Jonathan Silverberg, MD, PhD, MPH
Clinicians everywhere are excited to have more options, but they are also reeling from trying to keep up with the enormous amount of data. We are fortunate to have a lot of information for these therapies published in the past month, which provides important insight into how to best use them.
Let's start with some new data on dupilumab, which has emerged as a first-line systemic therapy for moderate to severe AD in the US. Patients who were enrolled in the phase 1-3 randomized clinical trials for dupilumab were allowed to enroll in a long-term open-label extension study where they received 300 mg dupilumab weekly. Beck and colleagues published the interim analysis of the ongoing international, multicenter, long-term extension study of 2677 adults with up to 4 years of dupilumab exposure. They found no major increases in adverse event rates, with high durable efficacy and high rates of drug persistence over time. It is important to note that this was an open-label study without a control group — that is, patients knew exactly what treatment they were receiving. In addition, the analysis presented efficacy among those patients who remained in the study over time, which may not adequately account for loss of efficacy over time in patients who dropped out of the study. Nevertheless, the results suggest that dupilumab can be a good long-term treatment option for patients with chronic AD, with no new major safety concerns.
There is now a large body of evidence generated by phase 4 studies showing the real-world effectiveness of dupilumab. Stingeni and colleagues published the results of a prospective study of 139 adolescents (aged 12-17 years) with moderate-to-severe AD who received dupilumab for 16 weeks. They found significant improvement in AD signs and quality of life overall and across different clinical phenotypes of AD, with robust endpoints achieved most in the diffuse eczema subtype. Despite the previously demonstrated heterogeneity of AD, 1,2 these results suggest that dupilumab can be effective across a variety of patient subtypes.
The JAK inhibitors are new additions to our therapeutic armamentarium for AD. Given how new they are to dermatology, we are always craving more data to inform clinical decision-making. Several recent studies provide additional insights into how we can use the JAK inhibitors in clinical practice.
One major question is how well they work in patients in whom dupilumab previously failed. Shi and colleagues published the results of an interesting and clinically relevant phase 3 study (JADE EXTEND), which included 203 patients with moderate-to-severe AD who were randomly assigned to receive 200 mg or 100 mg once-daily abrocitinib after previously receiving dupilumab for 14 weeks in the JADE COMPARE study. They found that at week 12, the majority of dupilumab nonresponders had high Eczema Area and Severity Index (EASI-75) responses with both doses of abrocitinib. Patients who previously had a good clinical response with dupilumab had even higher treatment responses on abrocitinib than those who were dupilumab nonresponders. These data provide important information to support the use of abrocitinib, and perhaps by extension other JAK inhibitors, in patients who previously had inadequate response to dupilumab.
Another major question is how to differentiate the JAK inhibitors from biologics in AD. One consideration is that patients taking JAK inhibitors may achieve more robust clinical responses compared with those on biologics. Stander and colleagues performed a post hoc analysis of pooled phase 2B/3 studies of abrocitinib (942 patients). They found that, at week 12, a higher proportion of patients receiving 200 mg and 100 mg abrocitinib achieved more robust endpoints, such as EASI-90 and EASI-100 scores, compared with placebo recipients. Of note, these data did not include any comparison data with dupilumab. However, on the basis of cross-study comparison, it would seem that abrocitinib, particularly at the higher 200 mg dose, may lead to more robust clinical responses than dupilumab. However, it is very important to acknowledge that this study focused on 12-week data and maximal efficacy with dupilumab may take longer to achieve.
Additional References
1. Chovatiya R, Silverberg JI. The heterogeneity of atopic dermatitis. J Drugs Dermatol. 2022;21(2):172-176. Doi: 10.36849/JDD.6408
2. Yew YW, Thyssen JP, Silverberg JI . A systematic review and meta-analysis of the regional and age-related differences in atopic dermatitis clinical characteristics. J Amer Acad Dermatol. 2019;80(2):390-401. Doi: 10.1016/j.jaad.2018.09.035