Targeting IL-13 with tralokinumab normalizes type 2 inflammation in atopic dermatitis both early and at 2 years.

BACKGROUND: Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)-13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2-year impacts of IL-13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate-to-severe AD. METHODS: Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long-term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay. RESULTS: Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15% worsening at Week 16 with placebo. At Week 16, tralokinumab significantly decreased type 2 serum biomarkers (CCL17/TARC, periostin, and IgE), reduced epidermal thickness versus placebo, and increased loricrin coverage versus baseline. Two years of tralokinumab treatment significantly reduced expression of genes in the Th2 (IL4R, IL31, CCL17, and CCL26), Th1 (IFNG), and Th17/Th22 (IL22, S100A7, S100A8, and S100A9) pathways as well as increased expression of epidermal differentiation and barrier genes (CLDN1 and LOR). Tralokinumab also shifted atherosclerosis signaling pathway genes (SELE, IL-37, and S100A8) toward non-lesional expression. CONCLUSION: Tralokinumab treatment improved epidermal pathology, reduced systemic markers of type 2 inflammation, and shifted expression of key AD biomarkers in skin towards non-lesional levels, further highlighting the key role of IL-13 in the pathogenesis of AD. CLINICAL TRIAL REGISTRATION: NCT03131648, NCT03587805.

Tralokinumab treatment improves the skin microbiota by increasing the microbial diversity in adults with moderate-to-severe atopic dermatitis: Analysis of microbial diversity in ECZTRA 1, a randomized controlled trial.

BACKGROUND: Atopic dermatitis (AD) is characterized by microbial dysbiosis, immune dysregulation, and an impaired skin barrier. Microbial dysbiosis in AD involves a reduction in diversity primarily driven by an increased abundance of Staphylococcus aureus. Tralokinumab, an approved treatment for adults with moderate-to-severe AD, improves the skin barrier and immune abnormalities by specifically targeting the interleukin 13 cytokine, but its impact on the skin microbiome is unknown. OBJECTIVE: To investigate how tralokinumab affects the skin microbiome by examining the lesional skin of adults with moderate-to-severe AD from the phase 3 ECZTRA 1 trial (NCT03131648). METHODS: Microbiome profiling, S aureus abundance, and biomarker data were assessed in a subset of ECZTRA 1 participants (S aureus abundance at baseline and week 16; microbiome profiling at baseline, and week 8/16; and serum sampling before dose and week 4/8/16/28/52). RESULTS: Tralokinumab treatment led to increased microbial diversity, reduced S aureus abundance, and increased abundance of the commensal coagulase-negative Staphylococci. LIMITATIONS: Limitations include a lack of S aureus abundance data at week 8, sampling site variation between participants, and possible influence from concomitant systemic antiinfectives. CONCLUSION: Our findings indicate specific targeting of the interleukin 13 cytokine with tralokinumab can directly and/or indirectly improve microbial dysbiosis seen in AD skin.

Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis: The Phase 3 ECZTRA 6 Randomized Clinical Trial.

Importance: Safe and effective long-term treatments for adolescents with moderate to severe atopic dermatitis (AD) are limited. Objective: To evaluate the efficacy and safety of interleukin-13-targeted treatment with tralokinumab monotherapy in adolescents with AD. Design, Setting, and Participants: The 52-week, randomized, double-blinded, placebo-controlled, phase 3 ECZTRA 6 trial was conducted from July 17, 2018, through March 16, 2021, at 72 centers across 10 countries in North America, Europe, Asia, and Australia. Enrolled patients were 12 to 17 years old with moderate to severe AD (Investigator's Global Assessment [IGA] score ≥3; Eczema Area and Severity Index [EASI] ≥16). Interventions: Patients were randomized (1:1:1) to tralokinumab (150 or 300 mg) or placebo every 2 weeks for 16 weeks. Patients with an IGA score of 0 (clear) or 1 (almost clear) and/or 75% or higher improvement in EASI (EASI 75) at week 16 without rescue medication received maintenance treatment; other patients switched to open-label tralokinumab, 300 mg, every 2 weeks. Main Outcomes and Measures: Primary end points at week 16 were an IGA score of 0 or 1 and/or achieving EASI 75. Key secondary end points were a reduction of Adolescent Worst Pruritus Numeric Rating Scale of 4 or more, change in SCORing AD, and change in Children's Dermatology Life Quality Index from baseline to week 16. Safety end points were the number of adverse events and serious adverse events. Results: Of 301 patients randomized, 289 comprised the full analysis set (median [IQR] age, 15.0 [13.0-16.0] years; 149 [51.6%] male). More patients receiving tralokinumab, 150 mg, (n = 98), and tralokinumab, 300 mg (n = 97), achieved an IGA score of 0 or 1 without rescue medication at week 16 (21 [21.4%] and 17 [17.5%], respectively) vs placebo (n = 94; 4 [4.3%]) (adjusted difference, 17.5% [95% CI, 8.4%-26.6%]; P < .001 and 13.8% [95% CI, 5.3%-22.3%]; P = .002, respectively). More patients receiving tralokinumab, 150 mg (28 [28.6%]), and tralokinumab, 300 mg, (27 [27.8%]) vs placebo (6 [6.4%]) achieved EASI 75 without rescue at week 16 (adjusted difference, 22.5% [95% CI, 12.4%-32.6%]; P < .001 and 22.0% [95% CI, 12.0%-32.0%]; P < .001, respectively). Proportions of patients with Adolescent Worst Pruritus Numeric Rating Scale reduction of 4 or more from baseline were greater with tralokinumab, 150 mg (23.2%), and tralokinumab, 300 (25.0%), vs placebo (3.3%), and adjusted mean changes were greater in SCORing AD with tralokinumab, 150 mg (-27.5), and tralokinumab, 300 mg (-29.1), vs placebo (-9.5) and in Children's Dermatology Life Quality Index with tralokinumab, 150 mg (-6.1), and tralokinumab, 300 mg (-6.7), vs placebo (-4.1) at week 16. At week 52, tralokinumab efficacy was maintained without rescue in more than 50% of patients meeting primary end point(s) at week 16. In the open-label phase, IGA score of 0 or 1 and EASI 75 were achieved in 33.3% and 57.8%, respectively, at week 52. Tralokinumab was well tolerated, without frequency of conjunctivitis increasing through week 52. Conclusions and Relevance: In this randomized clinical trial, tralokinumab was efficacious and well tolerated, supporting its value for treating adolescents with moderate to severe AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03526861.