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Nicola A Hanania - One of the best experts on this subject based on the ideXlab platform.

  • Targeting the interleukin-4 and interleukin-13 pathways in severe asthma: current knowledge and future needs
    Current Opinion in Pulmonary Medicine, 2020
    Co-Authors: Amit D Parulekar, Zuzana Diamant, Nicola A Hanania
    Abstract:

    Purpose of review Severe asthma is a heterogeneous disease that can be classified into phenotypes and endotypes based upon clinical or biological characteristics. Interleukin (IL)-4 and IL-13 play a key role in type 2 (T2) asthma. This article reviews the signaling pathway of IL-4 and IL-13 and highlights its targeted therapy in severe asthma. Recent findings Several clinical trials of biologics targeting the IL-4/IL-13 pathway have recently been completed. In patients with severe, uncontrolled asthma, targeting IL-13 alone with biologics including Lebrikizumab and tralokinumab has not shown consistent reduction in asthma exacerbations. Simultaneous targeting of both IL-4 and IL-13 by blocking IL-4 receptor α using dupilumab has yielded more consistent results in reducing asthma exacerbations and improving lung function, especially in patients with increased blood eosinophils. Other biomarkers of T2 inflammation such as exhaled nitric oxide and serum periostin may also predict response to biologics targeting the IL-4/IL-13 pathway. Summary No biologic targeting the IL-4/IL-13 pathway is currently available for treatment of asthma, but emerging data suggest that biologics targeting IL-4 and IL-13 together may benefit patients with T2 high asthma. Additional data are needed about long-term efficacy and safety prior to incorporating these drugs into routine clinical practice. (Less)

  • LATE-BREAKING ABSTRACT: LAVOLTA I and II: Results of 2 phase III studies to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma
    European Respiratory Journal, 2016
    Co-Authors: Nicola A Hanania, Phillip E Korenblat, Julie Olsson, Kenneth R Chapman, Eric D Bateman, Petr Kopecky, Pierluigi Paggiaro, Akihito Yokoyama, Sarah Gray, Cecile T J Holweg
    Abstract:

    Introduction In Phase II trials, Lebrikizumab, an anti-IL-13 mAb, improved exacerbation rates and FEV1 in patients with uncontrolled asthma, particularly in patients with higher levels of Type 2 biomarkers. Aims LAVOLTA I ([NCT01867125][1]) and II ([NCT01868061][2]) are replicate Phase III studies designed to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma despite ICS and at least a second controller. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40–80% predicted, and stable background therapy were randomized to receive Lebrikizumab 37.5 mg or 125 mg, or placebo SC, Q4W. The primary efficacy endpoint was rate of asthma exacerbations during the 52-week placebo-controlled period in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells/µL). Secondary endpoints included change in FEV1 and ACQ-5. Results 1081 and 1067 patients were randomized and treated in LAVOLTA I and II. Over 52 weeks, Lebrikizumab treatment reduced exacerbation rates in biomarker-high patients by 51% for the 37.5 mg dose ( p

  • efficacy and safety of Lebrikizumab in patients with uncontrolled asthma lavolta i and lavolta ii replicate phase 3 randomised double blind placebo controlled trials
    The Lancet Respiratory Medicine, 2016
    Co-Authors: Nicola A Hanania, Phillip E Korenblat, Julie Olsson, Kenneth R Chapman, Eric D Bateman, Petr Kopecky, Pierluigi Paggiaro, Akihito Yokoyama, Sarah Gray
    Abstract:

    Summary Background In phase 2 trials, Lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV 1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV 1 40–80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice–web-based response system to receive Lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ 2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061. Findings 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, Lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34–0·69], p vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both Lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both Lebrikizumab doses vs 4% [31 patients] for placebo) were similar between Lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with Lebrikizumab and one event of eosinophilic pneumonia in the placebo group. Interpretation Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out. Funding F Hoffmann-La Roche.

  • late breaking abstract lavolta i and ii results of 2 phase iii studies to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma
    European Respiratory Journal, 2016
    Co-Authors: Nicola A Hanania, Phillip E Korenblat, Julie Olsson, Kenneth R Chapman, Eric D Bateman, Petr Kopecky, Pierluigi Paggiaro, Akihito Yokoyama, Sarah Gray, Cecile T J Holweg
    Abstract:

