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Additional long-term treatments are needed for moderate-to-severe atopic dermatitis (AD). An ongoing, open-label, 5-year extension trial, ECZTEND (NCT03587805), assesses tralokinumab plus optional topical corticosteroids in participants from previous tralokinumab parent trials (PTs) with moderate-to-severe AD.To evaluate the safety and efficacy of up to 2 years tralokinumab treatment in a post hoc interim analysis.Safety analyses included adults from completed PTs enrolled in ECZTEND, regardless of tralokinumab exposure duration. Efficacy analyses included adult participants treated with tralokinumab in ECZTEND for ≥1 year and subgroup analyses of those on tralokinumab for 2 years (1 year from PT, 1 year in ECZTEND). Primary end point was the number of adverse events with additional efficacy end points.Participants on tralokinumab had an exposure-adjusted rate of 237.8 adverse events/100 patient-years' exposure (N = 1174) in the safety analysis set. Exposure-adjusted incidence rates of common adverse events were comparable to PTs, although at lower rates. With 2 years of tralokinumab, improvements in extent and severity of AD were sustained, with Eczema Area and Severity Index (EASI-75) in 82.5% of participants (N = 345).Possible selection bias; no placebo arm; some participants experienced treatment gaps between PTs and ECZTEND.Over 2 years, tralokinumab was well tolerated and maintained long-term control of AD signs and symptoms.

Introduction: Atopic dermatitis is a common dermatologic condition that affects millions of people worldwide, and a standardized approach to treatment was published by the American Academy of Dermatology (AAD) in 2013–14. Since 2014, new FDA-approved treatment options such as dupilumab and crisaborole have changed the landscape of AD management, and future therapies such as JAK inhibitors and anti-interleukin 13 and 31 antibodies appear effective, emphasizing the need for a comprehensive review to give clinicians an updated toolbox to aid in pharmacologic management. Areas Covered: In this review, the authors explore the updated efficacy and safety data on established therapeutic options for AD including topical corticosteroids, topical calcineurin inhibitors, cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil. In addition, the authors also explore trial data and studies on dupilumab, crisaborole, omalizumab, tofacitinib, ruxolinitib, abrocitinib, baricitinib, upadacitinib, delgocitinib, nemoliuzumab, and tralokinumab. Expert opinion: The AAD guidelines must be updated in the future to include several new treatment modalities that have revolutionized the pharmacologic management of patients with AD, including dupilumab and crisaborole. The future of AD treatment is also extremely bright, as JAK inhibitors and Il-13/31 antibodies have shown convincing results in the improvement of AD patients’ lives in various trials and studies that have been examined in this paper.

The atopic march refers to the natural history of allergic disorders as they develop from infancy to childhood. Classically, the atopic march begins with atopic dermatitis (AD), followed by food allergy, advancing to asthma, allergic rhinitis (AR), and finally to the fifth member eosinophilic esophagitis. The pathogenesis of the atopic march is complex, and involves genetic, immunological, and environmental factors. T helper type 2 (Th2) lymphocytes, and epithelial cells play a key role in the pathogenesis of the diseases in the atopic march. Th2 cells secrete cytokines, such as interleukin-5 (IL-5), IL-4, and IL-13, whereas, epithelial cell injury release alarmin cytokines, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Th2 cells and alarmin cytokines play an important role in the development of eczematous skin lesions, airway inflammation and remodeling, and oesophageal mucosal inflammation. Treatment of eosinophilic asthma and associated comorbid disorders is challenging, and requires a precision targeted approach with biologics. Dupilumab is a fully humanized IgG4 monoclonal antibody to the IL-4Rα, which mediates signaling to both IL-4 and IL-13, and blocks their immunopathological effects. Dupilumab is the only biologic that has been approved for the treatment of eosinophilic asthma, AD, and eosinophilic esophagitis. In patients with eosinophilic asthma treatment with dupilumab has been shown to improve asthma control, reduce exacerbations, and improve lung function. In patients with atopic dermatitis dupilumab has been demonstrated to improve the Eczema Area Severity Index (EASI) score, Investigator’s Global Assessment (IGA) response, SCORing Atopic Dermatitis (SCORAD) score, and the Peak Pruritus Numerical Rating (PNR) scale. Lebrikizumab and Tralokinumab (anti-IL-13) failed to show the expected results for the treatment of asthma, astoundingly, in several clinical trials they have been shown to significantly improvement EASI score, IGA response, SCORAD score, PNR scale, sleep architecture, and Dermatology Life Quality Index (DLQI). They have been granted First Tract Designation, and European Commission regulatory approval, respectively. Tezepelumab (anti-TSLP) is approved for the treatment of eosinophilic asthma, and has been shown to significantly reduce exacerbations, and improve asthma control, lung function, and HLQoL. However, tezepelumab did not meet the endpoints in phase II for the treatment of AD. Keywords:Atopic March; Atopic Dermatitis; Eosinophilic Asthma; Interleukin; Dupilumab; Tralokinumab https://www.raftpubs.com/ojprm-pulmonology-and-respiratory-medicine/articles/ojprm_raft1012.php

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains challenging to treat owing to the limited response to available therapies. However, recent advances in understanding of disease mechanisms have led to the discovery of novel potential therapeutic targets and drug candidates. In addition to regulatory approval for the IL-4Ra inhibitor dupilumab, the anti-IL-13 inhibitor tralokinumab and the JAK1/2 inhibitor baricitinib in Europe, there are now more than 70 new compounds in development. This Review assesses the various strategies and novel agents currently being investigated for AD and highlights the potential for a precision medicine approach to enable prevention and more effective long-term control of this complex disease., Recent advances in understanding of the complex phenotype and mechanisms underlying atopic dermatitis (AD) have revealed multiple new potential targets for pharmacological intervention. Here, Bieber reviews therapeutic strategies and assesses the expanding pipeline for the therapy of AD, highlighting the potential for a precision medicine approach to the management of this complex disorder.

Atopic dermatitis (AD) is a common chronic inflammatory disease characterized by recurrent eczematous lesions and intense pruritus, and it can have marked negative impact on those affected. Pathophysiologically, AD is complex with genetic predisposition and environmental provocation being important contributors. Mechanistically these can promote epidermal barrier dysfunction, skin microbiome abnormalities and a skewed immune response which is predominantly type-2 immunity-based. Our increased understanding of the immunological processes involved highlight a key role for interleukin-13 (IL-13). This mini-review evaluates tralokinumab, a high-affinity monoclonal antibody that specifically binds to and inhibits IL-13. Based on dose-finding study results, tralokinumab 300 mg every two weeks (Q2W) subcutaneously (SC) was investigated in three pivotal phase III clinical trials in adults with moderate-to-severe AD not adequately controlled on topical corticosteroids alone. Tralokinumab was significantly superior to placebo regarding the proportion of patients achieving IGA 0/1 and EASI-75 at week 16 (primary endpoints), as well as improving scores for worst daily pruritus, Dermatology Life Quality Index (DLQI), and Scoring Atopic Dermatitis (SCORAD) (secondary endpoints). The week 16 response was sustained during follow-up, and treatment with tralokinumab was found to be well-tolerated with an overall frequency and severity of adverse events comparable to placebo.

