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Competing Interests: Conflicts of interest the author declares they have no conflicts of interest.

Tralokinumab is the first biologic therapy for moderate-to-severe atopic dermatitis (AD) that specifically neutralizes interleukin-13 activity, a key driver of AD signs and symptoms. Tralokinumab is a human immunoglobulin G4 monoclonal antibody administered subcutaneously every 2 weeks (with possibility of maintenance dosing every 4 weeks). This population pharmacokinetic (PK) analysis aimed to identify sources of PK variability and relevant predictors of tralokinumab exposure in adults with moderate to severe AD. Nonlinear mixed-effect modeling, including covariate analysis, was used on a data set including 2561 subjects (AD, asthma, healthy) from 10 clinical trials. A 2-compartment model with first-order absorption and elimination adequately described the tralokinumab PK. Body weight was identified as a relevant predictor of tralokinumab exposure; other covariates including age, sex, race, ethnicity, disease type, AD severity, and renal and hepatic impairment were not. For body weight, the difference in exposure between the upper- and lower-weight quartiles in patients with AD was <2-fold, supporting the appropriateness of flat dosing (300 mg). Given the reduced exposure associated with higher body weight, coupled with the reduced exposure provided by dosing every 4 weeks, it is uncertain whether higher-weight patients will achieve sufficient exposure to maintain efficacy if dosed every 4 weeks instead of the standard every 2 weeks., (© 2022 LEO Pharma A/S. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Several clinical studies have evaluated the use of tralokinumab (CAT-354) administration in patients with moderate to severe asthma; no consensus on tralokinumab efficacy and safety was reached. Thus, further analysis is required on the efficacy and safety of tralokinumab as an asthma biologic., Objective: To assess the efficacy and safety of subcutaneous injection of tralokinumab in patients with moderate to severe asthma., Methods: Clinical trials were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to November 4, 2018. Only randomized clinical trials (RCTs) with tralokinumab versus placebo treatment in patients with moderate to severe asthma were evaluated. Efficacy and safety outcomes were extracted, and a meta-analysis was performed using a random-effects model. The Cochrane Collaboration's risk-of-bias assessment tool was used to assess the risk of bias., Results: Five studies describing 6 RCTs (including 2928 adults with moderate to severe asthma) were pooled and analyzed in this study. Absolute FEV 1 was statistically improved in patients receiving tralokinumab at 300 mg every 2 weeks (mean difference [MD], 0.14 L; 95% CI, 0.08-0.21) and 600 mg every 2 weeks (MD, 0.20 L; 95% CI, 0.01-0.39), as well as FEV 1 % changes (MD, 5.82%, 95% CI, 3.58-8.06, and MD, 11.8%, 95% CI, 0.79-22.81, respectively). Also, absolute forced vital capacity volume changes (MD, 0.11 L; 95% CI, 0.01-0.21) and percentage changes (MD, 4.44%; 95% CI, 0.84-8.04) improved in tralokinumab at 300 mg every 2 weeks. Asthma Quality of Life Questionnaire scores were not significantly different, and absolute Asthma Control Questionnaire 6 scores were statistically improved but did not reach the clinically meaningful difference. Tralokinumab treatment did not decrease annualized asthma exacerbation rate in unselected patients with moderate to severe asthma, but it was associated with improved annualized asthma exacerbation rate in patients with severe asthma with high fractional exhaled nitric oxide levels (rate ratio, 0.72; 95% CI, 0.53-0.97). Tralokinumab was not associated with an increased incidence of serious adverse events, but it did show an increase in mild injection-site reactions (odds ratio, 5.92; 95% CI, 1.61-21.76)., Conclusion: This pooled analysis of 6 RCTs suggested that tralokinumab was well tolerated and it modestly improved FEV 1 and forced vital capacity in patients with moderate to severe asthma. It did not render clinically important improvements in asthma-related quality of life, and nor did it reduce asthma exacerbations., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Tralokinumab is an anti-interleukin (IL)-13 monoclonal antibody investigated for the treatment of severe, uncontrolled asthma in