    Introduction In Phase II trials, Lebrikizumab, an anti-IL-13 mAb, improved exacerbation rates and FEV1 in patients with uncontrolled asthma, particularly in patients with higher levels of Type 2 biomarkers. Aims LAVOLTA I ([NCT01867125][1]) and II ([NCT01868061][2]) are replicate Phase III studies designed to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma despite ICS and at least a second controller. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40–80% predicted, and stable background therapy were randomized to receive Lebrikizumab 37.5 mg or 125 mg, or placebo SC, Q4W. The primary efficacy endpoint was rate of asthma exacerbations during the 52-week placebo-controlled period in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells/µL). Secondary endpoints included change in FEV1 and ACQ-5. Results 1081 and 1067 patients were randomized and treated in LAVOLTA I and II. Over 52 weeks, Lebrikizumab treatment reduced exacerbation rates in biomarker-high patients by 51% for the 37.5 mg dose ( p <0.0001) and 30% for the 125 mg dose ( p <0.05) in LAVOLTA I and 26% for both doses in LAVOLTA II (not-significant) vs placebo. FEV1 improved vs placebo ( p <0.05) in biomarker-high patients in LAVOLTA I (103 and 113 mL) and LAVOLTA II (88 and 82 mL). There were no improvements in ACQ-5 vs placebo. Proportion of patients with treatment-emergent AEs, SAEs and AEs leading to discontinuation were balanced between groups. Conclusion In these replicate Phase III trials, LAVOLTA I met its primary endpoint and LAVOLTA II did not. Further work is ongoing to understand the trial results in more detail. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01867125&atom=%2Ferj%2F48%2Fsuppl_60%2FOA1975.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01868061&atom=%2Ferj%2F48%2Fsuppl_60%2FOA1975.atom

  • Lebrikizumab in the treatment of asthma
    Expert Opinion on Biological Therapy, 2016
    Co-Authors: Stephen Bujarski, Amit D Parulekar, Nicola A Hanania
    Abstract:

    ABSTRACTIntroduction: Severe asthma continues to be a major clinical problem despite the availability of effective asthma medications such as inhaled corticosteroids. Several targeted biologic therapies are emerging to treat patients with severe asthma.Areas covered: This review provides an update of information on Lebrikizumab, a novel monoclonal antibody that targets IL-13 and is currently in advanced stages of development. It describes the role of IL-13, a key effector cytokine in Type 2 (T2) airway inflammation in asthma and discusses the results of recent phase 2 trials investigating Lebrikizumab’s efficacy and safety in patients with severe asthma. Furthermore, it provides insight into the current ongoing trials with Lebrikizumab and outlines future research needs.Expert opinion: Several emerging therapeutic targets have been identified for patients with severe asthma. By specifically targeting IL-13, Lebrikizumab has the potential to block several downstream signals that play a role in disease prog...

John G Matthews - One of the best experts on this subject based on the ideXlab platform.

  • Seasonal variability of lung function and Asthma Quality of Life Questionnaire Scores in adults with uncontrolled asthma
    BMJ Open Respiratory Research, 2019
    Co-Authors: Rebecca N. Bauer, Joseph R Arron, John G Matthews, Cecile T J Holweg, Julie Olsson, Tracy Staton, Xiaoying Yang, David F Choy
    Abstract:

    Introduction Asthma exacerbations spike in the spring and autumn months, yet the seasonal variation of asthma symptoms and lung function is poorly studied. Methods Seasonal variation of lung function, rescue medication use and patient-reported symptoms was evaluated by posthoc analyses of the Phase III Lebrikizumab (anti-IL-13) LAVOLTA I and II studies in 2148 subjects with uncontrolled asthma. Lung function measurements (prebronchodilator FEV1, forced vital capacity (FVC) and peak expiratory flow (PEF)), rescue medication use and Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) were measured every 4 weeks over 52 weeks. By-month estimates normalised by hemispheric season were based on mixed-effect models with repeated measures (MMRM), adjusted by study stratification factors as covariates when appropriate. The dependency of clinical outcomes with seasonal variability was assessed by employing linear contrasts comparing hemisphere normalised December versus July group means from an MMRM regression and presented as the difference in means (adjusted 95% CI). Results FEV1, FVC and PEF, rescue medication use and AQLQ(S) progressively worsened towards winter, unlike spring and autumn surges in asthma exacerbations. The December versus July mean differences were: (1) PEF=−6.5 (–8.7 to –4.2) L/min, 2) prebronchodilator FEV1=−42 (–57 to –27) mL, (3) FVC=−41 (−59 to –23) mL and (4) AQLQ(S)=−0.15 (–0.19 to –0.1) units. Among AQLQ questions, discomfort or distress related to cough was most variable with respect to season (−0.33 (−0.42 to –0.24) units). Discussion Interpretation of interventional studies biased by seasonal exposures may be confounded by seasonal variability. Trials registration numbers NCT01867125 and NCT01868061.