Background Tralokinumab is a fully human monoclonal antibody that neutralizes the activity of interleukin-13, a key pathogenic driver of atopic dermatitis (AD). Clinical trials including adults with moderate-to-severe AD, of up to 52 weeks’ duration, showed tralokinumab was efficacious and well tolerated. Objectives To characterize the safety profile of tralokinumab for the treatment of moderate-to-severe AD. Methods Safety and laboratory measures were assessed in pooled analyses of phase II and III placebo-controlled clinical trials of tralokinumab in moderate-to-severe AD (NCT02347176, NCT03562377, NCT03131648, NCT03160885, NCT03363854). Results In total, 2285 patients were randomized in the initial treatment periods up to 16 weeks (1605 tralokinumab, 680 placebo). The frequencies of any adverse event (AE) were 65·7% for tralokinumab and 67·2% for placebo. The respective rates were 640 and 678 events per 100 patient-years of exposure (ep100PYE); rate ratio 1·0, 95% confidence interval (CI) 0·9–1·1. Serious AEs occurred in 2·1% of patients with tralokinumab and 2·8% with placebo (7·4 and 11·9 ep100PYE; rate ratio 0·7, 95% CI 0·4–1·2). The most common AEs occurring at a higher frequency and rate with tralokinumab vs. placebo were: viral upper respiratory tract infection (15·7% vs. 12·2%; 65·1 vs. 53·5 ep100PYE); upper respiratory tract infection (5·6% vs. 4·8%; 20·8 vs. 18·5 ep100PYE); conjunctivitis (5·4% vs. 1·9%; 21·0 vs. 6·9 ep100PYE); and injection-site reaction (3·5% vs. 0·3%; 22·9 vs. 4·0 ep100PYE). Some events in safety areas of interest occurred at a lower frequency and rate with tralokinumab vs. placebo: skin infections requiring systemic treatment (2·6% vs. 5·5%; 9·7 vs. 22·8 ep100PYE), eczema herpeticum (0·3% vs. 1·5%; 1·2 vs. 5·2 ep100PYE), opportunistic infections (3·4% vs. 4·9%; 13·0 vs. 21·3 ep100PYE) and serious infections (0·4% vs. 1·1%; 1·3 vs. 3·7 ep100PYE). AEs did not increase with continued maintenance and open-label treatment, including rates of common or serious AEs and AEs leading to study drug discontinuation. No clinically meaningful changes in mean laboratory measures were observed with treatment up to 1 year. Conclusions Across the AD population pool from five clinical trials, tralokinumab was well tolerated, with consistent safety findings during treatment of patients with moderate-to-severe AD. The safety profile during prolonged tralokinumab treatment was consistent with that during the initial treatment period; the frequency of events did not increase over time. What is already known about this topic? Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key cytokine driving skin inflammation and epidermal barrier dysfunction in atopic dermatitis (AD).In clinical trials in moderate-to-severe AD, tralokinumab provided significant and early improvements in the extent and severity of AD and was well tolerated, with an overall safety profile comparable with placebo over 52 weeks. What does this study add? We report the frequency and rate of adverse events (AEs) from pooled observations of over 2000 patients from five phase II and phase III placebo-controlled clinical trials of tralokinumab in moderate-to-severe AD.During initial treatment up to 16 weeks, the frequencies of any AE and of serious AEs were similar for tralokinumab and placebo. AE rates did not increase with continued treatment up to 52 weeks.Common AEs occurring more frequently with tralokinumab vs. placebo were viral and upper respiratory tract infection, conjunctivitis and injection-site reaction. Some events occurred at a lower frequency and rate with tralokinumab vs. placebo, such as skin infections requiring systemic treatment, eczema herpeticum and opportunistic and serious infections.No clinically meaningful changes in mean laboratory measures were observed.

Atopic dermatitis (AD) is a common inflammatory dermatologic disease clinically characterized by intense itch, recurrent eczematous lesions, and a chronic or relapsing disease course. Mild-to-moderate AD can be controlled by using moisturizers and topical immunomodulators such as topical corticosteroids and calcineurin inhibitors. If topical therapies fail, phototherapy and systemic immunosuppressant therapies, such as ciclosporin, methotrexate, and azathioprine, can be considered. However, relapse and side effects could still occur. The pathogenesis of AD involves epidermal barrier dysfunction, skin microbiome abnormalities, and cutaneous inflammation. Inflammatory mediators, such as interleukin (IL)-4, IL-13, IL-31, IL-33, IL-17, IL-23, and thymic stromal lymphopoietin, are involved in AD development. Therefore, a series of biological agents targeting these cytokines are promising approaches for treating AD. Dupilumab is the first biological agent approved for the treatment of AD in patients aged 6 years and older in the United States. Tralokinumab, lebrikizumab, and nemolizumab have also been confirmed to have significant efficacy against AD in phase III or IIb clinical trials. Also, fezakinumab was effective in severe AD patients in a phase IIa trial. However, phase II trials of ustekinumab, tezepelumab, etokimab, secukinumab, and omalizumab have failed to meet their primary endpoints. Phase II trials of GBR 830 and KHK 4083 are ongoing. In general, further studies are needed to explore new therapeutic targets and improve the efficacy of biological agents.

BackgroundSeveral biologics for atopic dermatitis (AD) have demonstrated good efficacy in clinical trials, but with a substantial proportion of patients being identified as poor responders. This study aims to understand the pathophysiological backgrounds of patient variability in drug response, especially for dupilumab, and to identify promising drug targets in dupilumab poor responders.MethodsWe conducted model-based meta-analysis of recent clinical trials of AD biologics and developed a mathematical model that reproduces reported clinical efficacies for nine biological drugs (dupilumab, lebrikizumab, tralokinumab, secukinumab, fezakinumab, nemolizumab, tezepelumab, GBR 830, and recombinant interferon-gamma) by describing systems-level AD pathogenesis. Using this model, we simulated the clinical efficacy of hypothetical therapies on virtual patients.ResultsOur model reproduced reported time courses of %improved EASI and EASI-75 of the nine drugs. The global sensitivity analysis and model simulation indicated the baseline level of IL-13 could stratify dupilumab good responders. Model simulation on the efficacies of hypothetical therapies revealed that simultaneous inhibition of IL-13 and IL-22 was effective, whereas application of the nine biologic drugs was ineffective, for dupilumab poor responders (EASI-75 at 24 weeks: 21.6% vs. max. 1.9%).ConclusionOur model identified IL-13 as a potential predictive biomarker to stratify dupilumab good responders, and simultaneous inhibition of IL-13 and IL-22 as a promising drug therapy for dupilumab poor responders. This model will serve as a computational platform for model-informed drug development for precision medicine, as it allows evaluation of the effects of new potential drug targets and the mechanisms behind patient variability in drug response.

