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Department of Dermatology
Icahn School of Medicine at Mount Sinai
Director, Skin of Color Center
Mount Sinai West and Mount Sinai Morningside
New York, New York
Andrew Alexis, MD, MPH, has disclosed that he has received contracted research support from Almirall, Bristol-Myers-Squibb, Cara, Celgene, Galderma, Leo, Menlo, Novartis, and Valeant (Bausch Health); and has served as a consultant for Beiersdorf, Bristol-Myers-Squibb, Cassiopea, Celgene, Dermavant, Foamix, Galderma, Leo, L’Oreal, Menlo, Novartis, Pfizer, Sanofi-Regeneron, Scientis, UCB, Unilever, and Valeant (Bausch Health).
In spring 2020, several interesting virtual conferences in dermatology played host to new research findings on treatment for atopic dermatitis (AD). Here I describe several of the most clinically relevant data on approved and investigational treatments that have the potential to improve outcomes for our patients.
LIBERTY AD PEDS
Presented at the Revolutionizing Atopic Dermatitis (RAD) virtual conference, the randomized phase III LIBERTY AD PEDS trial evaluated the safety and efficacy of dupilumab for severe AD in children aged 6‑11 years. Dupilumab is a fully human monoclonal antibody that inhibits signaling of both IL-4 and IL-13, the primary drivers of type 2 inflammation in many diseases. This study randomized 367 children with AD covering a mean of 60% body surface area to receive dupilumab 300 mg subcutaneously every 4 weeks, weight-based dupilumab (100 mg if < 30 kg or 200 mg if ≥ 30 kg) subcutaneously every 2 weeks, or placebo. All patients received concomitant topical corticosteroids.
In an exciting result, the primary analysis found that 33% of patients who received dupilumab every 4 weeks and 30% who received dupilumab every 2 weeks achieved Investigator’s Global Assessment (IGA) score of 0 or 1 at Week 16 compared with 11% of patients who received placebo (P < .0001 and P < .001, respectively). In addition, 70% of patients treated with dupilumab every 4 weeks and 67% of patients treated every 2 weeks achieved Eczema Area and Severity Index (EASI) 75 (indicating ≥ 75% clearance) by Week 16. By comparison, only 27% of those in the placebo plus topical corticosteroids group achieved that benchmark (P < .0001 for both comparisons). The safety analysis showed that dupilumab plus topical corticosteroids was well tolerated in this pediatric population, with a safety profile consistent with that observed in adults.
Based in part on these new phase III data, dupilumab received an expanded FDA approval for use in patients 6 years of age or older with moderate to severe AD. Without a doubt, this will have a significant impact on the management of a debilitating condition in pediatric populations.
Also presented at the RAD virtual conference was the randomized, placebo-controlled, double-blind phase III JADE MONO‑2 trial. This study assessed the safety and efficacy of the investigational oral JAK1-selective inhibitor abrocitinib in patients aged 12 years or older with moderate to severe AD. The investigators randomized 391 patients to receive abrocitinib once daily at a dose of 100 mg or 200 mg or to receive placebo.
At Week 12, a significantly greater proportion of patients receiving either dose of abrocitinib achieved the coprimary endpoints of IGA 0/1 or EASI 75 vs those receiving placebo. Peak Pruritus Numerical Rating Scale scores were also significantly improved with abrocitinib treatment. Remarkably, even the higher benchmark of EASI 90 (≥ 90% reduction in EASI score) was significantly higher among patients treated with abrocitinib compared with placebo. Specifically, 37.7% of patients in the 200-mg abrocitinib arm and 23.9% in the 100-mg abrocitinib arm achieved EASI 90 compared with 3.9% in the placebo arm (P < .0001 for both comparisons).
Adverse events resulting in discontinuation were low with abrocitinib, 3.2% to 3.8%, compared with 12.8% in the placebo group. Serious infections were infrequent in all groups.
These data are particularly exciting and relevant to clinical practice and the anticipated FDA approval of abrocitinib would represent a major advance in our therapeutic armamentarium. Adding an oral JAK1 selective inhibitor that is safe and efficacious for our patients with moderate to severe AD would give us a valuable oral treatment option for patients who are not candidates for or who are unwilling to receive regular injections. Moreover, based on the mechanism of action of JAK1 inhibitors, we anticipate more rapid reduction in pruritus and more rapid improvement in the clinical severity of AD compared with other treatment options. I also expect that we will have the flexibility for dose adjustment of abrocitinib, assuming that the indication will include a 200-mg and 100-mg dosing option. This is advantageous when managing the spectrum of patients we see with AD in the clinical setting. Finally, an oral JAK inhibitor would afford us the ability to start and stop therapy without concerns about immunogenicity, which is a risk with monoclonal antibody therapy.
Baricitinib is an oral selective JAK1 and JAK2 inhibitor under investigation for moderate to severe AD. At the 2020 RAD virtual meeting, Simpson and colleagues reported on the efficacy and safety of baricitinib in adults with moderate to severe AD in the randomized, double‑blind, placebo‑controlled phase III BREEZE‑AD5 trial. This trial enrolled 440 patients, including a diverse patient population that was approximately 57% white, 18% black, and 19% Asian. We like to see this diversity of patients in clinical trials since it represents a population that is more reflective of the demographics of the United States. Patients in this trial were randomized to receive once-daily baricitinib dosed at 1 mg or 2 mg or placebo.