  • efficacy and safety of Lebrikizumab in adult patients with mild to moderate asthma not receiving inhaled corticosteroids
    Respiratory Medicine, 2018
    Co-Authors: Philip Korenblat, Wendy S Putnam, Edwin Kerwin, Igor Leshchenko, Cecile T J Holweg, Judith Anzurescabrera, Carmen Martin, Laura Governale, Julie Olsson, John G Matthews
    Abstract:

    Abstract Background Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, Lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of Lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting β2-agonist therapy alone. Methods Adult patients with mild-to-moderate asthma were randomised to receive Lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV1 from baseline at Week 12. Findings A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV1 from baseline at Week 12 was higher in the Lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI: −3, 170]; p = .06). Montelukast did not improve FEV1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study. Interpretation Lebrikizumab did not significantly improve FEV1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of Lebrikizumab in patients not receiving ICS. Clinical Trials Registry number This trial was registered under NCT02104674 at http://www.clinicaltrials.gov .

  • model based clinical pharmacology profiling and exposure response relationships of the efficacy and biomarker of Lebrikizumab in patients with moderate to severe asthma
    Pulmonary Pharmacology & Therapeutics, 2017
    Co-Authors: Yanan Zheng, John G Matthews, Cecile T J Holweg, Julie Olsson, Kun Peng, Nathanael L Dirks, Shweta Vadhavkar, Wendy S Putnam
    Abstract:

    Abstract Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize Lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics. Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s [FEV 1 ], and fractional exhaled nitric oxide [FeNO]) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, Lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline. Lebrikizumab PK was described by a two-compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day −1 for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half-life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV 1 and FeNO showed increased response at higher exposure quartiles, while flat or unclear exposure-response relationships were observed in exacerbation rate. Lebrikizumab PK is as expected for a typical immunoglobulin G4 monoclonal antibody. Results from the exposure-response analyses suggested that, compared to 125 mg Q4W, the 37.5 mg Q4W dose did not achieve the maximum responses for FEV 1 and FeNO, although it appeared to maximize the effect on exacerbation reduction. This suggests that the antibody levels needed to improve these outcomes may not be the same. In addition, the role of IL-13 in airflow obstruction/airway inflammation and asthma exacerbations might be different and targeting multiple pathways may be required to treat this heterogeneous disease and provide clinically meaningful benefits to asthma patients.

  • specific immune response to phospholipase b like 2 protein a host cell impurity in Lebrikizumab clinical material
    Aaps Journal, 2017
    Co-Authors: Saloumeh Kadkhodayan Fischer, John G Matthews, Melissa Cheu, Elaine Murray, Kun Peng, John B Lowe, James Araujo, Dana Mcclintock, Patricia Siguenza, An Song
    Abstract:

    Host cell proteins are manufacturing process-related impurities that may co-purify with the product despite extensive efforts to optimize the purification process. The risks associated with these impurities can vary and may be patient and/or therapeutic dependent. Therefore, it is critical to monitor and control the levels of these impurities in products and their potential impact on safety and efficacy. Lebrikizumab is a humanized immunoglobulin G4 monoclonal antibody (mAb) that binds specifically to soluble interleukin 13. This mAb is currently in phase III clinical development for the treatment of asthma. Following initial phase III studies, the material used in Lebrikizumab clinical trials was found to have a process-related impurity identified as Chinese hamster ovary phospholipase B-like 2 (PLBL2) which co-purified with Lebrikizumab. The immunogenic potential of PLBL2 and its potential impact on the immunogenicity of Lebrikizumab in clinical studies were therefore evaluated. Data from the clinical studies demonstrated that ∼90% of subjects developed a specific and measurable immune response to PLBL2. Given the high incidence of antibodies to PLBL2 as well as the comparable safety profile observed between placebo- and drug-treated subjects, no correlation between safety events and anti-PLBL2 antibodies could be made. Additionally, no impact on the incidence of anti-Lebrikizumab antibodies was observed, suggesting the lack of an adjuvant effect from PLBL2. Interim analysis from ongoing phase III studies using material with substantially reduced levels of PLBL2 with patients having had longer exposure shows significantly less and dose-dependent frequency of immune responses to PLBL2.