Background: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide. AD pathogenesis is multifactorial, involving environmental and genetic factors. IL-13 stands out as one of the main cytokines in the pathophysiology of AD. Currently, dupilumab, which targets both IL-4 and IL-13 signalling, is the only biologic agent approved for the treatment of moderate-to-severe AD. New targeted biologic therapies are being developed, such as lebrikizumab and tralokinumab, two selective IL-13 inhibitors. This article reviews the role of IL-13 in AD and the most recent data on lebrikizumab and tralokinumab. Methods: A narrative review of the literature was written after retrieving relevant articles in the PubMed database (up until December 2020) using the following keywords present in the title, abstract or body: atopic dermatitis; interleukin 13; IL-13; tralokinumab; lebrikizumab, biologic therapy. Discussion: A phase IIb trial showed that all three dosing regimens evaluated (lebrikizumab 125 mg every 4 weeks (Q4W), 250 mg Q4W or 250 mg every 2 weeks) achieved rapid and dose-dependent efficacy concerning the signs and symptoms of AD, with a statistically significant improvement, at week 16. Tralokinumab was studied in three phase III clinical trials and reached its primary endpoints at week 16 (ECZTRA 1 and 2 in monotherapy and ECZTRA 3 with concomitant topical corticosteroids), with response maintained over time. Both lebrikizumab and tralokinumab exhibited good safety profiles in AD trials, with adverse effects usually being comparable between the control and treatment groups. Conclusion: The evidence supports the hypothesis that selective antagonism of IL-13 is sufficient to control AD, providing an improvement in the patient’s quality of life. Therefore, the development of lebrikizumab and tralokinumab represents a new and exciting phase in the management of AD.

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by intense pruritus and recurrent eczematous lesions that significantly impair quality of life. It is a heterogeneous disease affecting both children and adults. The treatment of moderate-to-severe forms of AD is challenging, as topical corticosteroids are often insufficient to achieve disease control or inappropriate and off-label use of immunosuppressants may have significant undesirable side effects. The development of targeted biologic therapies specifically for AD is thus highly desirable. Dupilumab is the only biologic therapy that is Food and Drug Administration approved for the treatment of moderate-to-severe AD in patients 6 years and older, with consistent long-term efficacy and safety trial data. In this article, we review the mechanisms, safety, and efficacy of dupilumab from recent clinical trials, and we review the current data, mechanism of action, clinical efficacy, and limitations of new biologics currently in phase 2 and 3 clinical trials (lebrikizumab, tralokinumab, nemolizumab, tezepelumab, and ISB 830).

Background Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD).Objectives To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate-to-severe AD who were candidates for systemic therapy.Methods This was a double-blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator's Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.Results At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38 center dot 9% vs. 26 center dot 2% [difference (95% confidence interval): 12 center dot 4% (2 center dot 9-21 center dot 9); P = 0 center dot 015] and EASI 75: 56 center dot 0% vs. 35 center dot 7% [20 center dot 2% (9 center dot 8-30 center dot 6); P < 0 center dot 001]. Of the patients who were tralokinumab responders at week 16, 89 center dot 6% and 92 center dot 5% of those treated with tralokinumab Q2W and 77 center dot 6% and 90 center dot 8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30 center dot 5% and 55 center dot 8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups.Conclusions Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate-to-severe AD.

The efficacy and safety of tralokinumab, a fully human monoclonal antibody that specifically neutralizes interleukin-13, plus topical corticosteroids (TCS) as needed were evaluated over 32 weeks in the phase III ECZTRA 3 trial. Significantly more tralokinumab- versus placebo-treated patients achieved the primary endpoints of Investigator's Global Assessment (IGA) score of 0/1 and 75% improvement in Eczema Area and Severity Index (EASI-75) and all confirmatory endpoints at Week 16.This post hoc analysis investigated the impact of tralokinumab plus TCS on atopic dermatitis (AD) severity, symptoms, and health-related quality of life (QoL) over the entire 32-week treatment period of ECZTRA 3, including all patients initiated on tralokinumab irrespective of the response achieved at Week 16.Patients were randomized 2:1 to receive subcutaneous tralokinumab 300 mg or placebo every 2 weeks (q2w) with TCS as needed for an initial 16 weeks. At Week 16, patients who achieved the clinical response criteria (IGA 0/1 and/or EASI-75) with tralokinumab were re-randomized 1:1 to tralokinumab q2w or every 4 weeks (q4w), with TCS as needed, for another 16 weeks. Patients not achieving the clinical response criteria with tralokinumab received tralokinumab q2w plus TCS from Week 16. All patients randomized to tralokinumab in the initial treatment period were pooled for this analysis, irrespective of response at Week 16 or dosing regimen beyond Week 16.Continued tralokinumab (q2w, N = 164; q4w, N = 69) plus TCS treatment provided progressive improvements from Week 16 onwards in AD signs, with 70.2% (177/252) of patients achieving EASI-75 and 50.4% (127/252) achieving EASI-90 at Week 32. Improvements in patient-reported outcomes were observed within the first few weeks of tralokinumab q2w plus TCS treatment and were sustained throughout the 32-week period. At Week 32, patients initiated on tralokinumab q2w plus TCS achieved a relative improvement versus baseline of 70.8% (standard error (SE), 2.4) in eczema-related sleep interference numeric rating scale (NRS) and 66.8% (SE, 3.1) in Dermatology Life Quality Index (DLQI). Mean TCS use during Weeks 16-32 ranged from 9.2 to 13.6 g (SE, 1.2-2.0) q2w. Most patients (89.9% (222/247)) initiated on tralokinumab q2w plus TCS achieved a meaningful improvement in at least one of the three disease domains, including AD signs (EASI-50), symptoms (pruritus NRS improvement ≥ 3), and QoL (DLQI improvement ≥ 4) at Week 16. Of patients initiated on tralokinumab q2w plus TCS, 53.4% (132/247) achieved a clinically meaningful improvement in all three domains at Week 16 (vs. placebo, 28.5% (35/123); p 0.001).Continued tralokinumab treatment plus TCS as needed provides progressive and sustained improvements in AD signs, symptoms, and health-related QoL over 32 weeks.NCT03363854; study start date: 22 February 2018; primary completion date: 8 March 2019; study completion date: 26 September 2019.Atopic dermatitis (AD) is a chronic inflammatory disease that causes excessively dry and itchy skin that can negatively impact sleep and overall quality of life for patients. Topical corticosteroids (TCS) are the most common medication used for AD, but they are not able to control the most severe cases. Tralokinumab is a treatment injected under the skin that targets an immune messenger protein called interleukin 13, which plays a key role in driving the signs and symptoms of AD. The ECZTRA 3 clinical trial, funded by LEO Pharma, compared the use of TCS as needed with either tralokinumab or placebo in over 350 adult patients with moderate-to-severe AD over a 32-week period. After 16 weeks, more patients taking tralokinumab plus TCS had clear or almost clear skin compared with patients taking placebo plus TCS. Patients taking tralokinumab also used less TCS than patients taking placebo. In new analyses presented here, we found that the proportion of patients with clear or almost clear skin continued to increase with on-going treatment from Week 16 to Week 32. Tralokinumab plus TCS treatment also led to clinically meaningful improvements in outcomes important to patients, including itch, sleep, and quality of life. Improvements occurred early, within the first few weeks of therapy, and lasted through Week 32. Our assessment of multiple outcomes over time clearly demonstrates the positive impact of tralokinumab on different aspects of AD.

