Trends in Atopic Dermatitis: Treatments and Trial Design

The last two years have seen a surge in proposed and initiated clinical trials for atopic dermatitis (AD), or eczema. This surge in clinical research around AD is not new. AD has been a highly researched indication for the last several years, spurred on in large part by the development of new biologics and JAK inhibitors following the approval of Dupixent for AD in 2017. This trend is not only continuing but accelerating, with evolving study designs focusing on quality of life and an increased emphasis on the skin barrier and microbiome.

AD trials have slowly changed over the last decade, in part due to new developments in fundamental research, but also following general trends in dermatology. Newer AD studies have a much heavier emphasis on patient quality of life (QoL), with almost all new studies containing a QoL metric of some kind. Additionally, there has been increased focus on patient reported outcomes (PROs). The majority of recently conducted and upcoming AD studies utilize a combination of QoL and PRO evaluations, with some studies having several of each. This is not unique to AD, studies in almost every dermatology indication have put greater focus on patient satisfaction in the last five years. AD studies have adhered to this trend in much the same way, with patient outcome measurements growing in number and complexity each year.

Investigator Global Assessment, or IGA, was the undisputed mainstay in AD efficacy evaluations just a decade ago. This dominance has slowly eroded over time, and while many clinical trials still include IGA as a co-primary endpoint, the Eczema Area and Severity Index (EASI) has become the preferred efficacy evaluation in clinical research. This trend is not new; in 2014 the Harmonising Outcome Measures for Eczema (HOME) statement endorsed the use of EASI as the primary efficacy endpoint in AD trials due to its validity, responsiveness, internal consistency, and intraobserver reliability.[1] Dupixent’s approval for AD in 2016 using EASI as a co-primary spurred on its use in most future studies. Newer studies often include an IGA responder endpoint, but will have several EASI evaluations as well, including EASI-50, EASI-75, and EASI-90.

Coinciding with the increased push for QoL measurements is an increased emphasis on the treatment of the itch present in AD. Disturbed sleep in patients with AD is a major driver of reduced QoL, and is primarily caused by the urge to scratch at night.[2] While itch measurement has often been included in studies through its use in other scales, such as DLQI or the Atopic Dermatitis Severity Index (ADSI), it is now often included as an independent endpoint. Often itch is measured through a numerical rating scale (NRS) that evaluates the “worst” itch of a subject over a certain time frame, usually 24 hours. Like many trends in AD research, use of Pruritis NRS scales kicked off when Dupixent was approved with an NRS itch scale as a secondary endpoint. Since itch is such a distressing symptom in AD, a drug that effectively reduces itch provides a clear patient benefit and improves the risk/benefit profile of a therapeutic agent.

In addition to improving the tracking and measurement of itch, new research aims to uncover the mechanisms of AD itch. A good example of this new emphasis is Regeneron’s recent DIFFEREN-STAD study, a Phase IV clinical trial examining the neuronal structure of skin in AD patients treated with Dupixent. This study specifically evaluated nerve fiber density in AD patients with chronic itch, and used a Peak Pruritis NRS scale to measure subjective patient outcomes.[3] Another developing field of study is the neuronal aspect of AD itch and how neuron signaling in the skin results in itch and inflammation. One particular target of interest has been TRP calcium ion channels in the skin; these channels “modulate neuroimmune interactions and mediate itch and pain”.[4] The channel TRPV1 in particular has been seen as a potential therapeutic target, as it is expressed in keratinocytes, mast cells, and sensory nerves in the skin. Asivatrep, an antagonist of this TRPV1 receptor, recently completed a successful Phase III clinical trial, paving the way for future therapeutic options in this class.[5]

Another intriguing trend in the AD space is the increased attention given to the skin barrier and skin microbiome. Research in the human microbiome has flourished in recent years, and this trend has spread to dermatology, specifically in the study of AD. Patients suffering from AD carry S. aureus on their skin at rates of 30% to 100%, compared to just 20% in healthy controls. S. aureus is believed to produce a variety of molecules that promote inflammation and disrupt the skin barrier, potentially contributing to the symptoms of AD and exposing the skin to further infection and colonization.[6] There are no FDA approved AD drugs currently on the market that target the skin microbiome. However, initial research into microbiome modulation has yielded promising results. A small study testing the effects of R. mucosa, a bacterium existing in high proportions in healthy controls, found that application of R. mucosa to AD lesions reduced disease severity and inflammatory signaling.[7]

While nearly decade-old trends in AD clinical research remain strong, the field is beginning to diversify as new treatments and methods of evaluation come to the forefront. Biologics and JAK inhibitors continue to be developed and refined but may soon be joined by microbiome modulators and TRPV antagonists. Clinical trials continue to feature QoL assessments, specifically itch, and tilt increasingly in favor of EASI as a primary evaluator of efficacy.

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References

1. Schmitt, J.; Spuls, P. I.; Thomas, K. S.; Simpson, E.; Furue, M.; Deckert, S.; Dohil, M.;A pfelbacher, C.; Singh, J. A.; Chalmers, J.; et al. The Harmonising Outcome Measures for Eczema (HOME) statement to assess clinical signs of atopic eczema in trials. J Allergy Clin Immunol 2014, 134 (4), 800-807. DOI: 10.1016/j.jaci.2014.07.043 From NLM Medline.

2. Fasseeh, A. N.; Elezbawy, B.; Korra, N.; Tannira, M.; Dalle, H.; Aderian, S.; Abaza, S.; Kaló, Z. Burden of Atopic Dermatitis in Adults and Adolescents: a Systematic Literature Review. Dermatology and Therapy 2022, 12 (12), 2653-2668. DOI: 10.1007/s13555-022-00819-6.

3. Dupilumab Effect on Pruritis Neuro-mechanisms in Patients with Atopic Dermatitis (DIFFEREN-STAD). https://clinicaltrials.gov/study/NCT04823130 (accessed.

4. Kwatra, S. G.; Misery, L.; Clibborn, C.; Steinhoff, M. Molecular and cellular mechanisms of itch and pain in atopic dermatitis and implications for novel therapeutics. Clin Transl Immunology 2022, 11 (5), e1390. DOI: 10.1002/cti2.1390 From NLM.

5. Park, C. W.; Kim, B. J.; Lee, Y. W.; Won, C.; Park, C. O.; Chung, B. Y.; Lee, D. H.; Jung, K.; Nam, H. J.; Choi, G.; et al.A sivatrep, a TRPV1 antagonist, for the topical treatment of atopic dermatitis: Phase 3, randomized, vehicle-controlled study (CAPTAIN-AD). J Allergy Clin Immunol 2022, 149 (4), 1340-1347.e1344. DOI: 10.1016/j.jaci.2021.09.024 From NLM.

6. Kim, J. E.; Kim, H. S. Microbiome of the Skin and Gut inA topic Dermatitis (AD): Understanding the Pathophysiology and Finding Novel Management Strategies. J Clin Med 2019, 8 (4). DOI: 10.3390/jcm8040444 From NLM.

7. Myles, I. A.; Castillo, C. R.; Barbian, K. D.; Kanakabandi, K.; Virtaneva, K.; Fitzmeyer, E.; Paneru, M.; Otaizo-Carrasquero, F.; Myers, T. G.; Markowitz, T. E.; et al. Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair. Sci Transl Med 2020, 12 (560). DOI: 10.1126/scitranslmed. aaz8631 From NLM.