two Phase III clinical trials, STRATOS 1 and 2. The STRATOS 1 biomarker analysis plan was developed to identify biomarker(s) indicative of IL-13 activation likely to predict tralokinumab efficacy and define a population in which there was an enhanced treatment effect; this defined population was then tested in STRATOS 2., Methods: The biomarkers considered were blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum dipeptidyl peptidase-4, serum periostin and total serum immunoglobulin E. Tralokinumab efficacy was measured as the reduction in annualised asthma exacerbation rate (AAER) compared with placebo (primary endpoint measure of STRATOS 1 and 2). The biomarker analysis plan included negative binomial and generalised additive models, and the Subgroup Identification based on Differential Effect Search (SIDES) algorithm, supported by robustness and sensitivity checks. Effects on the key secondary endpoints of STRATOS 1 and 2, which included changes from baseline in standard measures of asthma outcomes, were also investigated. Prior to the STRATOS 1 read-out, numerous simulations of the methodology were performed with hypothetical data., Results: FeNO and periostin were identified as the only biomarkers potentially predictive of treatment effect, with cut-offs chosen by the SIDES algorithm of > 32.3 ppb and > 27.4 ng/ml, respectively. The FeNO > 32.3 ppb subgroup was associated with greater AAER reductions and improvements in key secondary endpoints compared with the periostin > 27.4 ng/ml subgroup. Upon further evaluation of AAER reductions at different FeNO cut-offs, ≥37 ppb was chosen as the best cut-off for predicting tralokinumab efficacy., Discussion: A rigorous statistical approach incorporating multiple methods was used to investigate the predictive properties of five potential biomarkers and to identify a participant subgroup that demonstrated an enhanced tralokinumab treatment effect. Using STRATOS 1 data, our analyses identified FeNO at a cut-off of ≥37 ppb as the best assessed biomarker for predicting enhanced treatment effect to be tested in STRATOS 2. Our findings were inconclusive, which reflects the complexity of subgroup identification in the severe asthma population., Trial Registration: STRATOS 1 and 2 are registered on ClinicalTrials.gov ( NCT02161757 registered on June 12, 2014, and NCT02194699 registered on July 18, 2014).

Introduction: Tralokinumab is a monoclonal antibody (mAb) that neutralizes interleukin (IL)-13, a cytokine involved in the pathogenesis of asthma., Objective: The objectives of this study were to characterize the potential immunogenic properties of tralokinumab and report data for anti-drug antibodies (ADAs) and hypersensitivity reactions from two phase III clinical trials., Methods: The oligosaccharide structure of tralokinumab, Fab-arm exchange, and ADAs were characterized by standard techniques. Hypersensitivity adverse events (AEs) were evaluated in two pivotal clinical trials of tralokinumab in severe, uncontrolled asthma: STRATOS 1 and 2 (NCT02161757 and NCT02194699)., Results: No galactose-α-1,3-galactose (α-Gal) epitopes were found in the Fab region of tralokinumab and only 4.5% of glycoforms contained α-Gal in the Fc region. Under non-reducing conditions, Fab-arm exchange did not take place with another immunoglobulin (Ig) G 4 mAb (mavrilimumab). However, following glutathione reduction, a hybrid antibody with monovalent bioactivity was detected. ADA incidences (titers) were as follows: STRATOS 1-every 2 weeks (Q2 W) 0.8% (26.0), every 4 weeks (Q4 W) 0.5% (26.0), placebo 0.8% (52.0); STRATOS 2-Q2 W 1.2% (39.0), placebo 0.8% (13.0). Participant-reported hypersensitivity AE rates were as follows: STRATOS 1-Q2 W 25.9%, Q4 W 25.0%, placebo 25.5%; STRATOS 2-Q2 W 13.2%, placebo 9.0%. External evaluation for anaphylaxis by Sampson criteria found no tralokinumab-related severe hypersensitivity or anaphylaxis reactions., Conclusion: Preclinical assessments suggested a low likelihood of immunogenicity for tralokinumab. In STRATOS 1 and 2, ADA incidence was low, no differences were found between tralokinumab-treated and placebo groups in reporting of hypersensitivity reactions, and there were no Sampson criteria-evaluated anaphylaxis events with tralokinumab treatment. Together, the results suggest that tralokinumab treatment would not increase the risk for severe hypersensitivity or anaphylactic reactions.

