Clinical Pearls & Morning Reports
Published March 22, 2023
Silverberg et al. conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trials — ADvocate1 (trial 1) and ADvocate2 (trial 2) — that evaluated the efficacy and safety of lebrikizumab monotherapy during an induction period of 16 weeks in adult and adolescent patients with moderate-to-severe atopic dermatitis. Read the NEJM Original Article here.
Q: Why are additional treatments for atopic dermatitis needed?
A: First-line treatment for mild-to-moderate disease and acute flares includes topical medicines such as emollients and topical glucocorticoids. When the response to topical therapy is inadequate in patients with moderate-to-severe disease, the addition of systemic therapy or phototherapy (or both) is recommended. Therapeutic monoclonal antibodies such as dupilumab and tralokinumab, as well as new Janus kinase inhibitors, have been approved in many countries to treat moderate-to-severe atopic dermatitis. Despite these advances, there remains an unmet medical need for long-term management of atopic dermatitis owing to the heterogeneous nature of the disease.
Q: What is the mechanism of action of lebrikizumab?
A: The multifaceted pathogenesis of atopic dermatitis is associated with skin-barrier dysfunction and a complex interaction of genetic, immunologic, and environmental factors. The dysregulation of type 2 helper T cells, which preferentially produce cytokines such as interleukins 4, 13, and 31, plays a central role in the pathogenesis of atopic dermatitis. Interleukin-13 is implicated as the primary cytokine in atopic dermatitis, and serum levels of interleukin-13 correlate with disease severity. Lebrikizumab is a high-affinity IgG4 monoclonal antibody that selectively binds soluble interleukin-13 with a slow rate of dissociation and high potency. Lebrikizumab prevents the formation of the interleukin-4Rα–interleukin-13Rα1 heterodimer signaling complex, thus blocking interleukin-13 signaling without interfering with interleukin-4 signaling.
A: The primary outcome of the 16-week induction period was an Investigator’s Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe lesions]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. In both trials, a significantly higher percentage of patients in the lebrikizumab group than in the placebo group had a primary outcome response at week 16. In trial 1, a primary outcome response occurred in 43.1% of the patients in the lebrikizumab group, as compared with 12.7% of those in the placebo group (P<0.001); in trial 2, the corresponding percentages were 33.2% and 10.8% (P<0.001). Most adverse events during the induction period were nonserious and mild or moderate in severity, including a low incidence (≤2.5%) of injection-site reactions in both trials.
A: Conjunctivitis was more frequently reported in lebrikizumab-treated patients than in patients who received placebo. A higher incidence of conjunctivitis has also been reported in patients treated with other interleukin-13– and interleukin-4–targeting biologic agents, such as dupilumab and tralokinumab. Although several theories have been proposed for the pathogenesis of conjunctivitis in patients with atopic dermatitis treated with this class of biologic agents, the mechanism remains unclear and warrants further study.