  • p157 seasonal variability of severe asthma exacerbations and clinical benefit from Lebrikizumab
    Thorax, 2016
    Co-Authors: David F Choy, Joseph R Arron, Julie Olsson, Tracy Staton, Ctj Holweg, S Grey, Akiko Chai, John G Matthews
    Abstract:

    Introduction and objectives Epidemiologic studies have implicated aeroallergens and respiratory infections as triggers underlying seasonal increases in asthma exacerbations in spring and autumn months. These seasonal factors may trigger or amplify airway inflammation in atopic, Type 2 high asthma patients that precipitates acute worsening of symptoms. Biologic therapies targeting Type 2 cytokine pathways have demonstrated efficacy in reducing the rate of severe asthma exacerbations, particularly in patients selected on the basis of Type 2 biomarkers. In children with asthma, increased inhaled corticosteroid or anti-IgE therapy has been found to reduce the rate of seasonal exacerbations. We hypothesised that Lebrikizumab (anti-IL-13) therapy would likewise be effective in reducing seasonal exacerbations in adults with asthma. Methods We conducted post-hoc analyses of the Phase III LAVOLTA studies (NCT01867125 and NCT01868061) to assess the seasonal dependence of exacerbations and efficacy of Lebrikizumab in 2,148 adults with moderate to severe asthma. We employed Poisson regression utilising linear mixed models to estimate the per-month (normalised by hemisphere) annualised exacerbation rate and treatment effect of Lebrikizumab in reducing exacerbations (percent rate reduction). Results Per-month exacerbation rates in placebo treated eosinophil-low ( Conclusions We conclude that seasonal spikes in exacerbations may be primarily dependent on Type 2 inflammatory processes. The molecular pathways underlying asthma exacerbations are heterogeneous and therapeutic strategies targeting Type 2 biology alone may have the greatest efficacy in limiting seasonal spikes in exacerbation rates. Overall, these data highlight that a significant proportion of asthma exacerbations may be independent of seasonal influences and/or Type 2 biology and that increased therapeutic efficacy may require targeting multiple distinct pathways in asthma.

Phillip E Korenblat - One of the best experts on this subject based on the ideXlab platform.

  • LATE-BREAKING ABSTRACT: LAVOLTA I and II: Results of 2 phase III studies to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma
    European Respiratory Journal, 2016
    Co-Authors: Nicola A Hanania, Phillip E Korenblat, Julie Olsson, Kenneth R Chapman, Eric D Bateman, Petr Kopecky, Pierluigi Paggiaro, Akihito Yokoyama, Sarah Gray, Cecile T J Holweg
    Abstract:

    Introduction In Phase II trials, Lebrikizumab, an anti-IL-13 mAb, improved exacerbation rates and FEV1 in patients with uncontrolled asthma, particularly in patients with higher levels of Type 2 biomarkers. Aims LAVOLTA I ([NCT01867125][1]) and II ([NCT01868061][2]) are replicate Phase III studies designed to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma despite ICS and at least a second controller. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40–80% predicted, and stable background therapy were randomized to receive Lebrikizumab 37.5 mg or 125 mg, or placebo SC, Q4W. The primary efficacy endpoint was rate of asthma exacerbations during the 52-week placebo-controlled period in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells/µL). Secondary endpoints included change in FEV1 and ACQ-5. Results 1081 and 1067 patients were randomized and treated in LAVOLTA I and II. Over 52 weeks, Lebrikizumab treatment reduced exacerbation rates in biomarker-high patients by 51% for the 37.5 mg dose ( p

  • efficacy and safety of Lebrikizumab in patients with uncontrolled asthma lavolta i and lavolta ii replicate phase 3 randomised double blind placebo controlled trials
    The Lancet Respiratory Medicine, 2016
    Co-Authors: Nicola A Hanania, Phillip E Korenblat, Julie Olsson, Kenneth R Chapman, Eric D Bateman, Petr Kopecky, Pierluigi Paggiaro, Akihito Yokoyama, Sarah Gray
    Abstract:

    Summary Background In phase 2 trials, Lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV 1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV 1 40–80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice–web-based response system to receive Lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ 2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061. Findings 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, Lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34–0·69], p vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both Lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both Lebrikizumab doses vs 4% [31 patients] for placebo) were similar between Lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with Lebrikizumab and one event of eosinophilic pneumonia in the placebo group. Interpretation Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out. Funding F Hoffmann-La Roche.

