Lebrikizumab Joins Atopic Dermatitis Armamentarium

The US Food and Drug Administration recently approved lebrikizumab (Ebglyss), a new first-line biologic treatment for atopic dermatitis in individuals with moderate-to-severe disease despite the use of topical therapies. An interleukin-13 (IL-13) inhibitor, this targeted drug class has been found to be highly efficacious and minimally toxic. Additional related therapies are at various stages of development for atopic dermatitis (AD), as outlined and compared below.

IL-13 Therapies Treat Atopic Dermatitis Below the Surface

A common type of eczema, atopic dermatitis is more than a superficial skin disorder; it presents from a complex multitude of genetic, immunological, and environmental factors. Mutations in the gene filaggrin, essential for maintaining skin barrier integrity, are common in those with AD. Food allergies can also trigger symptoms, especially in children.

Type 2 signaling is the immune response driven primarily by T-helper type 2 (Th2) cells and the associated cytokines including IL-4, IL-5, and particularly, IL-13, which are now known to be fundamental to AD disease pathogenesis. IL-13 downregulates the expression of key structural proteins and lipids (ie, filaggrin), which are essential for maintaining the skin barrier. Overproduction of these cytokines results in increased skin permeability, making the skin more prone to dryness, irritation, and infection. IL-13 also contributes to the intense itch patients experience by acting on sensory neurons in the skin and increasing nerve sensitivity.

Available IL-13 Targeted Biologics

As understanding of atopic dermatitis grows, so does the potential to trial novel therapeutic approaches that target its underlying mechanisms. These therapies have been found to effectively treat AD as defined by the Eczema Area and Severity Index (EASI).

Lebrikizumab

Lebrikizumab is a targeted IL-13 inhibitor newly approved as first-line treatment with or without topical corticosteroids (TCS) for adults and children 12 years of age or older (weighing 40 kg or more) with moderate-to-severe atopic dermatitis not well controlled with topical therapies alone. Approval was based on results of the ADvocate 1, ADvocate 2, and ADhere studies.

ADvocate 1 and ADvocate 2 assessed lebrikizumab as monotherapy, showing significant improvements in skin clearance, itch reduction, and quality of life compared to placebo. At 16 weeks, 38% of participants achieved clear or almost clear skin (versus 12% with placebo), of which 77% maintained at 1 year with continued use.

ADhere examined lebrikizumab in combination with topical corticosteroids for patients with an inadequate response to topicals alone. Combination therapy resulted in better symptom control and efficacy compared to corticosteroid monotherapy.

These trials highlight lebrikizumab’s potential as high-affinity targeted IL-13 therapy for long-term AD management, with a convenient once-monthly maintenance dose.

The recommended starting dose of lebrikizumab is 500 mg (two 250 mg injections) at week 0 and week 2, 250 mg every other week until week 16, followed by a maintenance dose of 250 mg monthly. With a strong safety profile and no demonstration of immune suppression, notable side effects are conjunctivitis, injection site reactions, and herpes infection.

Dupilumab

Dupilumab (Dupixent) was the first biologic FDA-approved for systemic treatment of moderate-to-severe AD in 2019. Dupilumab blocks IL-4Rα, thereby inhibiting signaling activated by IL-4 and IL-13, preventing inflammation. It is FDA-approved as first-line therapy with or without TCS for moderate-to-severe atopic dermatitis, and since 2022, dupilumab has been the only biologic approved for children as young as 6 months. While it has shown efficacy, only 40% of patients achieved clear or almost clear skin in clinical trials, and real-world data suggest around a 70% improvement in EASI scores after 3 months. Its use is limited by adverse effects such as conjunctivitis and injection site reactions in 8% to 38% of patients.

Dupilumab is available as 200 mg and 300 mg subcutaneous injections and dosing is weight-based.

Tralokinumab

Tralokinumab (Adbry) is FDA-approved for moderate-to-severe AD refractory to TCS in children 12 years and older and for adults with or without TCS. Tralokinumab inhibits IL-13 cytokine directly and can be used with or without TCS. Tralokinumab is available as a 150 mg prefilled syringe and a 300 mg auto-injector (adults only) for subcutaneous use. In the ECZTRA trials, tralokinumab showed significant improvements in skin clearance and symptoms in patients with moderate-to-severe AD, with many achieving EASI-75 (75% improvement from baseline).However, its efficacy appears to be slightly lower compared to dupilumab.

Recommended dosing for children 12 years and older is a loading dose of 300 mg followed by 150 mg every other week. Adults should receive a loading dose of 600 mg followed by 300 mg every other week. Common side effects include upper respiratory tract infections, conjunctivitis and keratitis, injection site reactions, and eosinophilia as found in the ECZTRA trials.

Emerging IL-13 Targeted Therapies

Eblasakimab and cendakimab are two IL-13 inhibitors currently being investigated in Phase 2 trials for atopic dermatitis treatment. Eblasakimab, a monoclonal antibody targeting the IL-13Rα1 receptor, showed considerable efficacy in early trials presented at the 2022 Annual Meeting of the American Academy of Dermatology (AAD). A small sample of patients treated with eblasakimab demonstrated significant reductions in EASI scores and pruritus, with higher doses yielding better outcomes compared to placebo. Despite its promise, further trials are needed to confirm long-term efficacy and safety.

A recent study evaluated cendakimab’s efficacy and safety in patients with moderate-to-severe atopic dermatitis. Approximately 200 participants were randomized to receive doses of cendakimab or placebo over 16 weeks. Key outcomes included improvements in the EASI scores and assessments of adverse events. The results were promising, demonstrating cendakimab's effectiveness in reducing disease severity, indicating its potential as a systemic therapy for atopic dermatitis.

Atopic Dermatitis Treatment Mainstays

Treatments for mild AD are over-the-counter emollients and barrier creams, topical corticosteroids, and various prescription nonsteroidal topicals. Individuals with moderate-to-severe disease struggle to manage their disease with TCS alone as these drugs carry limited efficacy and long-term toxicity risks. Symptom management for these patients includes systemic agents and/or phototherapy. The availability of targeted biologics has shifted the standard away from broad-spectrum immunosuppressants to safer and more effective alternatives for managing moderate-to-severe AD.