditions in order to improve therapeutic decision-making and outcomes: an expert panel consensus statement [published online ahead of print, 2021 Aug 16]. J Dermatolog Treat. 2021;1-3. doi:10.1080/09546634.2021.1966356

19. Czarnowicki T, He H, Krueger JG, et al. Atopic dermatitis endotypes and implications for targeted therapeutics. J Allergy Clin Immunol. 2019;143(1):1-11. doi:10.1016/j.jaci.2018.10.032

20. Alexis AF, Rendon M, Silverberg JI, et al. Efficacy of dupilumab in different racial subgroups of adults with moderate-to-severe atopic dermatitis in three randomized, placebo-controlled phase 3 trials. J Drugs Dermatol. 2019;18(8):804-813.

21. Papp K, Szepietowski JC, Kircik L, et al. Efficacy of ruxolitinib cream for the treatment of atopic dermatitis by baseline clinical characteristics: pooled subgroup analysis from two randomized phase 3 studies. Abstract/poster 27716. Presented at: American Academy of Dermatology VMX; April 23-25, 2021.