Long-term oral corticosteroid (OCS) use in patients with severe asthma is associated with significant adverse effects.This 40-week, randomised, double-blind trial evaluated the OCS-sparing potential of tralokinumab in patients with severe, uncontrolled asthma requiring maintenance OCS treatment plus inhaled corticosteroids/long-acting β 2 -agonists. Overall, 140 patients were randomised to tralokinumab 300 mg or placebo (n=70 in each group) administered subcutaneously every 2 weeks. The primary end-point was percentage change from baseline in average OCS dose at week 40, while maintaining asthma control. Secondary end-points included proportion of patients with a prescribed maintenance OCS dose of ≤5 mg, those with a ≥50% reduction in prescribed maintenance OCS dose and asthma exacerbation rate. Safety was also assessed.At week 40, the percentage reduction from baseline in the final daily average OCS dose was not significantly different between tralokinumab and placebo (37.62% versus 29.85%; p=0.271). There were no significant between-treatment differences for any secondary end-point. Overall, reporting of adverse events and serious adverse events were similar for the tralokinumab and placebo groups. Although a greater proportion of tralokinumab-treated patients reported upper respiratory tract infections (35.7% versus 14.3%), there were no reported cases of pneumonia.Overall, tralokinumab did not demonstrate an OCS-sparing effect in patients with severe asthma., Competing Interests: Conflict of interest: W.W. Busse reports personal fees for consultancy from AstraZeneca, during the conduct of the study; personal fees for consultancy from 3M, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi-Regeneron and Teva, personal fees for data and safety monitoring board work from Boston Scientific and Genentech, personal fees (royalties) from Elsevier, personal fees for educational videos from Medscape, personal fees for joint oversight committee work from ICON Clinical Research Limited, and personal fees from Pfizer, Roche, AstraZeneca and Circassia, and grants from NIH-NIAID and NIH-NHLBI, outside the submitted work. Conflict of interest: G.G. Brusselle reports honoraria for advisory boards and/or lectures from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, Sanofi/Regeneron, Teva, UCB and Zambon, during the conduct of the study. Conflict of interest: S. Korn reports consulting and lecture fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Teva and Roche, and grants and personal fees from GlaxoSmithKline and Novartis, during the conduct of the study. Conflict of interest: P. Kuna reports personal fees from Adamed, Allergopharma, ALK, AstraZeneca, Bayer Celon Pharma, Chiesi, FAES, HAL Allergy, Lekam, Polpharma, Pfizer, Sandoz and Teva, during the conduct of the study; and personal fees from Berlin Chemie, Boehringer Ingelheim and Novartis, outside the submitted work. Conflict of interest: A. Magnan reports personal fees and non-financial support from GlaxoSmithKline, Novartis, Boehringer Ingelheim, AstraZeneca, Stallerg nes, ALK, MundiPharma, Teva, Menarini and Meda Pharma, during the the past 5 years. Conflict of interest: D. Cohen is an employee of AstraZeneca. Conflict of interest: K. Bowen is an employee of and own shares in AstraZeneca. Conflict of interest: T. Piechowiak is an employee of and owns stock options in AstraZeneca. Conflict of interest: M.M. Wang is an employee of and owns shares in AstraZeneca. Conflict of interest: G. Colice is an employee of and owns shares and stock options in AstraZeneca., (Copyright ©ERS 2019.