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A Phase 2 Randomized, Double-blind Pilot Study of IL-17-Targeting with 2 Secukinumab in Moderate-to-Severe Atopic Dermatitis

ABSTRACT: This randomized, double-blind, phase 2 study aimed to investigate the efficacy and safety of secukinumab as compared to placebo in 41 subjects with moderate-to-severe AD over a 16-week period, with evaluations of clinical outcomes and molecular and cellular profiles in skin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137430 | GEO | 2020/09/01

REPOSITORIES: GEO

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Project description:IntroductionAtopic dermatitis (AD) is a heterogeneous disease, with involvement of the T-helper cell (Th) 2, Th22, and potentially Th17 pathways, supporting the use of interleukin (IL)-23 and IL-22 blockade in AD.MethodsThis phase 2, multicenter, randomized, double-blind, placebo-controlled trial (NCT03706040) evaluated the efficacy and safety of risankizumab, an IL-23 inhibitor, in patients (≥ 12 years old) with moderate-to-severe AD, defined by an Eczema Area and Severity Index (EASI) ≥ 16, affected body surface area ≥ 10%, and a Validated Investigator Global Assessment for AD (vIGA-AD) score ≥ 3. Patients were randomized 2:2:1 to 16-week treatment with risankizumab 150 mg, risankizumab 300 mg, or placebo in period A; patients receiving placebo were re-randomized 1:1 to risankizumab 150 mg or 300 mg and patients receiving risankizumab continued on their randomized dose in 36-week period B. Study drug was administered at baseline and weeks 4, 16, 28, and 40. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction from baseline in EASI (EASI 75) at week 16. Safety was analyzed in all randomized patients who received study medication.ResultsNeither the risankizumab 150 mg (n = 69) nor the 300 mg dose group (n = 69) demonstrated a significantly higher proportion of patients achieving EASI 75 at week 16 compared with the placebo group (n = 34; treatment difference [95% CI] 13.0% [-1.7 to 27.7%; P = 0.084] and 10.0% [-4.6 to 24.6%; P = 0.179], respectively). Most adverse events were mild to moderate in severity; five patients receiving risankizumab reported serious adverse events, including two patients who reported cellulitis.ConclusionsRisankizumab was generally well tolerated, with no new safety concerns identified. The study's primary endpoint was not met, with no significant difference in the proportion of patients achieving an EASI 75 response at week 16 with risankizumab 150 mg or 300 mg versus placebo.Trial registrationClinicalTrials.gov NCT03706040.

Project description:ImportanceCendakimab selectively targets interleukin (IL)-13, a type 2 cytokine implicated in atopic dermatitis (AD) pathogenesis, by inhibiting binding to its receptors (IL13R-α1 and IL13R-α2). Proof-of-concept work in AD supports using cendakimab for type 2 inflammatory diseases.ObjectiveTo evaluate the efficacy and safety of cendakimab compared with placebo in patients with moderate to severe AD.Design, setting, and participantsThis phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial was conducted from May 2021 to November 2022. Adult patients with moderate to severe AD and inadequate response to topical medications were enrolled at 69 sites in 5 countries (US [n = 26], Japan [n = 17], Canada [n = 9], Poland [n = 9], and Czech Republic [n = 8]). Data were analyzed between April 25, 2023, and October 16, 2023.InterventionsPatients were randomized (1:1:1:1) to receive subcutaneous cendakimab, 360 mg, every 2 weeks; 720 mg, every 2 weeks; 720 mg, once weekly; or placebo.Main outcome and measureMean percentage change in Eczema Area and Severity Index scores from baseline to week 16. Hierarchical testing with multiplicity adjustment was performed for 720 mg, once weekly vs placebo, then 720 mg, every 2 weeks vs placebo, and then 360 mg, every 2 weeks vs placebo.ResultsOverall, 221 patients were randomized, and 220 received study drug (95 women [43%]; mean [SD] age, 37.7 [13.9] years; 720 mg, once weekly [54 (24%)]; 720 mg, every 2 weeks [55 (25%)]; 360 mg, every 2 weeks [55 (25%)]; placebo [56 (26%)]). The primary efficacy end point was met for cendakimab, 720 mg, once weekly vs placebo (-84.4 vs -62.7; P = .003) but missed statistical significance for 720 mg, every 2 weeks (-76.0 vs -62.7; P = .06). The treatment effect for 360 mg, every 2 weeks (-16.3; nominal P = .03 vs placebo) was comparable with 720 mg, once weekly (-21.8); however, significance was not claimed because the hierarchical testing sequence was interrupted. Of patients with treatment-emergent adverse events leading to discontinuation, 4 (7.4%) received 720 mg, once weekly; 2 (3.6%) 720 mg, every 2 weeks; 1 (1.8%) 360 mg, every 2 weeks; and 2 (3.6%) placebo.Conclusions and relevanceThe results of this randomized clinical trial indicated that cendakimab was effective, generally safe, and well-tolerated in patients with moderate to severe AD. The primary end point was met with a significant reduction in Eczema Area and Severity Index scores with 720 mg, once weekly at week 16. Cendakimab demonstrated progressive AD improvement at all doses during 16 weeks of treatment.Trial registrationClinicalTrials.gov Identifier: NCT04800315.

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A Phase 2 Randomized, Double-blind Pilot Study of IL-17-Targeting with 2 Secukinumab in Moderate-to-Severe Atopic Dermatitis

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