AIM OF THE STUDY:Lebrikizumab monotherapy demonstrated efficacy for adults and adolescents with moderate-to-severe atopic dermatitis (AD). This study aims to evaluate the relationship between lebrikizumab serum levels and stable deep response after treatment cessation in Week 16-responder patients who maintained stable EASI 90 response post-induction up to Week 52. MATERIALS AND METHODS:Analysis was pooled from two identically designed, randomized, double-blind, placebo-controlled, phase 3 trials, ADvocate1 (NCT04146363; conducted from September 24, 2019, to May 3, 2022) and ADvocate2 (NCT04178967; conducted from October 29, 2019, to April 28, 2022). The analysis subgroup includes those patients who were Week-16 responders, have been re-randomized to receive placebo (withdrawal arm), and maintained a stable EASI 90 response for at least 80% of visits up to 52 weeks, without rescue medication. Serum lebrikizumab was measured at Weeks 4, 16, 32, and 52. RESULTS:During withdrawal, 28% of responders (17/60) maintained a stable EASI 90 response with no or minimal fluctuations, including at Week 52, without rescue medication. Mean serum lebrikizumab decreased by 92% and over 99% from Week 16 to Weeks 32 and 52, respectively (Week 16 = 92.4 μg/mL; Week 32 = 7.3 μg/mL; Week 52 = 0.15 μg/mL). CONCLUSION:Lebrikizumab demonstrated off-therapy maintenance of response in an AD patient subset for at least 38 weeks post-discontinuation.

Background: Atopic dermatitis (AD) negatively impacts the daily lives of pediatric and adolescent patients, potentially leading to poor developmental and behavioral outcomes. Understanding the real-world disease burden and the impact of AD on the patients’ quality of life (QoL) after the introduction of new treatments for AD will help identify unmet clinical needs and approaches to improve the patients' QoL. Therefore, this study aims to understand the impact of AD on daily functioning in adolescent patients. Methods: This analysis used data from the 2025 Adelphi Pediatric AD Wave II Disease Specific Programme, which links cross-sectional surveys with retrospective data from patient their consulting physicians in the United States. Primary care physicians/internal medicine specialists, dermatologists, pediatricians, and allergists reported clinical information, including current AD severity, using patient record forms. Adolescent patients with physician-reported moderate-to-severe AD at the date of consultation were included for this analysis. Patients self-reported the impact of AD on different areas of their daily life on a scale using ‘all the time’, ‘sometimes’, ‘rarely’, and ‘never’, with rarely and never combined. Descriptive analyses were conducted. Results: Among 288 patients with moderate-to-severe AD, 24% (n=70) of patients self-reported the impact of AD. The patients had a mean (SD) age of 14.9 (1.5) years, with 47% female, and of those with known data (n=46) mean (SD) disease duration was 6.1 (5.3) years. Patients reported that due to their AD, they feel embarrassed (all the time: 24%; sometimes: 51%; rarely/never: 24%), self-conscious (all the time: 29%; sometimes: 44%; rarely/never: 27%), irritated or have mood swings (all the time: 9%; sometimes: 33%; rarely/never: 59%), anxious or constant worry (all the time: 13%; sometimes: 33%; rarely/never: 54%), and overwhelmed (all the time: 17%; sometimes: 22%; rarely/never: 61%). They also reported having low self-esteem (all the time: 16%; sometimes: 34%; rarely/never: 50%), difficulty in concentrating (all the time: 13%; sometimes: 20%; rarely/never: 67%), difficulty in relaxing (all the time: 11%; sometimes: 24%; rarely/never: 64%), and have low mood or feel depressed (all the time: 9%; sometimes: 29%; rarely/never: 63%). Conclusion: These results highlight the profound impact of AD on daily life in adolescent patients with moderate-to-severe disease, with one-quarter of patients feeling embarrassed or self-conscious about their AD all the time. These disease-associated burdens occur during key developmental milestones and can impact the overall course of the patient’s life. Therefore, these findings emphasize the need to carefully assess and consider patients' QoL when discussing treatment options.