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear. Tralokinumab is a human monoclonal antibody that neutralises interleukin 13. We aimed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration, blood and sputum eosinophil concentrations, eosinophil activation, and airway remodelling., Methods: We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 15 centres across the UK, Denmark, and Canada. We enrolled participants of either sex aged 18-75 years with inadequately controlled moderate-to-severe asthma for 12 months or more, requiring treatment with inhaled corticosteroids at a stable dose. We randomly assigned participants (1:1) to receive tralokinumab (300 mg) or placebo by an interactive web-based system or voice response system. Participants and study personnel were masked to treatment allocation. Both tralokinumab and placebo were administered subcutaneously every 2 weeks. The primary outcome measure was change from baseline to week 12 in bronchial biopsy eosinophil count. Secondary outcome measures included change in blood and sputum eosinophil counts. Exploratory outcomes included fractional exhaled nitric oxide (FENO) and blood IgE concentrations. Safety analyses were carried out in all participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT02449473, and with the European Clinical Trials Database, EudraCT 2015-000857-19., Findings: Between Sept 25, 2015, and June 21, 2017, 224 participants were enrolled and screened. Of these participants, 79 were randomly assigned to receive tralokinumab (n=39) or placebo (n=40). Tralokinumab did not significantly affect bronchial eosinophil count compared with placebo at week 12 (treatment effect ratio 1·43, 95% CI 0·63-3·27; p=0·39). Compared with placebo, tralokinumab did not significantly affect blood eosinophil count (treatment effect ratio 1·21, 95% CI 1·00-1·48; p=0·055) or sputum eosinophil count (0·57, 0·06-6·00; p=0·63), but FENO concentration (0·78, 0·63-0·96; p=0·023) and total blood IgE concentration (0·86, 0·77-0·97; p=0·014) were significantly reduced. 33 (85%) of 39 patients receiving tralokinumab and 32 (80%) of 40 receiving placebo reported at least one adverse event during the treatment period. No deaths in either treatment group were observed. Treatment-related adverse events occurred more frequently in the tralokinumab group than in the placebo group (11 [28%] of 39 vs seven [18%] of 40)., Interpretation: Tralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma., Funding: AstraZeneca., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G 4 monoclonal antibody that specifically binds to IL-13. Two placebo-controlled phase II studies (phase IIa, NCT00873860 and phase IIb, NCT01402986) have been conducted in which tralokinumab was administered subcutaneously. This investigation aimed to characterize tralokinumab's dose-exposure-response (forced expiratory volume in 1 s (FEV 1 )) relationship in patients with asthma and to predict the most appropriate dose for phase III. An integrated population pharmacokinetic-pharmacodynamic (PK/PD) modeling analysis was required for phase III dose selection, due to differing phase II patient populations, designs, and regimens. Analysis of combined datasets enabled the identification of tralokinumab's dose-exposure-FEV 1 response relationship in patients with asthma. Near-maximal FEV 1 increase was predicted at a dose of 300 mg SC once every 2 weeks (Q2W). This dose was chosen for tralokinumab in the phase III clinical development program for treatment of severe, uncontrolled asthma., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Tralokinumab, a fully human IgG 4 monoclonal antibody, specifically neutralizes IL-13. The ATMOSPHERE clinical development program comprised four randomized, placebo-controlled clinical trials and an open-label study that aimed to assess the efficacy and safety of tralokinumab for the treatment of severe, uncontrolled asthma. The two pivotal trials (STRATOS 1 and STRATOS 2; NCT02161757 and NCT02194699) evaluated the efficacy and safety of tralokinumab, with STRATOS 1 identifying a subgroup most likely to demonstrate enhanced response to treatment. Further trials have assessed the ability of tralokinumab to reduce oral corticosteroid use (TROPOS; NCT02281357) and determined its mechanistic effects (MESOS; NCT02449473). An open-label study in Japanese individuals (NCT02902809) assessed the long-term safety and tolerability of tralokinumab in this population.