Dupilumab, a monoclonal antibody against the common receptor of interleukin (IL)-4 and IL-13, was the first biologic therapy approved in Canada for treatment of moderate-to-severe atopic dermatitis (AD). While it is considered safe and effective, dupilumab is not universally effective and 8%-38% of patients develop conjunctivitis, while some patients develop head and neck dermatitis. Thus, new therapeutic options are warranted. While both IL-4 and IL-13 play important roles in the pathogenesis of AD, it has been recently demonstrated that IL-13 is the primary upregulated cytokine in AD skin biopsy samples. A placebo-controlled phase 2b clinical trial evaluating the efficacy and safety of lebrikizumab, an IL-13 inhibitor, in AD demonstrated that, at 16 weeks, Eczema Area and Severity Index (EASI) 75 and Investigator’s Global Assessment (IGA) 0/1 were achieved by 60.6% and 44.6% of patients taking lebrikizumab at its highest dose (vs 24.3% and 15.3% of patients taking placebo, respectively). Moreover, treatment with lebrikizumab was associated with rapid improvement of pruritus and low rates of conjunctivitis (1.4%-3.8%). Another IL-13 monoclonal antibody, tralokinumab, was evaluated for safety and efficacy in moderate-to-severe AD. By week 12, among adults receiving 300 mg tralokinumab, 42.5% achieved EASI-75 and 26.7% achieved IGA 0/1 score (vs 15.5% and 11.8% in the placebo group, respectively). Both lebrikizumab and tralokinumab demonstrated acceptable safety profiles in AD (and non-AD) trials with adverse events often being comparable between treatment and control groups. Thus, IL-13 inhibitors may provide a safe and effective treatment alternative for patients with moderate-to-severe AD.

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by erythematous lesions, pruritus, and a skin barrier defect. Long-term treatment in children is challenging, as there is only one Food and Drug Administration-approved systemic medication. Current treatments may have limited efficacy or serious side effects in children. With a deeper understanding of AD pathogenesis and the advent of target-specific medications, several biologics are undergoing clinical trials for future use in pediatric AD. Areas covered: This article reviews the current and emerging biologic therapies for treatment of pediatric AD. It allows for comprehensive comparison of medications and their clinical trials to help providers optimize patient treatment plans while providing expert insight into upcoming advancements in the treatment of pediatric AD. Expert opinion: Treating pediatric AD is complicated given the variety of disease severity, psychosocial impact, and relative lack of approved medications for severe disease. Given the safety data on dupilumab, newer biologics will likely be second-line. We do not yet understand the long-term impact of newer biologics on an immature immune system, nor do we fully understand their risks and toxicities. We should proceed optimistically, yet cautiously, with the study of biologics in children.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that has become a global health problem. The pathophysiology of AD includes both skin barrier and immune abnormalities, with type 2 immune deviation central to several clinical phenotypes and underlying endotypes. Recognition of the persistent nature and systemic aspects of AD provides a rationale for treatment with a biologic. Dupilumab has been approved for patients 6 years of age and older with moderate to severe AD. Monoclonal antibodies are in phase 3 trials and may become part of a precision medicine approach to AD.

A variety of skin diseases are associated with impaired barrier function. The crucial pillars in therapy of previously mentioned conditions are avoidance of triggers, skin protection and individually adapted medical therapy. Until recently, besides of topical corticosteroids, the treatment options were limited. However, a variety of new therapies of skin barrier-related skin diseases became available over the last years. Our goal was to investigate new findings and treatment options in skin diseases with barrier dysfunction, emphasizing on contact dermatitis, hand eczema and atopic dermatitis. Besides of new relatively nonspecific anti-inflammatory therapies, such as topical calcineurin inhibitors, crisaborole and delgocitinib, also highly specific targeted treatments are currently under investigation, and some already available on the market. Worth mentioning is dupilumab, the first biologic drug approved for treatment of atopic dermatitis, but used also off-label for treatment of hand eczema. There are ongoing trials investigating tralokinumab and lebrikizumab for atopic dermatitis therapy. Anti-IL-31 monoclonal antibodies were reported to improve atopic dermatitis-related pruritus. This review focuses on new findings and treatment options for skin diseases with barrier dysfunction regarding their efficacy, safety profile and mechanism of action.

This review forms part of an annual update series on atopic eczema (AE), where systematic reviews (SRs) are gathered and appraised to provide a summary of key recent research findings. The focus of this article is systemic therapies used in AE, while a review on prevention and topical therapies is provided in Part 1. In total, 17 SRs on various systemic treatments used in AE were first published or indexed in 2018. There is a lack of evidence to support vitamin D supplementation, montelukast and naltrexone in AE treatment. The adverse effects of systemic corticosteroids are the main barrier to their use, and there is also a lack of data to determine the optimal delivery and duration of treatment with them. Of other immunosuppressants, ciclosporin has the most robust evidence of efficacy. Biologic therapies in AE treatment are being increasingly investigated, and to date, the greatest quantity of data and evidence of efficacy relates to dupilumab. The most commonly reported adverse effects are injection-site reactions and conjunctivitis. Other biologics showing some evidence of efficacy include nemolizumab, lebrikizumab and tralokinumab, although further data are needed. There are currently insufficient data on oral small molecules, including Janus kinase inhibitors, in the treatment of AE. A Cochrane review on probiotics showed no significant benefit, and SRs and meta-analyses on complementary and alternative medicines, including probiotics, in paediatric AE demonstrated significant heterogeneity, thereby limiting their interpretation. This summary of recent SRs provides up-to-date evidence for clinicians on systemic therapies in AE.