Lebrikizumab is a novel monoclonal antibody that selectively binds to interleukin (IL)-13 with high affinity and a slow dissociation rate. We assayed serum from select patients enrolled in ADvocate1 and ADvocate2 to determine the impact of lebrikizumab on circulating biomarkers and pathways relevant to atopic dermatitis (AD) and to assess the correlation between key biomarkers and clinical measures of improvement. At baseline, IL-13, CC motif chemokine ligand (CCL)13, CCL17, CCL22, total immunoglobulin (Ig)E, IL-5, and periostin were elevated in patients with moderate-to-severe AD versus healthy controls (p < 0.001). Baseline Eczema and Area Severity Index (EASI) and Investigator’s Global Assessment (IGA) scores were significantly correlated with IL-13, IL-5, CCL13, CCL22, and CCL26. Lebrikizumab induced rapid and progressive reductions in CCL13, CCL17, CCL22, and periostin at weeks 4, 16, and 52 compared with baseline (p < 0.05). AD-associated pathways linked to cytokine signaling were significantly improved at weeks 4 and 16. Improvements in EASI, IGA, and the Pruritus Numeric Rating Scale were correlated with reductions in CCL13, CCL17, CCL22, CCL26, and periostin across all time points. After multiple testing correction and adjusting for sex and race as covariates, we identified the chemokine CCL26 as a pharmacodynamic marker for lebrikizumab response at weeks 4 and 16. Selective inhibition of IL-13 with lebrikizumab monotherapy induced progressive inhibition of systemic biomarkers and pathways of type 2 inflammation, which correlated with clinical measures of improvement in patients with moderate-to-severe AD. NCT04146363 and NCT04178967. Atopic dermatitis (AD, also called atopic eczema) can cause various debilitating symptoms including red, scaly, and itchy skin that can worsen a person’s quality of life. Imbalance of normal immune system molecules, such as cytokines (substances released by cells involved in inflammation), play a central role in the development of AD. The aim of this study was to assess the impact of lebrikizumab, a treatment for AD that targets a cytokine called interleukin (IL)-13, on normalizing the levels of immune system molecules. Patients with AD were treated with lebrikizumab in two phase 3, placebo-controlled studies for 52 weeks. The results of this analysis demonstrated that numerous cytokines and other immune system molecules, including IL-13, were elevated in patients with moderate-to-severe AD at the start of the study compared with healthy controls (people who did not have AD). However, after patients with AD received treatment with lebrikizumab, rapid and progressive reductions in molecules associated with AD were observed through 52 weeks. In addition, the pathways that signal the cytokines associated with AD were significantly improved 4 and 16 weeks after receiving treatment. These improvements correlated with improved disease activity measures. Overall, this analysis demonstrated that treatment with lebrikizumab normalized several molecular pathways in patients with moderate-to-severe AD as compared with the levels of these molecules in healthy controls. These results suggest that lebrikizumab works in inhibiting IL-13 levels in patients with AD and is sufficient to improve the signs and symptoms of the disease.

Abstract Introduction In ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), lebrikizumab demonstrated statistical superiority vs. placebo in patients with moderate-to-severe atopic dermatitis (AD). The objective of this analysis is to test for correlations between improvements in clinical outcomes and reductions in AD-relevant serum biomarkers during ADvocate1 and ADvocate2. Objectives To assess the correlation between clinical measures of atopic dermatitis (AD) and AD-specific biomarkers at baseline; and to assess the correlation between clinical measures of AD and changes in AD-specific biomarkers after treatment with lebrikizumab. Methods Full details of these studies were previously reported. Protein biomarkers were determined in available serum samples from patients receiving lebrikizumab 250 mg every 2 weeks (n=72) or placebo (n=36). Tested biomarkers included: IL-13 (baseline only), CCL2, CCL4, CCL11, CCL13, CCL17 (TARC), CCL22, CCL26 (eotaxin-3), CXCL10, total IgE, IL-4, IL-5, and periostin. Baseline biomarker levels and baseline clinical endpoints were compared using a Spearman correlation. A repeated measures correlation analysis was used to characterize paired measurement of within-patient biomarker levels and clinical endpoints at baseline, week 4, week 16, and week 52. Clinical measures of AD included Investigator’s Global Assessment (IGA), Eczema Area and Severity Index (EASI), and Pruritus Numeric Rating Scale (NRS). Results At baseline, EASI score was positively correlated with IL-13, periostin, IL-5, IgE, CCL13, CCL17, CCL22 and CCL26 (correlation coefficient>0.3, p<0.05), but not IL-4. During the studies, improvements in EASI, IGA, and Pruritus NRS were each correlated with reductions in periostin, CCL13, CCL17, CCL22, and CCL26 (correlation coefficient>0.3, p<0.05). Improvement in IGA was also correlated with a reduction in IgE (correlation coefficient>0.3, p<0.05). Conclusions Clinical measures of improvement in the signs and symptoms of AD are correlated with reductions in AD biomarkers in patients treated with lebrikizumab.