  • late breaking abstract lavolta i and ii results of 2 phase iii studies to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma
    European Respiratory Journal, 2016
    Co-Authors: Nicola A Hanania, Phillip E Korenblat, Julie Olsson, Kenneth R Chapman, Eric D Bateman, Petr Kopecky, Pierluigi Paggiaro, Akihito Yokoyama, Sarah Gray, Cecile T J Holweg
    Abstract:

    Introduction In Phase II trials, Lebrikizumab, an anti-IL-13 mAb, improved exacerbation rates and FEV1 in patients with uncontrolled asthma, particularly in patients with higher levels of Type 2 biomarkers. Aims LAVOLTA I ([NCT01867125][1]) and II ([NCT01868061][2]) are replicate Phase III studies designed to assess the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma despite ICS and at least a second controller. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40–80% predicted, and stable background therapy were randomized to receive Lebrikizumab 37.5 mg or 125 mg, or placebo SC, Q4W. The primary efficacy endpoint was rate of asthma exacerbations during the 52-week placebo-controlled period in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells/µL). Secondary endpoints included change in FEV1 and ACQ-5. Results 1081 and 1067 patients were randomized and treated in LAVOLTA I and II. Over 52 weeks, Lebrikizumab treatment reduced exacerbation rates in biomarker-high patients by 51% for the 37.5 mg dose ( p <0.0001) and 30% for the 125 mg dose ( p <0.05) in LAVOLTA I and 26% for both doses in LAVOLTA II (not-significant) vs placebo. FEV1 improved vs placebo ( p <0.05) in biomarker-high patients in LAVOLTA I (103 and 113 mL) and LAVOLTA II (88 and 82 mL). There were no improvements in ACQ-5 vs placebo. Proportion of patients with treatment-emergent AEs, SAEs and AEs leading to discontinuation were balanced between groups. Conclusion In these replicate Phase III trials, LAVOLTA I met its primary endpoint and LAVOLTA II did not. Further work is ongoing to understand the trial results in more detail. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01867125&atom=%2Ferj%2F48%2Fsuppl_60%2FOA1975.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01868061&atom=%2Ferj%2F48%2Fsuppl_60%2FOA1975.atom

  • Lebrikizumab in moderate to severe asthma pooled data from two randomised placebo controlled studies
    Thorax, 2015
    Co-Authors: Nicola A Hanania, Wendy S Putnam, Yanan Zheng, Jonathan Corren, Phillip E Korenblat, Michael Noonan, Saloumeh Kadkhodayan Fischer, Melissa Cheu, Elaine Murray, Heleen Scheerens
    Abstract:

    Introduction In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity. Methods LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of Lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received Lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies. Results The median duration of treatment was approximately 24 weeks. Treatment with Lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose–response was evident. Lung function also improved following Lebrikizumab treatment, with greatest increase in FEV 1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed. Conclusions These data are consistent with, and extend, previously published results demonstrating the efficacy of Lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment. Trial registration numbers The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov

  • dose ranging study of Lebrikizumab in asthmatic patients not receiving inhaled steroids
    The Journal of Allergy and Clinical Immunology, 2013
    Co-Authors: Michael Noonan, Wendy S Putnam, Heleen Scheerens, Joseph R Arron, Yanan Zheng, Phillip E Korenblat, Merdad V Parsey, Sofia Mosesova, Sean P Bohen, John G Matthews
    Abstract:

    Background Asthma is a disease with marked heterogeneity in its clinical course and response to treatment. IL-13 is central to type 2 inflammation, which contributes to many key features of asthma. Lebrikizumab is an anti–IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy, especially in periostin-high patients. Objective This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of Lebrikizumab in asthmatic patients not receiving inhaled corticosteroids. Methods Patients were randomized to receive 125, 250, or 500 mg of Lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period. The primary efficacy end point was the relative change in prebronchodilator FEV 1 from baseline to week 12. Results A total of 212 patients were randomized. The mean relative change in FEV 1 was numerically higher in all Lebrikizumab dose groups versus the placebo group, although the difference was neither statistically nor clinically significant. There were no meaningful differences in changes in FEV 1 between the dose groups and the placebo group by the periostin subgroup. Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo ( P Conclusion Blocking IL-13, a single cytokine, in this population of asthmatic patients is insufficient to improve lung function. There is evidence that IL-13 blockade may improve disease control, as measured by prevention of protocol-defined treatment failure in these patients.

Heleen Scheerens - One of the best experts on this subject based on the ideXlab platform.