Biologic medications are recent advances that have clinical significance in the treatment of moderate-to-severe AD. A systemic literature review was performed to examine the efficacy and safety of biologic therapies currently in phase II and phase III of clinical trials for moderate-to-severe AD. Our team searched the databases, PubMed, Google Scholar, and ClinicalTrials.gov, on September 2019 for studies pertaining to the use of biologic drugs in AD. Key words included each drug (lebrikizumab, tralokinumab, fezakinumab, etokimab, nemolizumab, tezepelumab, and GBR 830) or 'biologic drugs' or 'immunotherapies' combined with 'atopic dermatitis.' References within retrieved articles were also reviewed to identify potentially missed studies. A total of 19 articles were included in this review. Lebrikizumab, tralokinumab, fezakinumab, nemolizumab, and GBR 830 lead to statistically significant improvements in disease severity and multiple endpoint outcome scores. Tezepelumab and etokimab, however, did not demonstrate statistically significant changes in primary outcome endpoints. Further assessment of tezepelumab and etokimab are needed to assess their safety and efficacy in patients with moderate-to-severe AD. Tralokinumab, lebrikizumab, fezakinumab, nemolizumab, and GBR 830 are effective treatment options for adults with moderate-to-severe AD, but further large-scale studies are needed to confirm their efficacy as monotherapy in children with moderate-to-severe AD.

Atopic dermatitis is the most common inflammatory skin disease and up to 20% of cases can be classified as moderate to severe. Our understanding of the pathogenesis of this disease has improved in recent years. The process is primarily driven by the Th2 pathway, but with significant contributions from the Th22 pathway, the Th1 and Th17 axes, epidermal barrier dysfunction, pruritus, and JAK/STAT signaling. Advances in our understanding of the pathogenesis of atopic dermatitis have led to the development of new systemic treatments. Of particular note are biologic agents targeting IL-4 and IL-13 (e. g., dupilumab, tralokinumab, and lebrikizumab) and small molecules, such as JAK inhibitors (e. g., baricitinib, upadacitinib, and abrocitinib). Novel topical treatments include phosphodiesterase 4 and JAK/STAT inhibitors. In this article, we review the main advances in the treatment of atopic dermatitis. Characterization of clinical and molecular phenotypes with a key pathogenic role is essential for driving these advances.

A 23-year-old male presented with three months of worsening blepharoconjunctivitis and dermatitis on his eyelids with a background of at least five years of allergic conjunctivitis (Figure 1). The patient was taking tralokinumab for three years for severe atopic dermatitis (AD), low dose isotretinoin for acne vulgaris and had asthma and allergic rhinitis. The patient trialled over-the-counter ophthalmic lubricants, including preservative-free hypromellose, carmellose, hyaluronate, and autologous serum eye drops in addition to olopatidine but developed topical intolerance.

BACKGROUND Patients with severe atopic dermatitis (AD) not controlled with topical therapy have limited treatment options. Cyclosporine A (CSA) is a commonly used, broad immunosuppressant in AD, but treatment with CSA requires monitoring for potentially serious adverse effects. In a previous Phase 3 trial, tralokinumab plus topical corticosteroids (TCS) as needed provided early and sustained improvements in AD signs and symptoms. OBJECTIVES To evaluate the efficacy and safety of tralokinumab plus TCS in adult patients with severe AD, whose disease was not adequately controlled with or who had contraindications to oral CSA. METHODS In this 26-week, multicenter, parallel, randomized, double-blind, placebo-controlled, Phase 3 trial, European adults with severe AD were randomized 1:1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks plus TCS as needed. The primary endpoint was a 75% improvement in Eczema Area and Severity Index (EASI-75) at Week 16. RESULTS 277 patients were randomized. At Week 16, more patients treated with tralokinumab plus TCS vs placebo plus TCS achieved EASI-75 (64.2% vs 50.5%; difference [95% confidence interval] 14.1% [2.5-25.7]; P=0.018), which increased further up to Week 26. Improvements in AD severity were accompanied by early improvements in patient-reported outcomes, including Dermatology Life Quality Index, Patient-Oriented Eczema Measure, pruritus, and sleep interference. Tralokinumab plus TCS also showed a higher EASI-75 response at Week 16 among patients who had previously failed CSA therapy vs placebo plus TCS (57% vs 41%). The overall incidence of adverse events was similar between treatment arms. CONCLUSIONS Tralokinumab 300 mg plus TCS as needed was effective and well tolerated in patients with severe AD not adequately controlled with, or who had contraindications to, oral CSA.

Background Tralokinumab, a fully human immunoglobulin G4 monoclonal antibody that specifically binds to the interleukin-13 cytokine with high affinity, effectively reduces moderate-to-severe atopic dermatitis when given every 2 weeks. The incidence of conjunctivitis is elevated compared to placebo, but severity and etiology have not been examined. Objective To analyze conjunctivitis data recorded in five randomized, placebo-controlled trials of tralokinumab in adult patients with moderate-to-severe atopic dermatitis. Methods Overall, 2285 adults with atopic dermatitis were studied up to 16 weeks. Cochran-Mantel-Haenszel weights were applied to calculate adjusted adverse-event incidences. Results Incidence of conjunctivitis was higher (7.5%) with tralokinumab compared to placebo (3.2%). Most events were mild or moderate in severity and 78.6% and 73.9% of events resolved during the trial in the tralokinumab and placebo groups, respectively. Two (1.4%) events led to permanent discontinuation of tralokinumab. An increased incidence of conjunctivitis, regardless of treatment group, was associated with more severe baseline atopic dermatitis, and history of allergic conjunctivitis/atopic keratoconjunctivitis, as well as the number of atopic comorbidities. Limitation This analysis reports events up to Week 16 only, with limited confirmation of conjunctivitis and its etiology by an ophthalmologist and insufficient reporting of ophthalmic treatments. Conclusions Treatment with tralokinumab was associated with increased incidence of conjunctivitis compared to placebo, but these cases were mostly mild and transient.

Tralokinumab (Adtralza®) is a human IgG4 monoclonal antibody being developed by LEO Pharma for the treatment of atopic dermatitis. The T-helper cytokine IL-13 is thought to play a key role in the pathogenesis of atopic dermatitis. Tralokinumab specifically binds with high affinity to IL-13, inhibiting its interaction with the IL-13 receptor and thereby neutralising the biological activity of the cytokine. Based on results from the ECZTRA 1-3 trials, tralokinumab has recently been approved in the EU for the treatment of moderate-to-severe atopic dermatitis in adult patients who are candidates for systemic therapy. This article summarizes the milestones in the development of tralokinumab leading to this first approval for atopic dermatitis. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01583-1.