Aims: Tralokinumab, an investigational human immunoglobulin G4 monoclonal antibody, potently and specifically neutralizes interleukin-13, a central mediator of asthma. Tralokinumab has shown improvements in clinical endpoints in adults with uncontrolled asthma. The present study explored the pharmacokinetics (PK) and safety of a single tralokinumab dose, and utilized a population PK modelling and simulation approach to evaluate the optimal dosing strategy for adolescents., Methods: Adolescent subjects with asthma, using daily controller medication, received a single subcutaneous dose of tralokinumab 300 mg. Safety, immunogenicity and PK data were collected during a 57-day follow-up. A population PK model was developed using data from the present study and prior studies in adults. Simulations were performed to evaluate dose adjustment requirements for adolescents., Results: Twenty adolescents (12-17 years) were enrolled; all completed the study. No clinically relevant safety findings or antidrug antibodies were detected. PK parameters were similar to those observed in adults. PK modelling showed that body weight was a minor predictor of tralokinumab PK; after incorporating body weight into the PK model, a 15% (nonparametric 95% confidence interval 5%, 26%) lower clearance was found in adolescents compared with adults [173 (151, 209) vs. 204 (191, 229) ml day(-1)]. Simulations showed no therapeutically relevant differences in exposures between adolescent and adult populations, and similar PK profiles for weight-based (4 mg kg(-1)) and fixed (300 mg) fortnightly subcutaneous doses of tralokinumab., Conclusion: Single-dose administration of tralokinumab 300 mg in adolescents was well tolerated, with a PK profile similar to that in adults. Exposure predictions suggest that dose adjustment is not required for adolescents., (© 2015 The British Pharmacological Society.)

Background: Interleukin 13 is a central mediator of asthma. Tralokinumab is a human interleukin-13 neutralising monoclonal antibody. We aimed to assess the efficacy and safety of two dosing regimens of tralokinumab in patients with severe uncontrolled asthma., Methods: We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2b study at 98 sites in North America, South America, Europe, and Asia. Patients aged 18-75 years with severe asthma and two to six exacerbations in the previous year were randomly assigned (1:1), via an interactive voice-response or web-response system, to one of two dosing regimen groups (every 2 weeks, or every 2 weeks for 12 weeks then every 4 weeks) and further randomised (2:1), via computer-generated permuted-block randomisation (block size of six), to receive tralokinumab 300 mg or placebo for 1 year. All participants received high-dose fluticasone and salmeterol and continued other pre-study controller drugs. Treatment was administered by an unmasked study investigator not involved in the management of patients; all other study site personnel, patients, the study funder, and data analysts were masked to treatment allocation. The primary endpoint was the annual asthma exacerbation rate at week 52 in the intention-to-treat population. Key secondary endpoints included prebronchodilator forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire-6 (ACQ-6), and Asthma Quality of Life Questionnaire-Standardised Version (AQLQ[S]). This trial is registered with ClinicalTrials.gov, number NCT01402986., Findings: Between Oct 4, 2011, and Feb 22, 2014, we randomly assigned 452 patients to receive placebo (n=151) or tralokinumab every 2 weeks (n=150) or every 4 weeks (n=151), of whom 383 (85%) completed the treatment period up to week 52. The annual asthma exacerbation rate at week 52 was similar between patients receiving tralokinumab every 2 weeks (0.91 per patient per year [95% CI 0.76-1.08]) and every 4 weeks (0.97 [0.81-1.14]), and those receiving placebo (0.90 [0.75-1.08]). At week 52, percentage changes in annual asthma exacerbation rate were not significant with tralokinumab every 2 weeks or every 4 weeks versus placebo (6% [95% CI -31 to 33; p=0.709] and -2% [-46 to 29; p=0.904], respectively), with positive changes showing a decrease in exacerbation rate and negative changes showing an increase. Prebronchodilator FEV1 was significantly increased compared with placebo for tralokinumab every 2 