Brett King, MD, PhD, FAAD
Yale School of Medicine

From March 25th to 29th, more than 12,000 attendees gathered in Boston, Massachusetts, for the 2022 American Academy of Dermatology (AAD) Annual Meeting to discuss current research and innovations in the management of dermatologic conditions.
 
Brett King, MD, PhD, FAAD, shared insights and highlighted key takeaways from presentations on the latest advances in the treatment for moderate to severe atopic dermatitis (AD). Dr King, an associate professor of dermatology at Yale School of Medicine in New Haven, Connecticut, specializes in inflammatory skin disease and pioneered the use of Janus kinase (JAK) inhibitors in dermatology.

Which abstracts presented at AAD 2022 did you find most interesting or clinically meaningful in terms of managing moderate-to-severe AD?

Dupilumab revolutionized the treatment of AD and paved the way for interleukin (IL)-13-specific inhibition. Among studies of novel agents presented at AAD this year, the investigational anti-IL-13 antibody lebrikizumab is farthest along in development.
 
At the meeting, data from the phase 3 clinical trials ADvocate1 (ClinicalTrials.gov Identifier: NCT04146363) and ADvocate2 (ClinicalTrials.gov Identifier: NCT04178967), were presented.1 In both studies, more than 50% of adolescents and adults with moderate-to-severe AD who received monotherapy with lebrikizumab experienced a 75% or higher reduction in disease severity (EASI-75) at 16 weeks compared with patients in the placebo group (ADvocate1: 59% vs 16%; ADvocate2: 51% vs 18%). Within 4 weeks, patients treated with lebrikizumab had clinically meaningful improvements in pruritis, sleep quality, and quality of life compared with patients randomized to placebo. In both studies, most adverse events were mild or moderate in severity.
 
Dupilumab, the current standard of care for moderate-to-severe AD, achieved a 75% or higher reduction in disease severity in 44% to 51% of patients in the SOLO1 and SOLO2 clinical trials.2 It will be interesting to see how future clinical studies differentiate lebrikizumab from dupilumab. There are obviously several years of real-world efficacy and safety data and multiple indications for dupilumab, including moderate-to-severe asthma, a common comorbidity of AD.3

Besides lebrikizumab, other novel therapies such as eblasakimab, RPT193, and oral difelikefalin are being evaluated in clinical trials. Which findings were the most compelling?

Besides lebrikizumab, the most provocative data were on RPT193, a novel oral agent targeting C-C chemokine receptor type 4 (CCR4). In a phase 1b, treatment with RPT193 yielded improvement in patients with AD vs patients treated with placebo 29 days after the end of treatment with continued improvement seen over an additional 2 week follow-up period.4 If these results are duplicated in larger studies, RPT193 could emerge as an additional oral option with a unique mechanism of action.

The US Food and Drug Administration (FDA) approved abrocitinib5 and upadacitinib6 for patients with moderate-to-severe AD, making them the first oral JAK inhibitors to be used in this setting. How do these agents fit in with the others we have discussed and what impact do you expect them to have on patient care?

It is impossible to answer this question without first discussing the prescribing information for both abrocitinib and upadacitinib which states that they are indicated for the treatment of adults with refractory moderate-to-severe AD whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.7,8 Up until a month ago, dupilumab was the only systemic drug approved for the treatment of moderate-to-severe AD. I think it is fair to say that dupilumab is the standard of care. In considering the prescribing information, biologics — dupilumab in particular but now tralokinumab, too — would only rarely be inadvisable. Thus, if we follow the prescribing information for the oral JAK inhibitors, their use would be appropriate in patients who have an inadequate response to dupilumab.
 