Lebrikizumab is a monoclonal antibody specifically targeting interleukin (IL)-13. It demonstrated statistical superiority vs. placebo in patients with moderate-to-severe atopic dermatitis (AD) across all primary and key secondary endpoints at weeks 4 and 16 of ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). The objective of this analysis is to determine the biological pathways by which lebrikizumab treatment positively impacts clinical severity measures in patients with AD by investigating changes in serum proteins using the Olink® Explore 3072 biomarker panel. Protein biomarkers were determined in available serum samples from a subset of ADvocate1 and ADvocate2 patients who consented to biomarker sampling. Patients were dosed with lebrikizumab 250 mg every 2 weeks (n=72) or placebo (n=36) and were compared to age-, sex-, race-, and ethnically-matched healthy controls (HC, n=29). The analysis included biomarkers that were detected in at least 25% of patients. A linear model R package (limma) compared biomarker changes in patients treated with lebrikizumab vs. placebo from baseline to weeks 4 and 16. Gene set enrichment analysis was performed using a curated pathway and protein signature database for AD. The Olink biomarker data revealed that, following lebrikizumab treatment, CCL26 (eotaxin-3) was significantly reduced from baseline as early as week 4 and progressively to week 16. Several AD-related pathways were significantly changed during lebrikizumab treatment. Additionally, the level of biomarkers in lebrikizumab-treated AD patients approached HC levels as early as week 4 and continuously to week 16. This trend was not seen with placebo-treated patients. In patients with AD, selective targeting of IL-13 with lebrikizumab treatment rapidly interrupts and normalizes several biomarker pathways toward healthy control levels. Data analysis across the curated pathways demonstrated changes in both serum immune response related protein signatures as well as skin cell specific signatures from keratinocytes and fibroblasts suggesting lebrikizumab treatment improved multiple facets of disease activity.

Abstract Introduction Lebrikizumab is an interleukin (IL)-13 inhibitor that has completed phase 3 studies. It demonstrated statistical superiority vs. placebo in patients with moderate-to-severe atopic dermatitis (AD) across all primary and key secondary endpoints at week 4 and week 16 of ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). Objectives The objective of this analysis is to determine lebrikizumab’s impact on AD-relevant serum biomarkers in patients from these studies through week 16. Methods Protein biomarkers were determined in available serum samples from patients receiving lebrikizumab 250 mg every 2 weeks (n=72) or placebo (n=36) from both ADvocate1 and ADvocate2. Pre- and post-treatment biomarkers were compared to healthy controls (HC, n=30) which were age, sex, race, and ethnically matched. The analysis included biomarkers known to be elevated in AD. IL-13 was only measured at baseline because of lebrikizumab’s known interference with IL-13 measurement. Results At baseline, CCL13, CCL17, CCL22, total IgE, IL-5, IL-13, and periostin were elevated in patients with AD (p<0.001) with IL-13 measuring approximately 7-fold greater in the AD population vs. HC. In patients with AD, IL-4, CCL11, CXCL10, CCL2, and CCL4 were not elevated at baseline vs. HC. At week 4, lebrikizumab significantly reduced levels of the key type 2 biomarkers, CCL13, CCL17, and periostin vs. placebo (p<0.01) with a trend toward levels consistent with HC (within 1.5-fold). At week 16, CCL13, CCL17, and periostin levels remained consistent with HC levels with CCL13 and periostin retaining statistically significant reductions vs. placebo (p<0.01). Conclusions In sum, selective targeting of IL-13 with lebrikizumab monotherapy reduced known molecular biomarkers of systemic type 2 inflammation in patients with moderate-to-severe AD.