  • LATE-BREAKING ABSTRACT: Serum IL-13 is a peripheral biomarker for Type 2 asthma
    European Respiratory Journal, 2015
    Co-Authors: David F Choy, Joseph R Arron, John G Matthews, Cecile T J Holweg, Jochen Brumm, Alyssa Morimoto, Heleen Scheerens
    Abstract:

    Serum periostin, blood eosinophils, and FeNO are biomarkers of Type 2 airway inflammation in asthma. Elevated levels of these biomarkers are associated with increased clinical benefit from Lebrikizumab, an anti-IL13 mAb, in uncontrolled asthma despite standard of care. We recently developed a highly specific serum IL-13 assay with a lower limit of quantification of 14 fg/ml (IMPACT TM ). We measured serum IL-13 levels in healthy volunteers (N=228), in uncontrolled moderate to severe asthma patients from three independent Lebrikizumab Phase 2 clinical studies (n=499 total)at baseline, and in uncontrolled severe asthma patients from an observational bronchoscopy study (n=62). Serum IL-13 levels were significantly elevated in severe asthma patients (median 0.87 pg/ml) relative to healthy volunteers (median 0.54 pg/ml). In addition, serum IL-13 levels strongly correlated with a Type 2 gene signature in bronchial epithelium from severe asthma patients in the observational bronchoscopy study (Spearman ρ=0.66). In moderate to severe asthma patients, serum IL-13 at baseline strongly correlated with blood eosinophils (Spearman ρ=0.61) and weakly correlated with FeNO and serum periostin (Spearman ρ=0.32 and 0.24, respectively). The elevated serum IL-13 levels at baseline enriched for future asthma exacerbations and predicted increased clinical benefits from Lebrikizumab treatment with respect to both FEV1 improvement and asthma exacerbations reduction. In conclusion, we have developed a highly sensitive and specific assay for serum IL-13, which may be an additional biomarker for identification of asthma patients with underlying Type 2 airway inflammation.

  • Lebrikizumab in moderate to severe asthma pooled data from two randomised placebo controlled studies
    Thorax, 2015
    Co-Authors: Nicola A Hanania, Wendy S Putnam, Yanan Zheng, Jonathan Corren, Phillip E Korenblat, Michael Noonan, Saloumeh Kadkhodayan Fischer, Melissa Cheu, Elaine Murray, Heleen Scheerens
    Abstract:

    Introduction In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity. Methods LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of Lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received Lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies. Results The median duration of treatment was approximately 24 weeks. Treatment with Lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose–response was evident. Lung function also improved following Lebrikizumab treatment, with greatest increase in FEV 1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed. Conclusions These data are consistent with, and extend, previously published results demonstrating the efficacy of Lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment. Trial registration numbers The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov

  • the effects of Lebrikizumab in patients with mild asthma following whole lung allergen challenge
    Clinical & Experimental Allergy, 2014
    Co-Authors: Heleen Scheerens, Wendy S Putnam, Joseph R Arron, Yanan Zheng, Rich Erickson, David F Choy, Jeffrey M Harris, Nizar N Jarjour, John G Matthews
    Abstract:

    SummaryBackground Interleukin 13 (IL13) is a T-helper type 2 (Th2) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma. We have shown that treatment with Lebrikizumab, an anti-IL13 monoclonal antibody, significantly improves prebronchodilator forced expiratory volume in 1 s (FEV1) in a subset of subjects with uncontrolled asthma. Objective To evaluate efficacy and safety of Lebrikizumab in subjects with mild asthma who underwent bronchial allergen challenge. Methods Twenty-nine subjects were randomized 1 : 1–5 mg/kg Lebrikizumab (n = 13) or placebo (n = 16) administered subcutaneously every 4 weeks over 12 weeks, a total of four doses. Primary efficacy outcome was late asthmatic response (LAR) at Week 13, defined as area under the curve of FEV1 measured 2–8 h following inhaled allergen challenge. Serum biomarkers were measured to verify IL13 pathway inhibition and identify patients with an increased response to Lebrikizumab. Results At Week 13, the LAR in Lebrikizumab subjects was reduced by 48% compared with placebo subjects, although this was not statistically significant (95% confidence interval, −19%, 90%). Exploratory analysis indicated that Lebrikizumab-treated subjects with elevated baseline levels of peripheral blood eosinophils, serum IgE, or periostin exhibited a greater reduction in LAR compared with subjects with lower baseline levels of these biomarkers. Lebrikizumab exerted systemic effects on markers of Th2 inflammation, reducing serum immunoglobulin E (IgE), chemokine ligands 13 and 17 by approximately 25% (P < 0.01). Lebrikizumab was well tolerated. Conclusion and Clinical Relevance Lebrikizumab reduced the LAR in subjects with mild asthma. Clinical trial number NCT00781443.