Although patients do very well under treatment with dupilumab, many need better disease control. Now that we have abrocitinib and upadacitinib in the armamentarium, patients have more options. Just as dupilumab was revolutionary in the treatment of AD, so will JAK inhibitors. Remember, JAK inhibitors modulate the activity of multiple drivers of AD, including IL-4, IL-5, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin.9 JAK inhibitors’ unique mechanism of action means that they add something truly different to the AD treatment toolbox. This is supported by very impressive clinical trial results for both abrocitinib and upadacitinib, including in patients with an inadequate response to dupilumab.

Another interesting role for the oral JAK inhibitors will be in patients with AD and comorbid autoimmune disease. Just as I believe that comorbid asthma in a patient with moderate to severe AD should push us to use dupilumab because this drug may treat both conditions, JAK inhibitors might be considered first-line therapy in patients with AD and other comorbid diseases for which JAK inhibitors have shown efficacy, including alopecia areata,10 vitiligo,11 rheumatoid arthritis, and ulcerative colitis.6 We need to be asking our patients about their overall health and we should consider their comorbidities when making treatment decisions.
 
Needless to say, we are going to use abrocitinib and upadacitinib a lot. These medicines are going to be enormously important and will elevate the treatment of AD.

JAK inhibitors’ unique mechanism of action means that they add something truly different to the AD treatment toolbox. This is supported by very impressive clinical trial results for both abrocitinib and upadacitinib, including in patients with an inadequate response to dupilumab.

Can you share some practical recommendations for assessing the severity of AD and measuring treatment response in patients?

In all of my patients with moderate-to-severe AD, I document Investigator Global Assessment for Atopic Dermatitis results, body surface area dermatitis, and pruritus score from 0 to 10 on the numerical rating scale. These quick and easy assessment tools tell us a lot about a patient’s disease and how the patient is doing. We can understand and document the effect of treatment by looking at changes in these assessments over a certain period of time.
 
Regarding response to treatment, while some patients experience treatment failure (that is, they have absolutely no response to treatment), usually the efficacy findings are more nuanced and the question is whether a particular treatment is achieving adequate control. Because AD is complex, with multiple aspects of disease including pruritus, dermatitis, and sometimes skin pain, the determination of adequate control is not always straightforward. While use of the Investigator Global Assessment for Atopic Dermatitis results, body surface area dermatitis, and pruritus score tools can be very helpful in guiding care, input from the patient is critical for confirming adequate control. I believe that with a growing number of treatments to offer patients, we will increasingly strive for near-complete remission of both dermatitis and pruritus.

What are key challenges or unmet needs in the management of moderate-to-severe AD?

We still have a lot of room for improvement in the care of AD. Just look at how the treatment of psoriasis has evolved in the last decade. For instance, adalimumab has shown a reduction in disability and improved joint and skin involvement in patients with psoriatic arthritis.12 Treatment goals for our patients with moderate-to-severe AD should be similar: We want to be able to achieve clear skin and no itch in all of our patients.

What final thoughts would you like to share?

Advances in the management of AD over the past 7 years have been amazing and improved the lives of many patients. We need to advance further, though. The AAD 2022 meeting was exciting because we saw promising data on new treatments for AD. We must not forget that AD is an awful disease; not only is it a miserable to be itchy and red, but there are also comorbidities of AD. Perhaps by making AD better we can have a positive impact on some of these comorbidities. Newer treatments with different mechanisms of action may help us to achieve that, so it is exciting to see an expanding drug pipeline for AD.

Key Takeaways

  • More treatment options are needed for the treatment of moderate-to-severe AD.
  • Results from the Advocate clinical trials indicated that lebrikizumab demonstrated promising efficacy in the treatment of moderate-to-severe AD in adolescents and adults.
  • JAK inhibitors have a unique mechanism of action and will be an important class of medicines for treatment of moderate-to-severe AD.
  • It is important to consider patients’ comorbidities and select an agent that can treat not only AD but also comorbid conditions such as asthma, alopecia areata, and other autoimmune conditions.

This Q&A was edited for clarity and length.