weeks (change from baseline 7.3% [95% CI 2.6-12.0]; p=0.003), but not every 4 weeks (1.8% [-2.9 to 6.6]; p=0.448); however, we did not identify significant changes in the other key secondary endpoints. In a post-hoc subgroup analysis of patients not on long-term oral corticosteroids and with baseline FEV1 reversibility of 12% or greater, we noted a non-significant improvement in asthma exacerbation rate (44% [95% CI -22 to 74]; p=0.147) and significant improvements in key secondary endpoints (FEV1 12.2% [1.7-22.7]; p=0.022; ACQ-6 -0.55 [-1.07 to -0.04]; p=0.036; and AQLQ[S] 0.70 [0.12-1.28]; p=0.019) in patients given tralokinumab every 2 weeks (n=33) compared with placebo (n=48). In patients in this subgroup who also had baseline serum dipeptidyl peptidase-4 (DPP-4) higher than the population baseline median, we noted additional improvements in prebronchodilator FEV1, ACQ-6, and AQLQ(S), and, in those with periostin concentrations higher than the median, we noted improvements in asthma exacerbation rate, prebronchodilator FEV1, and ACQ-6. The incidence of treatment-emergent adverse events was similar between the tralokinumab and placebo groups. Treatment-emergent serious adverse events regarded as related to the study drug were pneumonia (one [1%] patient in the placebo group), pneumococcal pneumonia (one [1%] in the tralokinumab every 2 weeks group), angioedema (one [1%] in the placebo group), and worsening asthma (one [1%] in the tralokinumab every 2 weeks group and two [1%] in the tralokinumab every 4 weeks group)., Interpretation: In this phase 2b study, both tralokinumab regimens had an acceptable safety and tolerability profile but did not significantly reduce asthma exacerbation rates in patients with severe uncontrolled asthma. Improvement in FEV1 with tralokinumab given every 2 weeks and results of post-hoc subgroup analyses suggested a possible treatment effect in a defined population of patients with severe uncontrolled asthma. This effect is being further investigated in ongoing phase 3 trials, along with the potential utility of DPP-4 and periostin as biomarkers of interleukin-13 pathway activation., Funding: MedImmune., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Pre-clinical data demonstrate a pivotal role for interleukin (IL)-13 in the development and maintenance of asthma. This study assessed the effects of tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, in adults with moderate-to-severe uncontrolled asthma despite controller therapies. 194 subjects were randomised to receive tralokinumab (150, 300 or 600 mg) or placebo subcutaneously every 2 weeks. Primary end-point was change from baseline in mean Asthma Control Questionnaire score (ACQ-6; ACQ mean of six individual item scores) at week 13 comparing placebo and combined tralokinumab dose groups. Secondary end-points included pre-bronchodilator lung function, rescue β(2)-agonist use and safety. Numerical end-points are reported as mean±sd. At week 13, change from baseline in ACQ-6 was -0.76±1.04 for tralokinumab versus -0.61±0.90 for placebo (p=0.375). Increases from baseline in forced expiratory volume in 1 s (FEV(1)) were 0.21±0.38 L versus 0.06±0.48 L (p=0.072), with a dose-response observed across the tralokinumab doses tested. β(2)-agonist use (puffs per day) was decreased for tralokinumab -0.68±1.45 versus placebo -0.10±1.49 (p=0.020). The increase in FEV(1) following tralokinumab treatment remained evident 12 weeks after the final dose. Safety profile was acceptable with no serious adverse events related to tralokinumab. No improvement in ACQ-6 was observed, although tralokinumab treatment was associated with improved lung function.

Asthma is a chronic inflammatory disease of the airways long known for phenotypic heterogeneity. Phenotyping studies in asthma have led to a better characterization of disease pathogenesis, yet further work is needed to pair available treatments with disease endotypes. In this review, the biology of targeted pathways is discussed along with the efficacy of biologic therapies targeting those pathways. Results of asthma clinical trials are included, as well as results of trials in related diseases. This review then analyzes how biologics help to inform the complex immunobiology of asthma and further guide their use while identifying areas for future research.

