Related abstracts
Efficacy and Safety of Lebrikizumab, a High-Affinity Interleukin 13 Inhibitor, in Adults With Moderate to Severe Atopic Dermatitis: A Phase 2b Randomized Clinical Trial
Guttman-Yassky E, Blauvelt A, Eichenfield LF, et al.
JAMA Dermatol 2020;156(4):411–20
Importance: Interleukin 13 (IL-13) is a central pathogenic mediator driving multiple features of atopic dermatitis (AD) pathophysiology.
Objective: To evaluate the efficacy and safety of lebrikizumab, a novel, high-affinity, monoclonal antibody targeting IL-13 that selectively prevents formation of the IL-13Rα1/IL-4Rα heterodimer receptor signaling complex, in adults with moderate to severe AD.
Design, setting, and participants: A phase 2b, double-blind, placebo-controlled, dose-ranging randomized clinical trial of lebrikizumab injections every 4 weeks or every 2 weeks was conducted from January 23, 2018, to May 23, 2019, at 57 US centers. Participants were adults 18 years or older with moderate to severe AD.
Interventions: Patients were randomized 2:3:3:3 to placebo every 2 weeks or to subcutaneous injections of lebrikizumab at the following doses: 125 mg every 4 weeks (250-mg loading dose [LD]), 250 mg every 4 weeks (500-mg LD), or 250 mg every 2 weeks (500-mg LD at baseline and week 2).
Main outcomes and measures: The primary end point was percentage change in the Eczema Area and Severity Index (EASI) (baseline to week 16). Secondary end points for week 16 included proportion of patients achieving Investigator's Global Assessment score of 0 or 1 (IGA 0/1); EASI improvement of at least 50%, 75%, or 90% from baseline; percentage change in the pruritus numeric rating scale (NRS) score; and pruritus NRS score improvement of at least 4 points. Safety assessments included treatment-emergent adverse events.
Results: A total of 280 patients (mean [SD] age, 39.3 [17.5] years; 166 [59.3%] female) were randomized to placebo (n = 52) or to lebrikizumab at doses of 125 mg every 4 weeks (n = 73), 250 mg every 4 weeks (n = 80), or 250 mg every 2 weeks (n = 75). Compared with placebo (EASI least squares mean [SD] percentage change, -41.1% [56.5%]), lebrikizumab groups showed dose-dependent, statistically significant improvement in the primary end point vs placebo at week 16: 125 mg every 4 weeks (-62.3% [37.3%], P = .02), 250 mg every 4 weeks (-69.2% [38.3%], P = .002), and 250 mg every 2 weeks (-72.1% [37.2%], P < .001). Differences vs placebo-treated patients (2 of 44 [4.5%]) in pruritus NRS improvement of at least 4 points were seen as early as day 2 in the high-dose lebrikizumab group (9 of 59 [15.3%]). Treatment-emergent adverse events were reported in 24 of 52 placebo patients (46.2%) and in lebrikizumab patients as follows: 42 of 73 (57.5%) for 125 mg every 4 weeks, 39 of 80 (48.8%) for 250 mg every 4 weeks, and 46 of 75 (61.3%) for 250 mg every 2 weeks; most were mild to moderate and did not lead to discontinuation. Low rates of injection-site reactions (1 of 52 [1.9%] in the placebo group vs 13 of 228 [5.7%] in all lebrikizumab groups), herpesvirus infections (2 [3.8%] vs 8 [3.5%]), and conjunctivitis (0% vs 6 [2.6%]) were reported.
Conclusions and relevance: During 16 weeks of treatment, lebrikizumab provided rapid, dose-dependent efficacy across a broad range of clinical manifestations in adult patients with moderate to severe AD and demonstrated a favorable safety profile. These data support the central role of IL-13 in AD pathophysiology. If these findings replicate in phase 3 studies, lebrikizumab may meaningfully advance the standard of care for moderate to severe AD.
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Efficacy and Safety of Lebrikizumab (An anti-IL-13 Monoclonal Antibody) in Adults With Moderate-To-Severe Atopic Dermatitis Inadequately Controlled by Topical Corticosteroids: A Randomized, Placebo-Controlled Phase II Trial (TREBLE)
Simpson EL, Flohr C, Eichenfield LF, et al.
J Am Acad Dermatol 2018;78(5):863–71.
Background: Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD).
Objective: We investigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment.
Methods: A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12.
Results: In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate.
Limitations: Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations.
Conclusion: When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD.
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Therapeutic Potential of Lebrikizumab in the Treatment of Atopic Dermatitis
Loh TY, Hsiao JL, Shi VY.
J Asthma Allergy 2020;13:109–14.
Background: Atopic dermatitis (AD) is a chronic, relapsing skin condition with a wide disease spectrum. Moderate-to-severe cases often need systemic treatment. Conventional immunosuppressants have extensive side effect profiles and require close monitoring. In recent decades, there has been increasing interest in developing targeted systemic immunomodulators for AD, as they have been shown to have efficacy for AD as well as favorable safety profiles. Herein, we review the recent data on lebrikizumab, an interleukin (IL)-13 inhibitor, and its potential role in the treatment of AD.
Objective: Review the mechanism of action, and available data on the efficacy and safety of lebrikizumab for the treatment of AD.
Methods: PubMed, Google Scholar, and clinicaltrials.gov searches were performed with the following terms: "atopic dermatitis," "dermatitis," "eczema," "lebrikizumab," "IL-4," and "IL-13."
Results: Two Phase II randomized controlled clinical trials have been conducted to evaluate the use of lebrikizumab in a total of 289 patients with moderate-severe AD and inadequate response to topical corticosteroids. Patients treated with lebrikizumab experienced significantly more improvement in their AD compared to placebo, as measured by Eczema Area and Severity Index (EASI)-50 and EASI-75 scores, pruritus scores, and reduction in body surface area (BSA). Its clinical efficacy appears to be dose-dependent, and it has a favorable side effect profile and is generally well tolerated.
Conclusion: Lebrikizumab appears to be a promising emerging targeted biologic for the treatment of moderate-to-severe AD. Further Phase III studies investigating optimal dosing regimens and safety profile are needed.
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