By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration has approved a humanized monoclonal antibody that targets interleukin (IL)-13 for the treatment of moderate-to-severe atopic dermatitis. Lebrikizumab binds to soluble IL-13 at the nonreceptor binding domain and prevents signal transduction. It is the second such monoclonal antibody after tralokinumab (Adbry). Another biologic for this indication, dupilumab, a monoclonal immunoglobulin G4 antibody, binds to the IL-4Rα subunit of IL-4 and IL-13 receptor complexes, resulting in inhibition of IL-4 and IL-13 signaling. Lebrikizumab will be marketed by Eli Lilly and Company as Ebglyss.
Indications
Lebrikizumab is indicated for the treatment of adult and pediatric patients (12 years of age and older weighing at least 40 kg) with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.1 The drug can be used with or without topical corticosteroids.
Dosage
The recommended dose is two 250-mg injections (subcutaneously) at week 0 and week 2, followed by 250 mg every two weeks until week 16 or later, when adequate clinical response is achieved.1 The maintenance dose is 250 mg every four weeks. Lebrikizumab will be available as a 250-mg/2-mL single-dose prefilled pen.
Potential Advantages
Lebrikizumab has higher affinity and slower binding dissociation rate and higher in vitro potency than tralokinumab.2 In addition, it does not interfere with the natural IL-13 clearance (internalization) through the IL-13Rα2 receptor.
Potential Disadvantages
The most common adverse reactions are conjunctivitis, injection site reaction, and herpes zoster.1 Conjunctivitis appears to be a class effect driven by IL-13 inhibition.
Comments
The approval of lebrikizumab was based on three randomized, double-blind, placebo-controlled trials (two as monotherapy and the third in combination with topical corticosteroids) in participants with moderate-to-severe atopic dermatitis.1,3,4 Subjects were not adequately controlled by topical medications and were candidates for systemic therapy. The first two 52-week studies were identical in design and involved a 16-week induction period and a 36-week maintenance period.
In all, 61% of participants had an Investigator Global Assessment (IGA) scale for Atopic Dermatitis score of 3, and 39% had a score of 4. The mean Eczema Area and Severity Index (EASI) was 29.5 and 46% of body surface affected. Of the participants, 12% were aged 12 to < 18 years, and 55% had prior systemic treatment. They were randomized 2:1 to lebrikizumab or placebo (283:141 and 281:146, respectively).
The primary outcome was an IGA score of 0 or 1 (clear or almost clear skin), with a reduction of at least two points from baseline at week 16. Other endpoints included EASI-75 (75% improvement in EASI score), EASI-90, and assessment of itch. In total, 43% of participants achieved the IGA outcome compared to 13% for placebo in study 1, and 33% achieved it vs. 11% with placebo for study 2 at week 16. Results for EASI-75 were 59% vs. 16% and 52% vs. 18%, and EASI-90 were 38% vs. 9% and 31% vs. 10%, respectively. Other findings included a reduction of at least four points on the Pruritus Numeric Rating Scale (NRS 0 to 10 scale), 46% vs. 13% and 40% vs. 12%, respectively. Significant relief was observed at week 4. After the induction period, less frequent dosing (every four weeks) was found to be sufficient to sustain a response for most patients at week 52.5 Lebrikizumab combined with low- to mid-potency topical steroids provided significant improvement compared to topical corticosteroids alone.1,4
Clinical Implications
Atopic dermatitis (AD) is the most common type of eczema, affecting more than 9.6 million children and about 16.5 million adults in the United States.6 It is a chronic relapsing condition, with 30% of adults and adolescents experiencing moderate-to-severe symptoms. Numerous cytokines have been implicated in the development of atopic dermatitis. Key cytokines (IL-13 and IL-4) are facilitated by the IL-4Ra, a common target for pharmaceutical intervention. The recommended therapy for moderate-severe disease is dupliumab or tralokinumb.7,8
There are no trials comparing lebrikizumab and tralokinumab or with dupilumab. It is not clear if the nuance of IL-13 inhibition between lebrikizumab and tralokinumab and the dual action of dupilumab offers any clear clinical advantages in terms of effectiveness or adverse events (e.g., conjunctivitis). In similar studies, lebrikizumab showed a larger drug-placebo difference for the IGA and EASI-75 endpoints. For example, the absolute percent differences achieving EASI-75 differentials were 33% to 42% for lebrikizumab vs. 22% to 12% for tralokinumab.1,9
A systematic review and network meta-analysis suggest that tralokinumab may be less effective than duplilumab.10 The systemic immunomodulatory options are numerous, also featuring Janus kinase inhibitors (e.g., updacitinib). The role of lebrikizumab within this mix of options remains to be determined. The cost for lebrikizumab was not available at the time of this review.
References
- Eli Lilly and Company. Ebgylss prescribing information. Revised September 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761306Orig1s000correctedlbl.pdf
- Okragly AJ, Ryuzoji A, Wulur I, et al. Binding, neutralization, and internalization of the interleukin-13 antibody, lebrikizumab. Dermatol Ther (Heidelb) 2023;13:1535-1547.
- Silverberg JI, Guttman-Yassky E, Thaçi D, et al. Two phase 3 trials of lebrikizumab for moderate-to-severe atopic dermatitis. N Engl J Med 2023;388:1080-1091.
- Simpson EL, Godderham M, Wollenberg A, et al. JAMA Dermatol 2023;159:182-191.
- Blauvelt A, Thyssen JP, Guttman-Yassky E, et al. Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials. Br J Dermatol 2023;188:740-748.
- National Eczema Association. Atopic dermatitis. https://nationaleczema.org/eczema/types-of-eczema/atopic-dermatitis/
- AAAAI/ACAAI JTF Atopic Dermatitis Guideline Panel; Chu DK, Schneider L, Abrams E, et al. Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations. Ann Allergy Asthma Immunol 2024;132:274-231.
- Davis DMR, Drucker AM, Alikhan A, et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol 2024;90:e43-e56.
- Leo Pharma Inc. Adbry prescribing information. Revised December 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761180s001lbl.pdf
- Drucker AM, Morra DE, Prieto-Merino D, et al. Systemic immunomodulatory treatments for atopic dermatitis: Update of a living systematic review and network meta-analysis. JAMA Dermatol 2022;158:523-632.
The U.S. Food and Drug Administration has approved a humanized monoclonal antibody that targets interleukin-13 for the treatment of moderate-to-severe atopic dermatitis.
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