Background: The aim of the study was to evaluate total immunoglobulin E (IgE), IL-13, and IL-33 serum level in people with bronchial asthma and atopy, and in healthy control group depending on their exposure to farm animals currently and in the first year of life., Methods: The study included 174 individuals living in rural areas and in a small town. Standardized questions from the International Study of Asthma and Allergy in Childhood and The European Community Respiratory Health Survey (ECRHS) questionnaires were used to define asthma. Atopic status was verified by skin prick tests. Rural exposure including contact with livestock was verified by adequate questionnaire. Total serum IgE, IL-13, and IL-33 levels were assessed by ELISA (enzyme-linked immunosorbent assay) tests., Results: Participants with atopy and bronchial asthma were characterized by high level of immunoglobulin E. Tendency to lower serum IgE level was observed among people reporting present contact with farm animals. Also, among those having contact with livestock in their first year of life, the analogous tendency was noticed. No difference in serum IL-13 levels in participants with asthma and atopy, and controls was observed, and there was no effect of exposure on farm animals on the concentration of IL-13. The highest IL-33 level was found in the atopic group, and the lowest in the control group. Participants currently exposed to farm animals were predisposed to have lower IL-33 serum level., Conclusion: Exposure of farm animals currently and in first year of life may result in a lower level of total IgE. Correlation between IL-13 and IL-33 serum levels and contact with livestock was not confirmed., Competing Interests: The authors have no conflict of interest to declare.

Asthma is classically considered to be a disease of type 2 immune dysfunction, since many patients exhibit the consequences of excess secretion of cytokines such as IL-4, IL-5, and IL-13 concomitant with inflammation typified by eosinophils. Mouse and human disease models have determined that many of the canonical pathophysiologic features of asthma may be caused by these disordered type 2 immune pathways. As such considerable efforts have been made to develop specific drugs targeting key cytokines. There are currently available multiple biologic agents that successfully reduce the functions of IL-4, IL-5, and IL-13 in patients, and many improve the course of severe asthma. However, none are curative and do not always minimize the key features of disease, such as airway hyperresponsiveness. Here, we review the current therapeutic landscape targeting type 2 immune cytokines and discuss evidence of efficacy and limitations of their use in adults and children with asthma., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

With the increasing number of options for the treatment of moderate-to-severe atopic dermatitis, clinicians need guidance on a practical approach to selecting a systemic agent for specific patient populations. We convened an expert panel consisting of 12 members to conduct a literature review and summarize relevant data related to six scenarios of clinical interest: comorbid asthma, ocular surface disease, history of cancer, past and ongoing infections of interest (including herpes simplex virus, herpes zoster, hepatitis B, and tuberculosis), pregnancy and lactation, and the elderly. We performed a literature search and examined each clinical scenario with respect to three major categories of available systemic agents: traditional systemics (azathioprine, cyclosporine A, methotrexate, and mycophenolate mofetil), Janus kinase inhibitors (abrocitinib, baricitinib, and upadacitinib), and biologics (dupilumab, lebrikizumab, and tralokinumab). The expert panel and steering committee met virtually to review the data and discuss the drafted consensus statements. A modified Delphi process was used to arrive at a set of final consensus statements related to the systemic treatment of AD in these specific patient populations. To provide practical guidance on the choice of systemic therapy for atopic dermatitis in these six topics of clinical interest, 25 expert consensus statements and a summary of the supporting data are presented herein., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Pharmaceutical companies regularly need to make decisions about drug development programs based on the limited knowledge from early stage clinical trials. In this situation, eliciting the judgements of experts is an attractive approach for synthesising evidence on the unknown quantities of interest. When calculating the probability of success for a drug development program, multiple quantities of interest-such as the effect of a drug on different endpoints-should not be treated as unrelated. We discuss two approaches for establishing a multivariate distribution for several related quantities within the SHeffield ELicitation Framework (SHELF). The first approach elicits experts' judgements about a quantity of interest conditional on knowledge about another one. For the second approach, we first elicit marginal distributions for each quantity of interest. Then, for each pair of quantities, we elicit the concordance probability that both lie on the same side of their respective elicited medians. This allows us to specify a copula to obtain the joint distribution of the quantities of interest. We show how these approaches were used in an elicitation workshop that was performed to assess the probability of success of the registrational program of an asthma drug. The judgements of the experts, which were obtained prior to completion of the pivotal studies, were well aligned with the final trial results., (© 2022 John Wiley & Sons Ltd.)