  • The effects of Lebrikizumab in patients with mild asthma following whole lung allergen challenge.
    Clinical & Experimental Allergy, 2013
    Co-Authors: Heleen Scheerens, Wendy S Putnam, Joseph R Arron, Yanan Zheng, Rich Erickson, David F Choy, Jeffrey M Harris, Nizar N Jarjour, John G Matthews
    Abstract:

    SummaryBackground Interleukin 13 (IL13) is a T-helper type 2 (Th2) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma. We have shown that treatment with Lebrikizumab, an anti-IL13 monoclonal antibody, significantly improves prebronchodilator forced expiratory volume in 1 s (FEV1) in a subset of subjects with uncontrolled asthma. Objective To evaluate efficacy and safety of Lebrikizumab in subjects with mild asthma who underwent bronchial allergen challenge. Methods Twenty-nine subjects were randomized 1 : 1–5 mg/kg Lebrikizumab (n = 13) or placebo (n = 16) administered subcutaneously every 4 weeks over 12 weeks, a total of four doses. Primary efficacy outcome was late asthmatic response (LAR) at Week 13, defined as area under the curve of FEV1 measured 2–8 h following inhaled allergen challenge. Serum biomarkers were measured to verify IL13 pathway inhibition and identify patients with an increased response to Lebrikizumab. Results At Week 13, the LAR in Lebrikizumab subjects was reduced by 48% compared with placebo subjects, although this was not statistically significant (95% confidence interval, −19%, 90%). Exploratory analysis indicated that Lebrikizumab-treated subjects with elevated baseline levels of peripheral blood eosinophils, serum IgE, or periostin exhibited a greater reduction in LAR compared with subjects with lower baseline levels of these biomarkers. Lebrikizumab exerted systemic effects on markers of Th2 inflammation, reducing serum immunoglobulin E (IgE), chemokine ligands 13 and 17 by approximately 25% (P 

  • dose ranging study of Lebrikizumab in asthmatic patients not receiving inhaled steroids
    The Journal of Allergy and Clinical Immunology, 2013
    Co-Authors: Michael Noonan, Wendy S Putnam, Heleen Scheerens, Joseph R Arron, Yanan Zheng, Phillip E Korenblat, Merdad V Parsey, Sofia Mosesova, Sean P Bohen, John G Matthews
    Abstract:

    Background Asthma is a disease with marked heterogeneity in its clinical course and response to treatment. IL-13 is central to type 2 inflammation, which contributes to many key features of asthma. Lebrikizumab is an anti–IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy, especially in periostin-high patients. Objective This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of Lebrikizumab in asthmatic patients not receiving inhaled corticosteroids. Methods Patients were randomized to receive 125, 250, or 500 mg of Lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period. The primary efficacy end point was the relative change in prebronchodilator FEV 1 from baseline to week 12. Results A total of 212 patients were randomized. The mean relative change in FEV 1 was numerically higher in all Lebrikizumab dose groups versus the placebo group, although the difference was neither statistically nor clinically significant. There were no meaningful differences in changes in FEV 1 between the dose groups and the placebo group by the periostin subgroup. Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo ( P Conclusion Blocking IL-13, a single cytokine, in this population of asthmatic patients is insufficient to improve lung function. There is evidence that IL-13 blockade may improve disease control, as measured by prevention of protocol-defined treatment failure in these patients.

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  • efficacy and safety of Lebrikizumab an anti il 13 monoclonal antibody in adults with moderate to severe atopic dermatitis inadequately controlled by topical corticosteroids a randomized placebo controlled phase ii trial treble
    Journal of The American Academy of Dermatology, 2018
    Co-Authors: Eric L Simpson, Carsten Flohr, Lawrence F Eichenfield, Thomas Bieber, H Sofen, A Taieb, Ryan Owen, Wendy S Putnam, Marcela Castro, Kendra Debusk
    Abstract:

    Background Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD). Objective We investigated the efficacy and safety of Lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment. Methods A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to Lebrikizumab 125 mg single dose, Lebrikizumab 250 mg single dose, Lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12. Results In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with Lebrikizumab 125 mg every 4 weeks (82.4%; P  = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of Lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all Lebrikizumab vs 66.0% placebo) and mostly mild or moderate. Limitations Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of Lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations. Conclusion When combined with TCS, Lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD.

  • efficacy and safety of Lebrikizumab in adult patients with mild to moderate asthma not receiving inhaled corticosteroids
    Respiratory Medicine, 2018
    Co-Authors: Philip Korenblat, Wendy S Putnam, Edwin Kerwin, Igor Leshchenko, Cecile T J Holweg, Judith Anzurescabrera, Carmen Martin, Laura Governale, Julie Olsson, John G Matthews
    Abstract:

    Abstract Background Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, Lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of Lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting β2-agonist therapy alone. Methods Adult patients with mild-to-moderate asthma were randomised to receive Lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV1 from baseline at Week 12. Findings A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV1 from baseline at Week 12 was higher in the Lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI: −3, 170]; p = .06). Montelukast did not improve FEV1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study. Interpretation Lebrikizumab did not significantly improve FEV1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of Lebrikizumab in patients not receiving ICS. Clinical Trials Registry number This trial was registered under NCT02104674 at http://www.clinicaltrials.gov .