Disclosure

Brett King, MD, PhD, FAAD, has reported affiliations with AbbVie Inc.; Bristol-Myers Squibb Company; Concert Pharmaceuticals, Inc.; Dermavant Sciences, Inc.; Eli Lilly and Company; Pfizer, Inc; Regeneron Pharmaceuticals, Inc.; Sanofi-Genzyme; and Twi Biotechnology, Inc.

References

1. Majority of patients treated with lebrikizumab achieved skin clearance in Lilly’s pivotal phase 3 atopic dermatitis studies. News release. Eli Lilly and Company. Published March 26, 2022. Accessed April 17, 2022. https://investor.lilly.com/news-releases/news-release-details/majority-patients-treated-lebrikizumab-achieved-skin-clearance
 
2. Simpson EL, Bieber T, Guttman-Yassky E, et al; for the SOLO1 and SOLO2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348. doi:10.1056/NEJMoa1610020
 
3. Wollenberg A, Beck LA, Blauvelt A, et al. Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS). Br J Dermatol. 2020;182(5):1120-1135. doi:10.1111/bjd.18434
 
4. RAPT Therapeutics Announces Late-Breaking Oral Presentation of Positive Results from Phase 1b Trial of RPT193 at the 30th European Academy of Dermatology and Venereology Congress. Globe Newswire. Updated September 30, 2021. Accessed April 25, 2022. https://www.globenewswire.com/news-release/2021/09/30/2306288/0/en/RAPT-Therapeutics-Announces-Late-Breaking-Oral-Presentation-of-Positive-Results-from-Phase-1b-Trial-of-RPT193-at-the-30th-European-Academy-of-Dermatology-and-Venereology-Congress.html
5. U.S. FDA approves Pfizer’s CIBINQO® (abrocitinib) for adults with moderate-to-severe atopic dermatitis. News release. Pfizer, Inc. Published January 14, 2022. Accessed April 17, 2022. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-cibinqor-abrocitinib-adults
 
6. U.S. FDA approves RINVOQ® (upadacitinib) to treat adults and children 12 years and older with refractory, moderate to severe atopic dermatitis. AbbVie, Inc. Published January 14, 2022. Accessed April 17, 2022. https://news.abbvie.com/news/press-releases/us-fda-approves-rinvoq-upadacitinib-to-treat-adults-and-children-12-years-and-older-with-refractory-moderate-to-severe-atopic-dermatitis.htmhttps://news.abbvie.com/news/press-releases/us-fda-approves-rinvoq-upadacitinib-to-treat-adults-and-children-12-years-and-older-with-refractory-moderate-to-severe-atopic-dermatitis.htm
 
7. Rinvoq. Prescribing information. AbbVie, Inc; 2022. Accessed April 17, 2022. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf.

8. CIBINQO. Prescribing information. Pfizer, Inc; 2022. Accessed April 2022. https://cdn.pfizer.com/pfizercom/USPI_Med_Guide_CIBINQO_Abrocitinib_tablet.pdf
 
9. Szalus K, Trzeciak M, Nowicki RJ. JAK-STAT inhibitors in atopic dermatitis from pathogenesis to clinical trials results. Microorganisms. 2020;8(11):1743. doi:10.3390/microorganisms8111743
 
10. King B, Ohyama M, Kwon O, et al; for the BRAVE-AA Investigators. Two phase 3 trials of baricitinib for alopecia areata. N Engl J Med. Published online March 26, 2022. doi:10.1056/NEJMoa2110343
 
11. Montilla AM, Gómez-García F, Gómez-Arias PJ, et al. Scoping review on the use of drugs targeting JAK/stat pathway in atopic dermatitis, vitiligo, and alopecia areata. Dermatol Ther (Heidelb). 2019;9(4):655-683. doi:10.1007/s13555-019-00329-y
 
12. Gladman DD, Mease PJ, Ritchlin CT, et al. Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. Arthritis Rheum. 2007;56(2):476-488. doi:10.1002/art.22379

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Reviewed April 2022