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Paul Baverel, Dewei She, Edward Piper, Shinya Ueda, Tomoko Yoshioka, Raffaella Faggioni, Hakop Gevorkyan
Tralokinumab is a human monoclonal antibody in clinical development for asthma and atopic dermatitis that specifically neutralizes interleukin-13. This phase I, single-blind, randomized, placebo-controlled, single ascending-dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous tralokinumab (150, 300, or 600 mg) in thirty healthy Japanese adults. The most frequent treatment-emergent adverse event (TEAE) in all treatment groups was injection-site pain. The frequency and severity of TEAEs was similar across tralokinumab doses...
December 12, 2017: Drug Metabolism and Pharmacokinetics
Reynold A Panettieri, Millie Wang, Martin Braddock, Karin Bowen, Gene Colice
Tralokinumab, a fully human IgG4 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...
March 14, 2018: Immunotherapy
J-P Lacour
The treatment of atopic dermatitis in adults is based on the use of topical steroids and emollients. When AD is resistant to a well-conducted topical treatment, phototherapy or systemic treatments can be used: ciclosporin, methotrexate, azathioprine or mycophenolate mofetil. The therapeutic landscape of adult AD is about to change and even be revolutionized by the imminent arrival of new treatments: topical phosphodiesterase 4 inhibitors, topical or systemic JAK inhibitors, anti-IL-4 and/or antiIL-13 biotherapies (dupilumab, tralokinumab, lebrikizumab), anti-IL-31 (nemolizumab), anti-TSLP...
December 2017: Annales de Dermatologie et de Vénéréologie
Yutaka Nakamura, Aki Sugano, Mika Ohta, Yutaka Takaoka
Interleukin-13 (IL-13) is associated with allergic airway inflammation and airway remodeling. Our group found a variant with a single nucleotide polymorphism in the IL13 gene at position +2044G>A (rs20541) that was expected to result in the non-conservative replacement of a positively charged arginine (R) with a neutral glutamine (Q) at position 144. IL-13Q144 was associated with augmented allergic airway inflammation and bronchial asthma remodeling. There is some indication that anti-IL-13 monoclonal antibodies can demonstrate a positive effect on the clinical course of refractory asthmatic patients...
2017: PloS One
Igor Snast, Ofer Reiter, Emmilia Hodak, Rivka Friedland, Daniel Mimouni, Yael Anne Leshem
BACKGROUND: Current systemic treatments for atopic dermatitis (AD) offer limited efficacy and are often restricted by safety concerns. Biologics may address the unmet need for improved AD therapeutics. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of biologic agents in AD. METHODS: A systematic review and meta-analysis of studies evaluating AD patients treated with biologics was performed. The primary outcome was the Eczema Area and Severity Index (EASI)-75 response, while secondary outcomes were SCOring Atopic Dermatitis (SCORAD)-75, EASI-50, SCORAD-50, Investigator Global Assessment 0/1 responses, change in responses from baseline, and adverse events...
November 2, 2017: American Journal of Clinical Dermatology
Amit D Parulekar, Christina C Kao, Zuzana Diamant, Nicola A Hanania
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...
January 2018: Current Opinion in Pulmonary Medicine
Mark G Jones, Giacomo Sgalla, Luca Richeldi
No abstract text is available yet for this article.
January 1, 2018: American Journal of Respiratory and Critical Care Medicine
Paul G Baverel, Nicholas White, Paolo Vicini, Mats O Karlsson, Balaji Agoram
Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G4 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 (FEV1 )) relationship in patients with asthma and to predict the most appropriate dose for phase III...
July 30, 2017: Clinical Pharmacology and Therapeutics
Meena Jain, Diane Doughty, Corbin Clawson, Xiaobai Li, Nicholas White, Balaji Agoram, René van der Merwe
OBJECTIVE: Tralokinumab, administered as two 1-mL subcutaneous injections every 2 weeks, at the target dose 300 mg, has been shown to improve lung function in patients with asthma. This study evaluated the pharmacokinetic (PK) and tolerability profile of tralokinumab 300 mg when administered by different rates of subcutaneous injection, as part of a pilot investigation of new injection regimens. METHODS: This phase I study randomized 60 healthy adults to receive 300 mg tralokinumab, as two 1-mL subcutaneous injections, each delivered over 10 seconds, or one 2-mL injection delivered over 10 seconds (12 mL/min), 1 minute (2 mL/min), or 12 minutes (0...
July 2017: International Journal of Clinical Pharmacology and Therapeutics
Elisabeth H Bel, Anneke Ten Brinke
Asthma and COPD are prevalent chronic inflammatory airway diseases that are responsible for a large global disease burden. Both diseases are complex and heterogeneous, and they are increasingly recognized as overlapping syndromes that may share similar pathophysiologic mechanisms and treatable traits. Eosinophilic airway inflammation is considered the most influential treatable trait of chronic airway disease, and over the last decade, several monoclonal antibodies and small molecule therapies have been developed to target this trait...