  • model based clinical pharmacology profiling and exposure response relationships of the efficacy and biomarker of Lebrikizumab in patients with moderate to severe asthma
    Pulmonary Pharmacology & Therapeutics, 2017
    Co-Authors: Yanan Zheng, John G Matthews, Cecile T J Holweg, Julie Olsson, Kun Peng, Nathanael L Dirks, Shweta Vadhavkar, Wendy S Putnam
    Abstract:

    Abstract Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize Lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics. Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s [FEV 1 ], and fractional exhaled nitric oxide [FeNO]) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, Lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline. Lebrikizumab PK was described by a two-compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day −1 for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half-life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV 1 and FeNO showed increased response at higher exposure quartiles, while flat or unclear exposure-response relationships were observed in exacerbation rate. Lebrikizumab PK is as expected for a typical immunoglobulin G4 monoclonal antibody. Results from the exposure-response analyses suggested that, compared to 125 mg Q4W, the 37.5 mg Q4W dose did not achieve the maximum responses for FEV 1 and FeNO, although it appeared to maximize the effect on exacerbation reduction. This suggests that the antibody levels needed to improve these outcomes may not be the same. In addition, the role of IL-13 in airflow obstruction/airway inflammation and asthma exacerbations might be different and targeting multiple pathways may be required to treat this heterogeneous disease and provide clinically meaningful benefits to asthma patients.

  • Lebrikizumab in moderate to severe asthma pooled data from two randomised placebo controlled studies
    Thorax, 2015
    Co-Authors: Nicola A Hanania, Wendy S Putnam, Yanan Zheng, Jonathan Corren, Phillip E Korenblat, Michael Noonan, Saloumeh Kadkhodayan Fischer, Melissa Cheu, Elaine Murray, Heleen Scheerens
    Abstract:

    Introduction In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity. Methods LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of Lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received Lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies. Results The median duration of treatment was approximately 24 weeks. Treatment with Lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose–response was evident. Lung function also improved following Lebrikizumab treatment, with greatest increase in FEV 1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed. Conclusions These data are consistent with, and extend, previously published results demonstrating the efficacy of Lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment. Trial registration numbers The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov

  • the effects of Lebrikizumab in patients with mild asthma following whole lung allergen challenge
    Clinical & Experimental Allergy, 2014
    Co-Authors: Heleen Scheerens, Wendy S Putnam, Joseph R Arron, Yanan Zheng, Rich Erickson, David F Choy, Jeffrey M Harris, Nizar N Jarjour, John G Matthews
    Abstract:

    SummaryBackground Interleukin 13 (IL13) is a T-helper type 2 (Th2) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma. We have shown that treatment with Lebrikizumab, an anti-IL13 monoclonal antibody, significantly improves prebronchodilator forced expiratory volume in 1 s (FEV1) in a subset of subjects with uncontrolled asthma. Objective To evaluate efficacy and safety of Lebrikizumab in subjects with mild asthma who underwent bronchial allergen challenge. Methods Twenty-nine subjects were randomized 1 : 1–5 mg/kg Lebrikizumab (n = 13) or placebo (n = 16) administered subcutaneously every 4 weeks over 12 weeks, a total of four doses. Primary efficacy outcome was late asthmatic response (LAR) at Week 13, defined as area under the curve of FEV1 measured 2–8 h following inhaled allergen challenge. Serum biomarkers were measured to verify IL13 pathway inhibition and identify patients with an increased response to Lebrikizumab. Results At Week 13, the LAR in Lebrikizumab subjects was reduced by 48% compared with placebo subjects, although this was not statistically significant (95% confidence interval, −19%, 90%). Exploratory analysis indicated that Lebrikizumab-treated subjects with elevated baseline levels of peripheral blood eosinophils, serum IgE, or periostin exhibited a greater reduction in LAR compared with subjects with lower baseline levels of these biomarkers. Lebrikizumab exerted systemic effects on markers of Th2 inflammation, reducing serum immunoglobulin E (IgE), chemokine ligands 13 and 17 by approximately 25% (P < 0.01). Lebrikizumab was well tolerated. Conclusion and Clinical Relevance Lebrikizumab reduced the LAR in subjects with mild asthma. Clinical trial number NCT00781443.