Although the relatively recent approval of dupilumab has expanded the treatment landscape for atopic dermatitis (AD), there is still a need for more effective and safe treatment options for patients with AD. In a recent paper in Dermatologic Clinics, a small team of researchers describe the historic and current treatment landscapes for AD and offer an overview of a robust pipeline of investigational and emerging agents for the disease, including targeted agents.
Historic Management, Recent Advancements
Management of AD predominantly focuses on relieving symptoms and preventing flares, according to the researchers. Current strategies involve goals such as restoring impaired skin barrier function, reducing pruritus, minimizing inflammation, and treating infection. Although there is no cure for the disease, the researchers note that accumulating data suggest that early inflammation control in patients with AD “may support normalized immune maturation and decrease long-term risk of extracutaneous atopy.”
Topical corticosteroids (TCS) have been used as a first-line approach to AD since the 1950s, the researchers wrote, but monitoring is needed with the use of these therapies in children to avoid risks associated with percutaneous absorption. The investigators explained that maintenance treatment with a TCS-sparing agent is recommended for children with AD who need daily medications, and choices for this include topical calcineurin inhibitors and crisaborole.
Methotrexate and cyclosporine have been the most commonly used standard-of-care medications for AD prior to the first approval of dupilumab for adults in 2017, the researchers explained. The investigators added that while low-dose methotrexate is generally well tolerated when administered weekly, common side effects such as abdominal pain and nausea can occur. The investigators stated that these adverse effects can be managed with folic acid. The researchers emphasize the role of standard monitoring for patients taking methotrexate and explained that the therapy is contraindicated in women of childbearing age, given that the treatment is an abortifacient and teratogen.
Dupilumab represents the first biologic agent medication for AD that targets type 2 immune dysfunction, and the approval of the agent, according to the researchers, fulfilled a significant unmet treatment need for patients with moderate to severe AD. The therapy was approved by the FDA for adult AD in March 2017, for adolescents with AD in March 2019, as well as for children aged 6 years or older in May 2020. The researchers noted that dupilumab, when compared with other systemic therapies, does not require regular laboratory monitoring.
The investigators explained that dupilumab, in addition to its ongoing research in AD, is currently undergoing investigation in other atopic diseases such as eosinophilic esophagitis. In addition, while efficacy and safety of dupilumab has been demonstrated in large clinical trials, the researchers indicated that insurance coverage for dupilumab is a significant barrier to treatment access for many patients. “Health care providers prescribing dupilumab are frequently challenged by need for prior authorization and subsequent denial,” the study authors wrote.
Treatments in the Pipeline
According to the researchers, there are currently several monoclonal antibodies (mAbs) targeting the type 2 T-helper pathway under development for AD. These include lebrikizumab and tralokinumab, which bind circulating interleukin (IL)-13, as well as ASLAN004 which binds the IL-13 subunit receptor and feature similar downstream effects as dupilumab IL-4 receptor subunit blockade. Additionally, nemolizumab, a mAb against IL-31 receptor A, is also under investigation for AD, particularly for pruritus symptoms.
In addition to mAbs, certain agents that target the Janus kinase (JAK) family of cytoplasmic protein tyrosine kinases are also undergoing investigation for AD, the researchers explained. The JAK inhibitors vary in their selectivity for the JAK targets JAK1, JAK2, JAK3, and TYK2. The researchers noted that these agents likely have a greater impact on immune function compared with mAbs and other therapies and may therefore increase the risk of carcinogenicity or infection over time. Additionally, the researchers noted that previous clinical trials communicate a concern regarding venous thromboembolism with JAK inhibitors, which have led to a new class black box warning for these agents.
The researchers point to several other investigational therapies under development for AD, including biologics that target thymic stromal lymphopoietin, cytokines IL-4, IL-22, and IL-17 C, immunoglobulin E, type 4 phosphodiesterase, and aryl hydrocarbon receptor. Despite the promise of emerging therapies, the researchers explained that many clinical trials on moderate to severe AD lack pediatric patients younger than 12 years of age, highlighting an unmet research need regarding the use of these agents in children with AD.
Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.
Lockhart MK, Siegfried EC. Evolving landscape of systemic therapy for pediatric atopic dermatitis. Dermatol Clin. 2022;40(2):137-143. doi:10.1016/j.det.2021.12.002