December 2017: Chest
Janice M Reichert
Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend toward first marketing approvals of at least 6-9 mAbs per year in the near-term. In the United States (US), a total of 6 and 9 mAbs were granted first approvals during 2014 and 2015, respectively; all these products are also approved in the European Union (EU). As of December 1, 2016, 6 mAbs (atezolizumab, olaratumab, reslizumab, ixekizumab, bezlotoxumab, oblitoxaximab) had been granted first approvals during 2016 in either the EU or US...
February 2017: MAbs
B Popovic, J Breed, D G Rees, M J Gardener, L M K Vinall, B Kemp, J Spooner, J Keen, R Minter, F Uddin, G Colice, T Wilkinson, T Vaughan, R D May
Interleukin (IL)-13 is a pleiotropic T helper type 2 cytokine frequently associated with asthma and atopic dermatitis. IL-13-mediated signalling is initiated by binding to IL-13Rα1, which then recruits IL-4Rα to form a heterodimeric receptor complex. IL-13 also binds to IL-13Rα2, considered as either a decoy or a key mediator of fibrosis. IL-13-neutralising antibodies act by preventing IL-13 binding to IL-13Rα1, IL-4Rα and/or IL-13Rα2. Tralokinumab (CAT-354) is an IL-13-neutralising human IgG4 monoclonal antibody that has shown clinical benefit in patients with asthma...
January 20, 2017: Journal of Molecular Biology
T Karelina, V Voronova, O Demin, G Colice, B M Agoram
Emerging T-helper type 2 (Th2 ) cytokine-based asthma therapies, such as tralokinumab, lebrikizumab (anti-interleukin (IL)-13), and mepolizumab (anti-IL-5), have shown differences in their blood eosinophil (EOS) response. To better understand these effects, we developed a mathematical model of EOS dynamics. For the anti-IL-13 therapies, lebrikizumab and tralokinumab, the model predicted an increase of 30% and 10% in total and activated EOS in the blood, respectively, and a decrease in the total and activated EOS in the airways...
November 2016: CPT: Pharmacometrics & Systems Pharmacology
Diego Bagnasco, Matteo Ferrando, Gilda Varricchi, Giovanni Passalacqua, Giorgio Walter Canonica
Asthma is a high-prevalence disease, still accounting for mortality and high direct and indirect costs. It is now recognized that, despite the implementation of guidelines, a large proportion of cases remain not controlled. Certainly, adherence to therapy and the education of patients remain the primary objective, but the increasingly detailed knowledge about the pathogenic mechanisms and new biotechnologies offer the opportunity to better address and treat the disease. Interleukin (IL)-13 and IL-4 appear as the most suitable targets to treat the T helper 2 (TH2)-mediated forms (endotypes) of asthma...
2016: International Archives of Allergy and Immunology
Ibrahim Sulaiman, Jonathan Chee Woei Lim, Hon Liong Soo, Johnson Stanslas
Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs...
October 2016: Pulmonary Pharmacology & Therapeutics
Renata Rubinsztajn, Ryszarda Chazan
Asthma is a heterogeneous inflammatory disease. Most patients respond to current standard of care, i.e., bronchodilators, inhaled glucocorticosteroids and other anti-inflammatory drugs, but in some adequate asthma control cannot be achieved with standard treatments. These difficult-to-treat patients would be the target population for new biological therapies. At present, omalizumab is the only biological agent approved for the treatment of early-onset, severe IgE-dependent asthma. It is safe, effective, and well tolerated...
2016: Advances in Experimental Medicine and Biology
Christopher E Brightling, Pascal Chanez, Richard Leigh, Paul M O'Byrne, Stephanie Korn, Dewei She, Richard D May, Katie Streicher, Koustubh Ranade, Edward Piper
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...
September 2015: Lancet Respiratory Medicine
Paul G Baverel, Meena Jain, Iwona Stelmach, Dewei She, Balaji Agoram, Sara Sandbach, Edward Piper, Piotr Kuna
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...
December 2015: British Journal of Clinical Pharmacology
Silvio Danese, Janusz Rudziński, Wolfgang Brandt, Jean-Louis Dupas, Laurent Peyrin-Biroulet, Yoram Bouhnik, Dariusz Kleczkowski, Peter Uebel, Milan Lukas, Mikael Knutsson, Fredrik Erlandsson, Mark Berner Hansen, Satish Keshav
OBJECTIVE: Interleukin-13 (IL-13) has been implicated as a key driver of UC. This trial evaluates the efficacy and safety of tralokinumab, an IL-13-neutralising antibody, as add-on therapy in adults with moderate-to-severe UC despite standard treatments. DESIGN: Non-hospitalised adults with UC (total Mayo score ≥6) were randomised to receive tralokinumab 300 mg or placebo subcutaneously every 2 weeks for 12 weeks. The primary end point was the rate of clinical response at week 8...
February 2015: Gut
Lynne A Murray, Huilan Zhang, Sameer R Oak, Ana Lucia Coelho, Athula Herath, Kevin R Flaherty, Joyce Lee, Matt Bell, Darryl A Knight, Fernando J Martinez, Matthew A Sleeman, Erica L Herzog, Cory M Hogaboam
The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease...
May 2014: American Journal of Respiratory Cell and Molecular Biology
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