Clinical Edge Journal Scan

Commentary: Something for Everyone in AD Treatment, September 2022

Dr. Silverberg scans the journals, so you don’t have to!

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Jonathan Silverberg, MD, PhD, MPH

It is an exciting time in the field of atopic dermatitis (AD). The treatment landscape is evolving at an incredibly fast pace. Since 2017, we have gained approval by the US Food and Drug Administration (FDA) for topical crisaborole ointment and ruxolitinib cream for mild-to-moderate AD, oral abrocitinib and upadacitinib for moderate-to-severe AD, and subcutaneous dupilumab for moderate-to-severe AD. Given all of these different options, we are left with the question of who the right patient for these medications is. My answer is that there is something for everyone. Data from studies published this month provide important context on when and how to use some of these new medications.

Let's start with tralokinumab. I previously had the privilege of being lead author on a study of the efficacy of tralokinumab beyond week 16 — the ECZTRA3 study.1 ECZTRA3 studied tralokinumab at the approved dose (600 mg loading dose followed by 300 mg every other week) vs placebo with concomitant topical corticosteroids (TCS) for an initial 16-week treatment period. Patients who achieved an Investigator's Global Assessment (IGA) score of 0 or 1 or 75% improvement in the Eczema Area and Severity Index (EASI-75) response were then randomly assigned again to receive 300 mg tralokinumab either continuously at every-other-week intervals or a prolonged interval of every 4 weeks (again with concomitant TCS).

With ECZTRA3, we found that patients continued to improve on tralokinumab + TCS well beyond week 16, with increased EASI-75 responses (week 16: 56%; week 32: 70.2%) and sustained or increased improvement across multiple patient-reported outcomes. Together, these results indicate that clinical responses may take more than 16 weeks to achieve with tralokinumab. In addition, some patients may be able to maintain clinical responses using fewer injections at 4-week intervals. This may allow tailoring dosing to individual patient needs. In fact, tralokinumab is approved in the United States and other regions with the option of every-2-week or every-4-week maintenance dosing in patients who have a good clinical response at week 16.

Since AD can be a lifelong disease, we expect that some patients will need to remain on various therapies for extended periods of time, perhaps many years, in order to maintain long-term control. It is imperative that any long-term treatment demonstrate a good long-term safety and efficacy profile. Blauvelt and colleagues published 2-year interim results from the ongoing ECZTEND long-term, open-label extension study of tralokinumab. They showed no new safety signals and stable rates of adverse events compared with earlier time points. Additionally, they showed that 82.5% of patients treated with open-label tralokinumab + TCS for 2 years maintained EASI-75 responses. These data are reassuring and support the potential use of tralokinumab as a long-term treatment option in AD.

While dupilumab is not approved for every-4-week maintenance dosing, a recent study by Spekhorst and colleagues confirmed that dupilumab can also be safely and effectively administered at intervals of every 4 weeks or every 6-8 weeks. Analyzing data from the BioDay real-world observational registry, they found that among patients who achieved good clinical responses (EASI scores ≤ 7) after 52 weeks of treatment with dupilumab administered every 2 weeks, many patients were able to maintain those responses at 3 months after the interval of administration was increased to every 4 weeks (> 80%) or 6-8 weeks (93.3%). These real-world data confirm the results previously observed in the phase 3 SOLO-CONTINUE study2 and support the use of maintenance dosing of dupilumab at prolonged intervals, though such use would technically be considered off-label.

Let’s also review some new data for abrocitinib, a once-daily oral preferential Janus kinase (JAK) 1 inhibitor. Reich and colleagues reported results from a phase 3 trial of adults with moderate-to-severe AD that compared the safety and efficacy of oral abrocitinib at the higher 200 mg dose vs subcutaneous dupilumab over 26 weeks. They found that more patients achieved ≥ 4-point improvement in the Peak Pruritus Numerical Rating Scale score at week 2 with 200 mg abrocitinib compared with 300 mg dupilumab every other week (48% vs 26%). There were also improved EASI-90 responses at week 4 (29% vs 15%). A dose of 200 mg abrocitinib was also significantly more effective than dupilumab for a number of additional investigator- and patient-reported outcomes. In general, abrocitinib had a faster onset of treatment benefit than dupilumab. However, treatment-emergent adverse events were more common with abrocitinib compared with dupilumab (74% vs 65%). Dupilumab was associated with more ocular adverse events (eg, conjunctivitis), whereas abrocitinib was associated with more headaches, nausea, and herpes zoster infections. These results provide important insights into the comparative effectiveness of treatments in moderate-to-severe AD. Of note, this study compared the higher dose of abrocitinib (200 mg) vs dupilumab. However, in the United States, the FDA-approved label recommends initiating abrocitinib therapy with the lower 100 mg dose and increasing to 200 mg only in those who had an inadequate response to 100 mg.

Additional References

1. Silverberg JI, Toth D, Bieber T, et al, for the ECZTRA 3 study investigators. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: Results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol. 2021;184(3):450-463. Doi: 10.1111/bjd.19573

2. Worm M, Simpson EL, Thaçi D, et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: A randomized clinical trial. JAMA Dermatol. 2020;156(2):131-143. Doi: 10.1001/jamadermatol.2019.3617

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