Wenzel, S., Wilbraham, D., Fuller, R., Getz, E.B. & Longphre, M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370, 1422-1431

University of Pittsburgh, Division of Pulmonary, Allergy, and Critical Care Medicine, Pittsburgh, PA, USA.
The Lancet (Impact Factor: 45.22). 11/2007; 370(9596):1422-31. DOI: 10.1016/S0140-6736(07)61600-6
Source: PubMed


Increases in T helper (Th) 2 cytokine concentrations have been seen in atopic asthma, with interleukin 4 and interleukin 13 thought to have a role in the physiological response to allergen challenge. Our aim was to assess the therapeutic effect of pitrakinra, an interleukin-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of interleukin 4 and interleukin 13 to interleukin-4Ralpha receptor complexes.
In two independent randomised, double-blind, placebo-controlled, parallel group phase 2a clinical trials, patients with atopic asthma were treated with pitrakinra or placebo via two routes. In study 1, patients were randomly assigned to receive either 25 mg pitrakinra (n=12) or placebo (n=12) by subcutaneous injection once daily. In study 2, patients were randomly assigned to receive either 60 mg pitrakinra (n=16) or placebo (n=16) by nebulisation twice daily. Inhaled allergen challenge was done before and after 4 weeks of treatment. The primary endpoint for study 1 was maximum percentage decrease in forced expiratory volume in 1 s (FEV1) over 4-10 h after allergen challenge, whereas that in study 2 was average percentage decrease in FEV(1) over 4-10 h after allergen challenge. All patients except those with baseline data only were included in our analyses. These trials are registered with, numbers NCT00535028 and NCT00535031.
No patients dropped out or were lost to follow-up in study 1; in study 2, two patients in the placebo group and one in the pitrakinra group dropped out or were lost to follow-up. These individuals had baseline data only, and were excluded from the analyses. In study 1, there was a 17.1% maximum percentage decrease in FEV1 in the pitrakinra group; by contrast, the maximum decrease was 23.1% in the placebo group (difference 6%, 95% CI -4.37 to 16.32; p=0.243). In study 2, there was a 4.4% average percentage decrease in FEV1 in the pitrakinra group; by contrast, the average percentage decrease was 15.9% in the placebo group (3.7 [95% CI 2.08-6.25] times lower in the pitrakinra group; p=0.0001). There were fewer asthma-related adverse events (p=0.069) and fewer adverse events requiring beta-agonist rescue (p=0.031) after subcutaneous administration of pitrakinra than with placebo. There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events.
Local treatment, targeted at inhibition of interleukins 4 and 13 in the lung, could substantially diminish the symptoms of asthma.

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    • "Moreover, in spite of some initial encouraging results with use of the soluble recombinant human IL-4 receptor altrakincept, subsequent studies have not shown any clinical effectiveness.32 Pitrakinra, a mutein obtained by site-directed changes performed on the IL-4 amino acid sequence, that behaves as a dual IL-4/IL-13 antagonist, appears to be characterized by a better therapeutic profile.33 Indeed, when received subcutaneously or via inhalation in asthmatic patients, pitrakinra is well tolerated, attenuates early and late allergic bronchoconstrictive reactions, and also decreases exacerbations of eosinophilic asthma.34,35 Further, in a recent pharmacogenetic, placebo-controlled trial focused on modulation of IL-4/IL-13-mediated mechanisms, several dosages (1 mg, 3 mg, or 10 mg twice a day for 12 weeks) of inhaled pitrakinra were evaluated in asthmatic patients with moderate-to-severe disease.36 "
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    ABSTRACT: Simultaneously with the steady progress towards a better knowledge of the pathobiology of asthma, the potential usefulness of anticytokine therapies is emerging as one of the key concepts in the newly developing treatments of this widespread airway disease. In particular, given the key role played by interleukin (IL)-4 and IL-13 in the pathophysiology of the most typical aspects of asthma, such as chronic airway inflammation, tissue remodeling, and bronchial hyperresponsiveness, these pleiotropic cytokines are now considered as suitable therapeutic targets. Among the recently developed antiasthma biologic drugs, the monoclonal antibody dupilumab is very promising because of its ability to inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. A recent trial showed that in patients with difficult-to-control asthma, dupilumab can markedly decrease asthma exacerbations and improve respiratory symptoms and lung function; these effects were paralleled by significant reductions in T-helper 2-associated inflammatory biomarkers. However, further larger and longer trials are required to extend and validate these preliminary results, and also to carefully study the safety and tolerability profile of dupilumab.
    Journal of Asthma and Allergy 09/2014; 7:123-30. DOI:10.2147/JAA.S52387
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    • "Pitrakinra is an antagonist targeting the IL-4/IL-13 cytokine heterodimeric receptor, composed of IL-13Rα1 and IL-4Rα subunits. When administered by the subcutaneous or inhaled route, pitrakinra inhibited allergen-induced early-phase and late-phase reactions.101 "
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    ABSTRACT: Eosinophilic asthma is now recognized as an important subphenotype of asthma based on the pattern of inflammatory cellular infiltrate in the airway. Eosinophilic asthma can be associated with increased asthma severity, atopy, late-onset disease, and steroid refractoriness. Induced sputum cell count is the gold standard for identifying eosinophilic inflammation in asthma although several noninvasive biomarkers, including fractional exhaled nitric oxide and periostin, are emerging as potential surrogates. As novel therapies and biologic agents become increasingly available, there is an increased need for specific phenotype-directed treatment strategies. Greater recognition and understanding of the unique immunopathology of this asthma phenotype has important implications for management of the disease and the potential to improve patient outcomes. The present review provides a summary of the clinical features, pathogenesis, diagnosis, and management of eosinophilic asthma.
    Journal of Asthma and Allergy 04/2014; 7(7):53-65. DOI:10.2147/JAA.S39119
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    • "As such, it blocks the signaling of both IL-4 and IL-13 through IL-4R/ c and IL-4R/IL- 13R1. Pitrakinra, dosed by two different routes, was assessed in an allergen challenge study in mild atopic asthmatics (n=24 for daily subcutaneous injection; n=32 for twicedaily nebulization) [104]. Treatment with nebulized pitrakinra resulted in reductions in the late phase asthmatic response to allergen challenge, compared to placebo treatment. "
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    ABSTRACT: Patients with severe asthma have disease that is poorly controlled despite use of standard combination therapies consisting of high doses of inhaled corticosteroids with other controller medications. Given the persisting disease and bur-den of morbidity for many of these patients, there remains a significant need for the development of new therapeutics to treat severe asthma. Preclinical studies have established a model of asthma pathogenesis that is driven by type 2 inflam-mation. Based on this paradigm, a number of therapeutic agents that target key features of type 2 inflammation, such as immunoglobulin E (IgE), mast cells, eosinophils, and type 2 inflammatory cytokines, have been generated and progressed into clinical development. Coupled with recent insights into the heterogeneity of asthma that have led to the development of diagnostic biomarkers to help select patients who may experience greater clinical benefit from these agents, several of these therapeutics have shown promising effects in clinical studies, with one therapeutic currently on the market. Here we review the results of clinical studies for these therapeutics and discuss how our understanding of asthma pathogenesis and disease heterogeneity may be leading to a new generation of therapies for severe asthma.
    Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Cu rrent Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) 04/2014; 1:2-10. DOI:10.2174/2212703801999131206110837
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