Despite sharing interleukin‐4 receptor α (IL‐4Rα) in their signaling cascades, IL‐4 and IL‐13 have different functions in atopic inflammation. IL‐13 preferentially participates in the peripheral tissues because tissue‐resident group 2 innate lymphoid cells produce IL‐13 but not IL‐4. In contrast, lymph node T follicular helper cells express IL‐4 but not IL‐13 to regulate B‐cell immunity. The dominant microenvironment of IL‐13 is evident in the lesional skin of atopic dermatitis (AD). The IL‐13‐rich local milieu causes barrier dysfunction by down‐regulating the OVOL1–filaggrin (FLG) axis and up‐regulating the periostin–IL‐24 axis. Genome‐wide association studies also point to the crucial involvement of the IL‐13, OVOL1 and FLG genes in the pathogenesis of AD. Biologics targeting IL‐13, such as the anti‐IL‐4Rα antibody dupilumab and the anti‐IL‐13 antibody tralokinumab, successfully improve AD lesions and further highlight the importance of IL‐13 in the pathogenesis of AD.

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by pruritus, inflammatory erythematous skin lesions, and skin-barrier defect. Current mainstay treatments of emollients, steroids, calcineurin inhibitors, and immunosuppressants have limited efficacy and potentially serious side effects. Recent advances and understanding of the pathogenesis of AD have resulted in new therapies that target specific pathways with increased efficacy and the potential for less systemic side effects. New FDA-approved therapies for AD are crisaborole and dupilumab. The JAK-STAT inhibitors (baricitinib, upadacitinib, PF-04965842, ASN002, tofacitinib, ruxolitinib, and delgocitinib) have the most promising results of the emerging therapies. Other drugs with potential include the aryl hydrocarbon receptor modulating agent tapinarof, the IL-4/IL-13 antagonists lebrikizumab and tralokinumab, and the IL-31Rα antagonist nemolizumab. In this review, new and emerging AD therapies will be discussed along with their mechanisms of action and their potential based on clinical study data.

Atopic dermatitis (AD) is a common inflammatory skin condition that has traditionally been considered a paradigmatic type 2 immunity (T2)-driven disease. Interleukin (IL)-4 and IL-13 are both pivotal cytokines involved in the generation of allergic diseases. Currently, besides dupilumab, which blocks the binding of both cytokines to their receptors, a number of new pharmacologic entities have been designed to target both T2 cytokines and/or their receptors and/or receptor-associated signal transduction machinery such as Janus kinases. Recently, IL-13 has been suggested to be the key T2 cytokine driving inflammation in the periphery, while IL-4 may merely have a central effect. There is increasing evidence that this concept holds true for the inflammatory reaction underlying AD, where IL-13 is overexpressed locally and has a significant impact on skin biology, including the recruitment of inflammatory cells, the alteration of the skin microbiome, and the decrease in the epidermal barrier function. This review provides an update on the role of IL-13 in AD and discusses the different strategies aimed at interfering with its biologic activity as well as their potential in a precision medicine approach in the management of AD.

Purpose of review Until recently there have been limited options for systemic therapy in atopic dermatitis, which is unresponsive to topical treatments. However, the last few years have seen a rapid progression in this field. The purpose of this review is to summarise some of the recent literature and ongoing studies in the field of biologicals in atopic dermatitis. Recent findings Dupilumab has been shown to be effective in moderate to severe atopic dermatitis and is now licensed in the USA and Europe. Tralokinumab is currently under review by the Food and Drug Administration and the European Medicines agency. Phase 2 and 3 studies are taking place with other biological therapies. There is increasing evidence for the use of biologicals in children and for their role in multisystem disease. Summary The recent breakthroughs in treatment represent an opportunity to resolve an unmet need; the management of atopic dermatitis which is unresponsive to topical therapy.

Atopic dermatitis (AD) is a prevalent inflammatory skin disease. IL-13 contributes significantly to the pathogenesis of AD in several ways, and beneficial results have been demonstrated with anti-IL-13 therapies. Currently, the only monoclonal antibody (mAb) approved for AD treatment is dupilumab, an antagonist of the IL-4 receptor alpha (IL-4Rα) subunit common to IL-4 and IL-13 receptors, but clinical trials evaluating anti-IL-13 mAbs are providing promising results. The topics of this review will be mAbs targeting IL-13 for the treatment of AD such as dupilumab, tralokinumab and lebrikizumab, small molecules targeting the IL-13 pathway, and a brief explanation of therapies targeting IL-13 for the treatment of other skin diseases.

Lay abstract Atopic dermatitis (AD) is a common inflammatory skin disease. IL-13 is a biologically active molecule that plays a central role in the inflammation underpinning the clinical manifestations of AD, such as itch and skin lesions. Beneficial results have been demonstrated with therapies directed against IL-13; among them, only dupilumab, which blocks the transmission of signals originated by binding of IL-13 and IL-4 to their receptors, has been approved for treatment of AD. Studies evaluating specific anti-IL-13 therapies are providing promising results. The subject of this review will be drugs directed against IL-13 or downstream transmission of the signal following its receptor binding that have been approved or are intended for the treatment of AD and other skin diseases. Atopic dermatitis (AD) is a prevalent inflammatory skin disease. IL-13 contributes significantly to the pathogenesis of AD in several ways, and beneficial results have been demonstrated with anti-IL-13 therapies. Currently, the only monoclonal antibody (mAb) approved for AD treatment is dupilumab, an antagonist of the IL-4 receptor alpha (IL-4R alpha) subunit common to IL-4 and IL-13 receptors, but clinical trials evaluating anti-IL-13 mAbs are providing promising results. The topics of this review will be mAbs targeting IL-13 for the treatment of AD such as dupilumab, tralokinumab and lebrikizumab, small molecules targeting the IL-13 pathway, and a brief explanation of therapies targeting IL-13 for the treatment of other skin diseases.

Introduction: Atopic dermatitis (AD) is a heterogeneous, chronic, inflammatory skin disease with a non-negligible prevalence at present. Its pathogenesis is complex, but mainly characterized by constitutive T helper type 2 (Th2)-cell activation. Systemic therapies for moderate-to-severe AD can be associated with adverse events that encumber their satisfactory long-term use. Several drugs targeting relevant molecules in the immunopathogenesis of AD have been approved or are under clinical development for the treatment of moderate to severe AD. To elaborate this review, literature searches were performed in PubMed on 29 August 2020. Areas covered: This narrative literature review is focused on the pivotal role of IL-13 in the immunopathogenesis of AD and other skin diseases. Expert opinion: Dupilumab has demonstrated the central role of IL-13 and IL-4 in the pathogenesis of AD, asthma, and other diseases in the atopic spectrum. In addition, phase III randomized clinical trials (RCTs) evaluating specific blockade of IL-13 with tralokinumab for treatment of AD also demonstrated favorable results, and phase III RCT evaluating lebrikizumab are ongoing. The role of IL-13 in other skin diseases should be further investigated.