This study aimed to assess the utility of serum YKL-40 and serum dipeptidyl peptidase IV (DPP4) as biomarkers for distinguishing between type 2 (T2)-high and T2-low asthma in the Chinese population. Additionally, we sought to explore the associations of serum YKL-40 and DPP4 levels with asthma characteristics and conventional markers. A real-world observational cross-sectional study was conducted, involving a total of 75 adult asthma patients. We collected general information, including demographics and medical history. Measurements included complete blood count, fractional exhaled nitric oxide (FeNO), post-bronchodilator spirometry, serum YKL-40 and serum DPP4 levels. Asthma endotypes, T2-high and T2-low, were defined through a comprehensive review of existing literature and expert group discussions. Logistic and linear regression models were employed. Our findings indicated no significant association between serum YKL-40 or serum DPP4 levels and T2-high asthma across all models. In the fully adjusted model, their odds ratios (OR) were 0.967 (95% CI: 0.920-1.017) and 0.997 (95% CI: 0.993-1.001), respectively. Notably, serum YKL-40 exhibited a positive correlation with FeNO (β = 0.382, 95% CI: 0.230-0.533) after adjusting for confounding factors. This association, however, diminished in patients under 40 years old (P = .24), males (P = .25), and those with FEV1%pred of 80% or higher (P = .25). Serum DPP4 demonstrated a negative correlation with FEV1/FVC in the fully adjusted model (β: -0.005, 95% CI: -0.009, -0.000). Among Chinese adult asthma patients, a positive correlation was observed between serum YKL-40 levels and FeNO in females aged over 40 with FEV1%pred less than 80%. Additionally, a weak negative correlation was found between serum DPP4 levels and FEV1/FVC. However, neither serum YKL-40 nor serum DPP4 levels exhibited the capability to differentiate between T2-high and T2-low asthma., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes., Objective: We sought to systematically synthesize the benefits and harms of AD systemic treatments., Methods: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna)., Results: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain., Conclusions: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Asthma is a respiratory allergic disease presenting a high prevalence worldwide, and it is responsible for several complications throughout life, including death. Fortunately, asthma is no longer recognized as a unique manifestation but as a very heterogenic manifestation. Its phenotypes and endotypes are known, respectively, as pathologic and molecular features that might not be directly associated with each other. The increasing number of studies covering this issue has brought significant insights and knowledge that are constantly expanding. In this review, we intended to summarize this new information obtained from clinical studies, which not only allowed for the creation of patient clusters by means of personalized medicine and a deeper molecular evaluation, but also created a connection with data obtained from experimental models, especially murine models. We gathered information regarding sensitization and trigger and emphasizing the most relevant phenotypes and endotypes, such as Th2- high asthma and Th2- low asthma, which included smoking and obesity-related asthma and mixed and paucigranulocytic asthma, not only in physiopathology and the clinic but also in how these phenotypes can be determined with relative similarity using murine models. We also further investigated how clinical studies have been treating patients using newly developed drugs focusing on specific biomarkers that are more relevant according to the patient's clinical manifestation of the disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Asthma is a common chronic inflammatory condition of the airways that affects about 350 million people globally. In 5%-10% of individuals, it is severe, with considerable morbidity and high health care utilization. The goal of asthma management is disease control by reducing symptoms and exacerbations and reducing corticosteroid-related morbidity. The era of biologics has revolutionized the management of severe asthma. Biologics have changed our expectations for severe asthma, especially in those people with type-2 mediated immunity. We can now explore the potential for changing disease trajectory and inducing remission. However, biologics are not a panacea for all severe asthma sufferers and despite their success there remains substantial unmet clinical need. We review the pathogenesis of asthma, phenotyping the heterogeneity of asthma, currently licensed and future biologic agents, how to choose the initial biologic, assessing the response, remission and switching of biologic therapies., (© 2023 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)