The proportion of patients achieving the primary endpoint of EASI 75 at Week 16 was 30% with 2-mg baricitinib vs 8% with placebo (P < .001). In addition, 24% of patients in the 2-mg baricitinib arm achieved an IGA 0/1 compared with 5% in the placebo arm (P < .001). Patients in the 1-mg baricitinib group also achieved a statistically significant improvement in IGA 0/1 vs placebo (P < .05).
The investigators also reported significant improvements in pain, itch, skin inflammation, sleep, and quality-of-life outcomes with baricitinib. The safety findings were consistent with previous trials of baricitinib, including low frequencies of serious adverse events across all treatment arms.
This study represents the fifth positive phase III trial for baricitinib in AD, and therefore, we are optimistic about its approval in the near future.
Lebrikizumab in AD
Turning to the American Academy of Dermatology (AAD) 2020 virtual meeting, Guttman and colleagues reported findings from a randomized, placebo-controlled, dose-ranging phase IIb study of the IL-13–targeted monoclonal antibody lebrikizumab in adults with moderate to severe AD. Enrolling 280 participants, the study design featured a 2:3:3:3 randomization to placebo every 2 weeks or subcutaneous lebrikizumab 125 mg every 4 weeks, 250 mg every 4 weeks, or 250 mg every 2 weeks (including loading doses of 250 mg, 500 mg, and 500 mg, respectively).
Lebrikizumab demonstrated statistically significant, dose-dependent improvements in the primary endpoint of EASI change from baseline to Week 16. Secondary endpoints were also met, including dose-dependent improvements in the proportion of patients achieving EASI 50, 75, and 90,as well as IGA 0/1. Furthermore, there were treatment-associated improvements in patient-reported outcomes across a range of AD‑specific measures, including itching, disease severity assessed by Patient-Oriented Eczema Measure, quality of life assessed by Dermatology Life Quality Index, and patient global assessment, all of which showed dose-dependent patterns. Hence, lebrikizumab‑treated patients experienced significant improvements across multiple assessments compared with placebo.
The safety profile of lebrikizumab was consistent with previous studies, including a low frequency of conjunctivitis, herpes virus infections, and injection-site reactions. Therefore, in this dose‑ranging phase IIb study, lebrikizumab was efficacious, showing significantly greater efficacy responses vs placebo, was generally well tolerated, and showed some very promising results regarding patient-reported outcomes.
Dupilumab for Erythrodermic AD
Erythrodermic AD is the most severe presentation of AD with erythroderma. Patients with erythrodermic AD absolutely require systemic therapies, and we have been limited in options that offer both safety and efficacy. The next abstract I discuss, presented at the AAD 2020 virtual meeting, examined the safety and efficacy of dupilumab in this important and clinically relevant subset of patients with erythrodermic AD.
In this report, Cork and colleagues performed a pooled analysis of phase II and III trials of dupilumab in adult and adolescent patients with AD, pulling out the subset of patients with erythrodermic AD, defined as > 90% body surface area of involvement and a baseline erythema score of ≥ 1 based on Global Individual Signs Score. In this post hoc analysis, both dupilumab monotherapy and dupilumab in combination with topical corticosteroids significantly improved the mean body surface area involved as well as the EASI score and daily Peak Pruritus Numerical Rating Scale score. In addition, the safety profile in this particular subset was acceptable without any new safety signals.
Therefore, clinicians can consider dupilumab as monotherapy or with concomitant topical corticosteroids to improve signs and symptoms of erythrodermic AD.
Dupilumab and Cutaneous T-Cell Lymphoma
Finally, I want to highlight another study of dupilumab: a report of dupilumab being associated with disease worsening or unmasking of cutaneous T‑cell lymphoma (CTCL). Presented at RAD 2020, this is a nice study that is clinically relevant to clinicians managing patients with AD.
CTCL is an extranodal non‑Hodgkin lymphoma of the skin, with the most common subtypes being mycosis fungoides and Sézary syndrome. In adult patients who present with a poorly controlled inflammatory condition of the skin with features resembling eczema, it is important to consider CTCL as a differential diagnosis because the treatment for each condition would differ.
In this study, Espinosa and colleagues presented the results of 7 patients who received dupilumab, including 4 who were presumed to have AD and 3 who were diagnosed with CTCL (and received dupilumab off label for treatment). The investigators found that 6 of the 7 patients experienced initial improvement, but this was followed by increased erythroderma, worsening itch, and for some patients, even lymphadenopathy and systemic symptoms. Looking first at the 4 patients who were presumed to have AD, after initial improvement, all 4 experienced worsening disease and were later biopsied and diagnosed with CTCL. The remaining 3 patients diagnosed with CTCL at the time of dupilumab initiation were ultimately diagnosed with Sézary syndrome while on treatment and 2 of the 3 actually died of disease progression.
This small, real-word study emphasizes the need for caution when treating patients who present with atypical dermatitis. In these cases, exclusion of CTCL via skin biopsy, testing for TCR gene rearrangement, and flow cytometry of the blood should be considered before initiating dupilumab. Finally, warning signs that may suggest CTCL in patients with presumed AD receiving dupilumab include a new onset of eczematous plaques that might progress to new anatomic areas, worsening pruritus, lymphadenopathy, and new onset moderate to severe AD in the older patient population.
Which new data from the recent dermatology meetings will most influence your practice? Answer the polling question and join the discussion by posting a comment. And for more details on new data in AD, download CCO’s Capsule Summaries and reuse the slides in your own presentations.