Background Atopic dermatitis (AD) is a chronic inflammatory skin disease. Interleukin (IL) 13 is a type 2 cytokine that is key to the inflammation underlying AD. Tralokinumab is a first-in-class, fully human, monoclonal antibody that specifically binds with high affinity to IL-13, neutralizing it in AD. Immunomodulatory treatments may impair vaccine-induced immune responses. Objective Assess the immune responses to standard vaccines in adults with moderate-to-severe AD who are undergoing treatment with tralokinumab. Methods ECZema TRAlokinumab Trial No. 5 (ECZTRA 5; NCT03562377 ) was a phase 2, double-blind, randomized, placebo-controlled trial taking place over 30 weeks. Eligible adults were randomized 1:1, with 107 patients receiving tralokinumab 300 mg and 108 patients receiving a placebo every 2 weeks for 16 weeks. All patients received Tdap (tetanus/diphtheria/pertussis) and meningococcal vaccines at week 12. The primary end points were positive antitetanus and antimeningococcal responses between weeks 12 and 16 (noninferiority margin, −25%; responder, >3-fold increase in IgG). Results The noninferiority of tralokinumab versus placebo for immune response to Tdap (91.9% vs 96.1%) and meningococcal (86.0% vs 84.2%) vaccines was demonstrated at week 16. During treatment, the rates of adverse events were lower for tralokinumab than for the placebo, with most events being mild or moderate. Limitations Responses to other vaccines (including influenza) were not examined. Conclusions Treatment with tralokinumab 300 mg every 2 weeks did not affect immune responses to Tdap and meningococcal vaccines. Treatment was well tolerated when administered concomitantly with the vaccines and demonstrated a safety profile comparable to phase 3 trials.

Summary Background Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD). Objectives To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy. Methods This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator’s Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks. Results At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8–30·6); P, What is already known about this topic? Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.In clinical practice, biologics are commonly initiated as add‐on therapy to topical corticosteroids (TCS).Tralokinumab is a fully human monoclonal antibody that binds specifically to the IL‐13 cytokine with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.Tralokinumab combined with TCS showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD. What does this study add? This is the first phase III trial evaluating a targeted anti‐IL‐13 biologic in combination with TCS.These data demonstrate that tralokinumab plus TCS can achieve significant improvements in AD signs and symptoms and quality of life, as well as exert a steroid‐sparing effect.Response with tralokinumab in combination with TCS was maintained over 32 weeks.Tralokinumab may be considered a targeted biological treatment option for patients with moderate‐to‐severe AD. Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387. Plain language summary available online

Asthma is a chronic and heterogenic respiratory tract disorder with a high global prevalence. The underlying chronic inflammatory process and airway remodeling (AR) contribute to the symptomatology of the disease. The most severely ill asthma patients may now be treated using a variety of monoclonal antibodies aiming key inflammatory cytokines involved in asthma pathogenesis. Although clinical data shows much beneficial effects of biological therapies in terms of reduction of exacerbation rates, improvement of lung functions, asthma control and patients' quality of life, little is known on the effects of these monoclonal antibodies on AR—a key clinical trait of long-term asthma management. In this review, the authors summarize the data on the proven effects of monoclonal antibodies in asthma on AR. To date, in terms of reversing AR, the mostly studied was omalizumab. However, some studies also addressed this clinical issue in context of other severe asthma biological therapies (mepolizumab, benralizumab, tralokinumab). Still, data on effects of particular biological therapies on AR in severe asthma are incomplete and require further studies. According to the American Thoracic Society research recommendations, future research shall focus on AR in asthma and improve drugs targeting AR, including the available and future monoclonal antibodies.

BACKGROUND Monoclonal antibody therapies have a growing role in treating refractory airway disease. OBJECTIVE The review aimed to summarize the response of respiratory mucosa to monoclonal antibody treatments in inflammatory airway conditions. DESIGN We conducted a systematic review including risk of bias assessment. DATA SOURCES MEDLINE, EMBASE and PubMed from 1 January 2000 to 16 November 2019 were searched. ELIGIBILITY CRITERIA Eligible studies assessed the immunological and histological response of airway mucosa to monoclonal antibody therapy compared with baseline or a comparison group in patients with respiratory diseases (asthma, chronic rhinosinusitis and allergic rhinitis). Any prospective interventional studies, including randomized controlled trials (RCTs) and single-arm trials, were eligible. RESULTS There were 4195 articles screened, and full-text analysis produced n = 11 studies with extractable data. Nine were RCTs, and two were single-arm trials. These studies focused on asthma (n = 9 articles), chronic rhinosinusitis (n = 1) and allergic rhinitis (n = 1). Five monoclonal antibody drugs were assessed (omalizumab, mepolizumab, dupilumab, benralizumab and tralokinumab). Risk of bias was low (n = 6) or unclear (n = 3) in the RCTs and moderate in the single-arm trials. Omalizumab reduced the mucosal concentration of its target, IgE. Dupilumab reduced the concentration of one of its targets, IL-13, but not IL-4. Omalizumab, mepolizumab and benralizumab reduced tissue eosinophil cell density. Dupilumab decreased mucosal eosinophil granule proteins. Tralokinumab did not affect airway mucosa. CONCLUSIONS Knowledge of the expected biological response of monoclonal antibody therapy on biomarkers in disease tissue provides an important supplement to data about clinical outcomes. An understanding of the biological effect is essential to identify likely responders, reasons for treatment failure and necessary adjustments to monoclonal antibody treatment. Further investigation into the effect of monoclonal antibody therapy on disease mucosa and more precise endotyping are required to move closer to achieving personalized medicine.

Introduction: Atopic dermatitis (AD) is a heterogeneous disease. Recent advancements in understanding AD pathogenesis resulted in the exponential expansion of its therapeutic pipeline, particularly...

Current population of patients with asthma is characterized by increasing resistance to standard pharmacotherapeutic agents such as inhaled corticosteroids, antileukotriene agents and anti-IgE antibodies. These findings were confirmed by international statistic data and indicate insufficient efficacy of the treatment. Asthma phenotyping encompassing a role of certain biomarkers for bronchial inflammation could contribute to achieving better response to treatment. Genetically engineered drugs could directly impact on mediators and modulators involved in the inflammation and bronchoconstriction. This is one of the most promising directions of the modern pharmacotherapy, particularly considering severe and difficult-to-treat asthma. A comparative analysis of efficacy and safety of currently available genetically engineered drug groups (monoclonal anti-IgE antibodies, monoclonal antibodies against interleukin (IL)-4/IL-13 and IL-5, and prostaglandin D2 receptor antagonists) was performed by the authors of this article on the basis of results of randomized controlled clinical trials (RCT). According to RCT results, omalizumab is still the leading genetically engineered drug. Moreover, evidence of efficacy and safety of novel agents has been published that allowed implementation these drugs in the routine clinical practice for treatment of severe eosinophilic asthma.