Abstract Missing data occur in clinical trials and have the potential to lead to biased results. Subsequently, the analytical methods for handling the missing data are important to evaluate. In atopic dermatitis (AD) trials, missing data are not handled consistently across studies. Lebrikizumab is a monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. In ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), two randomized, double-blinded, placebo-controlled Phase 3 trials evaluating the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe AD, a combined nonresponder/multiple imputation (NRI/MI) approach, was applied on the primary and key secondary endpoints. This study aims to illustrate the NRI/MI method using individual patient examples and to present Week 16 study results from ADvocate1 and ADvocate2 with NRI/MI and single imputation methods, NRI and last-observation carried forward (LOCF). In the combined NRI/MI method, data from patients after initiating rescue medication or discontinuing treatment due to lack of efficacy were imputed with NRI, and missing data for other reasons were imputed with MI, which uses a statistical model based on all available patient data to impute missing values. The MI method considers each patient’s trajectory and leverages information from other patients within the same treatment arm to impute the missing data. With NRI alone, the cause leading to the missing data is not considered and missing data for any reason are imputed as nonresponse. With LOCF, missing data are replaced with the last available measurement; LOCF assumes that the patient response would be stable over time and does not consider the reason for missing data. We determined the amount of missing data in ADvocate1 and ADvocate2, and we assessed patient-level imputed IGA scores to illustrate NRI/MI, NRI and LOCF. With these missing data handling methods, we evaluated the percentage of patients achieving the co-primary endpoints of ADvocate1 and ADvocate2: an Investigator’s Global Assessment score of 0 or 1 [IGA (0,1); clear or almost clear] with ≥2-point improvement from baseline or 75% improvement in Eczema Area and Severity Index (EASI 75) at Week 16. With the NRI/MI method, most missing data at Week 16 were imputed with NRI (ADvocate1: 73%, ADvocate2: 82%) compared with MI (ADvocate1: 27%, ADvocate2: 18%). Example imputed IGA scores based on patient-level data will be presented to demonstrate the missing data handling methods. For NRI/MI, NRI and LOCF, respectively, the percentage of patients achieving IGA 0,1 were 12.7%, 11.3% and 12.8% for placebo in ADvocate1 and 10.8%, 9.6% and 11.0% for placebo in ADvocate2; 43.1%, 41.0% and 42.4% for lebrikizumab in ADvocate1 and 33.2%, 31.3% and 33.5% for lebrikizumab in ADvocate2. The percentage of patients achieving EASI 75 were 16.2%, 14.2% and 16.3% for placebo in ADvocate1 and 18.1%, 17.1% and 19.2% for placebo in ADvocate2; 58.8%, 56.5% and 60.1% for lebrikizumab in ADvocate1 and 52.1%, 50.2% and 55.5% for lebrikizumab in ADvocate2. When using the NRI/MI method, we determined most missing data in ADvocate1 and ADvocate2 were handled with NRI. This analysis suggests that the NRI/MI method may provide a realistic estimation of response rate in ADvocate1 and ADvocate2.

The lifetime incidence of nail psoriasis in patients with psoriasis is 80–90%, with 23–27% of patients having nail psoriasis at any given time. Nail psoriasis is even more prevalent in patients with comorbid psoriatic arthritis. Complete psoriasis clearance, an achievable therapeutic goal, should ideally include the resolution of nail psoriasis. Here, we assessed simultaneous skin and nail clearance in patients with psoriasis across five head-to-head trials comparing ixekizumab with other biologics. Data were assessed in patients with moderate-to-severe psoriasis (with or without psoriatic arthritis) with nail psoriasis at baseline from the IXORA-R, IXORA-S, UNCOVER-2, UNCOVER-3, and SPIRIT-H2H trials. Ixekizumab patients received IXEQ2W to week 12 and IXEQ4W beyond week 12. PASI 100 depicted complete skin clearance, and PGA-F 0 (IXORA-R) or NAPSI 0 (all other trials) depicted complete nail clearance. Treatment comparisons were evaluated using the Cochran-Mantel-Haenszel test. Non-responder imputation was used for missing data. Ixekizumab achieved significantly greater simultaneous skin and nail complete clearance than etanercept (UNCOVER-2: p < 0.001 and UNCOVER-3: p < 0.001) at week 12, demonstrating an efficacious and rapid response. Across all five head-to-head trials, ixekizumab achieved a high rate of simultaneous skin and nail clearance (range: 28.6–45.9% of patients) by week 24 that was maintained up to week 52 (range: 40.5–51.4% of patients). Ixekizumab achieved numerically greater simultaneous complete clearance than guselkumab at week 24 (p = 0.079), but statistically significant greater simultaneous clearance compared to ustekinumab (p < 0.001) and adalimumab (p = 0.006) at week 24 and week 52 (p < 0.001 and p = 0.007, respectively). In five head-to-head trials, ixekizumab-treated patients had higher rates of simultaneous complete skin and nail clearance compared to etanercept, guselkumab, ustekinumab, and adalimumab, thereby reinforcing ixekizumab’s ability to achieve high levels of efficacy in multiple domains of psoriatic disease. NCT01474512, NCT01597245, NCT01646177, NCT03573323, NCT02561806, and NCT03151551.

Background: Ixekizumab has shown rapid onset of efficacy that is sustained through 5 years. Additionally, rapid onset of efficacy has been associated with achievement of long-term outcomes. Here we report outcomes for patients who achieved PASI 90 by Week 4.

Introduction/objective: Ixekizumab (IXE) demonstrated sustained efficacy and a consistent safety profile in psoriasis through 5 years. We evaluated effects of baseline psoriatic arthritis (PsA) on IXE efficacy and safety in moderate-to-severe psoriasis patients over 5 years in randomized, double-blinded Phase 3 trials.