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Associate Professor, Dermatology
Director of Clinical Research
Director of Patch Testing
George Washington University School of Medicine and Health Sciences
Jonathan Silverberg, MD, has disclosed that he has received consulting fees from AbbVie, Arena, Bluefin, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Galderma, GlaxoSmithKline, Incyte, Kiniksa, Leo, Novartis, Pfizer, RAPT, Regeneron, Sanofi; fees for non-CME services from Regeneron and Sanofi; and funds for research support from Galderma.
An important step forward in the field of atopic dermatitis (AD) has been the recent development of several selective JAK inhibitors. Although early data with the broad JAK inhibitor tofacitinib showed some benefit in AD, there were concerns about the safety of broad JAK inhibition. With more selective JAK inhibition, the hypothesis is that we could see equivalent efficacy, or perhaps improved efficacy by increasing the dose, without the safety tradeoffs of broad JAK inhibition.
Fortunately, we are now seeing data from trials assessing selective JAK inhibition in moderate to severe AD, and the data have been overall quite positive. The agents under investigation include the oral JAK inhibitors baricitinib, abrocitinib, and upadacitinib. Abrocitinib and upadacitinib are selective JAK1 inhibitors, which is a key mediator of cytokine signaling in AD, including IL-4, IL-13, and IL-31. Baricitinib is selective for both JAK1 and JAK2.
Across the available randomized, placebo-controlled phase II and phase III data, all of these agents have demonstrated positive efficacy results. Currently, the strongest data are from the phase III Measure Up study of upadacitinib monotherapy, which led to at least a 75% improvement in the Eczema Area Severity Index (EASI 75) in 70% to 80% of patients with moderate to severe AD at Week 16 vs 16% in the placebo arm (P < .001). Monotherapy with abrocitinib and baricitinib also led to statistically significant improvements in EASI 75 vs placebo in patients with moderate to severe AD in the phase III JADE MONO-1/2 and BREEZE-AD5 studies, respectively. All of these selective JAK inhibitors have also improved skin inflammation and itch scores and have tolerable safety profiles, with some caveats.
Regarding safety and tolerability, there appears to be some signal around dose-dependent increases in headache, nausea, and acne with upadacitinib and abrocitinib that is not seen with baricitinib. Hence, the more effective oral treatments may come with slightly greater safety/tolerability tradeoffs.
With multiple approvals anticipated during the next 3 years, I anticipate that each of these agents will be important additions to our treatment toolbox. Based on differences in safety and efficacy, we may have different approaches in using each therapy. For patients with moderate to severe AD who have had an inadequate response to topical therapy, the oral agents could theoretically be used as a substitute for a biologic. On the other hand, given the efficacy of the highest doses of abrocitinib and upadacitinib, these could be used as the “go-to” drugs for patients who have failed biologics and need stronger efficacy.
In addition, the oral JAK inhibitors may offer flexible dosing schedules. For example, they may be able to be used for shorter-term courses without the immunogenicity concerns that accompany monoclonal antibodies, and they also have the potential to be used longer term if patients are tolerating the medications well. Moreover, they can be prescribed alone or in combination with topical corticosteroids. Indeed, one potential secondary benefit of these systemic agents may be a reduced need for using topical therapies, particularly topical steroids, and I am optimistic that we will see a lot of patients experience clearance with JAK inhibitor monotherapy. However, for those who need greater efficacy, we know that there is synergistic efficacy of JAK inhibitors in combination with topical steroids.
Finally, the selective JAK inhibitors may have efficacy beyond AD and may be able to treat other comorbid disorders in this patient population. For example, baricitinib is also under investigation for alopecia areata.
Comparisons With Dupilumab
As for how the selective JAK inhibitors will compare with dupilumab in patients with AD, we will have to await further data from head-to-head trials that are currently underway. However, patient preference tends to lean toward orals vs injectables, and I suspect that the potential for flexible dosing of the JAK inhibitors will results in more widespread clinical preference.
How do you anticipate incorporating selective JAK inhibitors into your treatment decisions for patients with AD? Answer the polling question and join the discussion by posting a comment below. And for more details on new data in AD, download CCO’s Capsule Summaries and reuse the slides in your own presentations.