Several new biologics have been studied in patients with eosinophilic asthma with varying degrees of response on clinical outcomes. No head-to-head trial has directly compared the efficacy of these drugs. To synthesize data on the relative efficacy of benralizumab, dupilumab, lebrikizumab, mepolizumab, reslizumab, and tralokinumab using network meta-analysis. We searched PubMed from inception to December 15th, 2017. We used the ‘frequentist’ methodology with random effect models using primarily ‘netmeta’ function in R to generate network meta-analysis results. Outcomes assessed included changes in forced expiratory volume-in 1 s (FEV1), asthma control questionnaire (ACQ), and asthma quality of life questionnaire (AQLQ). We also separately analyzed the annualized rate ratios for asthma exacerbations for each drug and compared to placebo. For all outcomes assessed, all drugs were superior to placebo except tralokinumab. In terms of magnitude of effect, dupilumab, followed by reslizumab and benralizumab showed the greatest increase in FEV1, 0.16L (95% CIs: 0.08–0.24), 0.13L (0.10–0.17), and 0.12L (0.08–0.17), compared to placebo. While mepolizumab, followed by dupliumab, benralizumab, and reslizumab showed reductions in ACQ scores, in order of magnitude of effect, dupilumab, followed by mepolizumab, benralizumab, and reslizumab showed the greatest increase in AQLQ scores. All drugs decreased asthma exacerbations but the results were only significant for reslizumab and dupilumab. All drugs except for tralokinumab showed improvements in FEV1, ACQ, and AQLQ. Only reslizumab and dupilumab were associated with statistically significant reductions in asthma exacerbation rates.

Summary Background Tralokinumab is an anti-interleukin-13 human monoclonal antibody developed for the treatment of severe, uncontrolled asthma. These clinical trials aimed to assess the efficacy and safety of tralokinumab in this population. Methods STRATOS 1 and STRATOS 2 were randomised, double-blind, parallel-group, placebo-controlled, phase 3 clinical trials that enrolled participants aged 12–75 years with severe asthma that was inadequately controlled despite use of inhaled corticosteroids (≥500 μg per day fluticasone or equivalent) and a long-acting β 2 agonist (but not oral corticosteroids). STRATOS 1 was done at 246 sites in 14 countries, and STRATOS 2 was done at 242 sites in 13 countries. In STRATOS 1, participants were randomly assigned (2:1) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks or every 4 weeks for 52 weeks. In STRATOS 2, participants were randomly assigned (1:1) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks for 52 weeks. STRATOS 1 attempted to identify a biomarker-positive population with enhanced tralokinumab benefit, which was then tested in STRATOS 2. The primary endpoint was the annualised asthma exacerbation rate (AAER) reduction at week 52 in the all-comers population for STRATOS 1 and in the biomarker-positive population for STRATOS 2. All efficacy analyses for both trials were done on the full analysis set by an intention-to-treat approach. The safety analysis set comprised any participant who received the investigational drug and was categorised by treatment received. These trials are registered with ClinicalTrials.gov, numbers NCT02161757 (STRATOS 1) and NCT02194699 (STRATOS 2), and with the EU Clinical Trials Register, EudraCT 2013-005614-35 (STRATOS 1) and EudraCT 2013-005615-27 (STRATOS 2). Findings STRATOS 1 was done between June 13, 2014, and Feb 28, 2017. 1207 participants were randomly assigned and 1202 treated as follows: tralokinumab every 2 weeks (n=398), tralokinumab every 4 weeks (n=404), or placebo (n=400). STRATOS 2 was done between Oct 30, 2014, and Sept 21, 2017. 856 participants were randomly assigned and 849 treated as follows: tralokinumab every 2 weeks (n=427) and placebo every 2 weeks (n=422). In the STRATOS 1 all-comers population, tralokinumab every 2 weeks did not significantly reduce AAER compared with placebo (7·0% reduction [95% CI −20·8 to 28·4]; rate ratio 0·93 [95% CI 0·72 to 1·21]; p=0·59). Baseline fractional exhaled nitric oxide (FENO) 37 ppb or greater was identified as the preferred biomarker in STRATOS 1; in FENO-high participants, tralokinumab every 2 weeks (n=97) reduced AAER by 44·0% (95% CI 6·0 to 66·0; rate ratio 0·56 [95% CI 0·34 to 0·94]; p=0·028) compared with placebo (n=102). In the STRATOS 2 FENO-high population, tralokinumab every 2 weeks (n=108) did not significantly improve AAER (15·8% reduction [95% CI −33·7 to 47·0]; rate ratio 0·84 [95% CI 0·53 to 1·34]; p=0·47) compared with placebo (n=121). The safety profile was consistent with that of previous tralokinumab trials. Interpretation Tralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1, but not in STRATOS 2. These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations. Funding AstraZeneca.

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The Food and Drug Administration announced that they approved 46 new drugs in 2017 — about twice as many as the usual number and a new high for the past decade.1 (That number does not include new combinations of previously included molecules such as trelegy, the triple combination of fluticasone, umeclidinium, and vilanterol.) The only new pulmonary drug in 2017 was the AstraZeneca drug benralizumab (Fasenra). We also have mepolizumab (Nucala), and reslizumab (Cinqair). It is likely that we will also have dupilumab (Dupixent), tralokinumab, and tezepelumab2 all coming soon and all for asthma. But no monoclonals were approved for chronic obstructive pulmonary disease (COPD).

IL-13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing disease.Investigate efficacy and safety of tralokinumab, a human anti-IL-13 monoclonal antibody, in subjects with mild to moderate IPF.Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent predicted FVC in the intention-to-treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median.The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor tralokinumab 800 mg met the primary endpoint; least-squares mean difference (95% confidence interval) percent predicted FVC from baseline to Week 52: -1.77 (-4.13 to 0.59) (P = 0.140) and -1.41 (-3.73 to 0.91) (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent predicted FVC greater than or equal to 10% at Week 52 was numerically greater for tralokinumab-treated subjects compared with placebo. The most common treatment-emergent adverse events for tralokinumab 400 mg, tralokinumab 800 mg, and placebo were cough (17.5, 30.5, 22.8%), IPF progression and exacerbation (21.1, 16.9, 22.8%), and upper respiratory tract infection (17.5, 20.3, 12.3%), respectively.Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registered with www.clinicaltrials.gov (NCT01629667).