Allergy and Respiratory Research Unit

Buenos Aires, Argentina

Allergy and Respiratory Research Unit

Buenos Aires, Argentina
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Lee L.A.,Glaxosmithkline | Maspero J.,Allergy and Respiratory Research Unit | Clements D.,Glaxosmithkline | Ellsworth A.,Glaxosmithkline | Pedersen S.,Kolding Hospital
Journal of Allergy and Clinical Immunology: In Practice | Year: 2014

Background: The effect of fluticasone furoate nasal spray (FFNS) on growth in prepubescent children has not been evaluated. Objective: To characterize the difference in mean prepubescent growth velocities, as determined by stadiometry, between patients treated continuously for 1 year with FFNS 110mcg once daily and placebo nasal spray. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 76-week safety study. Nasal symptom assessments were used as a measure of adherence. Eligible patients were ages 5 to <8.5 years at screening and had at least a 1-year clinical history and diagnosis of perennial allergic rhinitis, including a positive skin test or specific IgE to an appropriate perennial allergen within the past year. Results: One hundred eighty-six patients in the FFNS group and 187 patients in the placebo group completed the entire 52-week treatment period. During treatment, the least squares mean growth velocity was 5.19 cm/y for the FFNS group and 5.46 cm/y for the placebo group; mean difference,-0.270 cm/y (95% CI,-0.48 to-0.06 cm/y). Other safety assessments, including 24-hour urinary cortisol excretion, were comparable between the treatment groups. Daily reflective total nasal symptom scores declined similarly in both the FFNS and placebo groups. Conclusion: Once-daily treatment with FFNS over 52 weeks in prepubescent children resulted in a small reduction in growth velocity compared with placebo. Clinicians will need to balance the reduction in growth observed with FFNS to its potential for clinical benefit. © 2014 American Academy of Allergy, Asthma & Immunology.


PubMed | Kolding Hospital, Allergy and Respiratory Research Unit and Glaxosmithkline
Type: Clinical Trial | Journal: The journal of allergy and clinical immunology. In practice | Year: 2014

The effect of fluticasone furoate nasal spray (FFNS) on growth in prepubescent children has not been evaluated.To characterize the difference in mean prepubescent growth velocities, as determined by stadiometry, between patients treated continuously for 1 year with FFNS 110mcg once daily and placebo nasal spray.This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 76-week safety study. Nasal symptom assessments were used as a measure of adherence. Eligible patients were ages 5 to <8.5 years at screening and had at least a 1-year clinical history and diagnosis of perennial allergic rhinitis, including a positive skin test or specific IgE to an appropriate perennial allergen within the past year.One hundred eighty-six patients in the FFNS group and 187 patients in the placebo group completed the entire 52-week treatment period. During treatment, the least squares mean growth velocity was 5.19 cm/y for the FFNS group and 5.46 cm/y for the placebo group; mean difference,-0.270 cm/y (95% CI,-0.48 to-0.06 cm/y). Other safety assessments, including 24-hour urinary cortisol excretion, were comparable between the treatment groups. Daily reflective total nasal symptom scores declined similarly in both the FFNS and placebo groups.Once-daily treatment with FFNS over 52 weeks in prepubescent children resulted in a small reduction in growth velocity compared with placebo. Clinicians will need to balance the reduction in growth observed with FFNS to its potential for clinical benefit.


PubMed | Allergy and Respiratory Research Unit, Regeneron Pharmaceuticals, Sanofi S.A., University of California at Los Angeles and University of Pittsburgh
Type: Clinical Trial, Phase II | Journal: Lancet (London, England) | Year: 2016

Dupilumab, a fully human anti-interleukin-4 receptor monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting 2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting 2 agonist, irrespective of baseline eosinophil count.We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged 18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting 2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per L assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16.769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per L, the greatest increases (200 mg every 2 weeks, p=00008; 300 mg every 2 weeks, p=00063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 039 L [SE 005]; mean difference 021 [95% CI 006-036; p=00063]) and in the 200 mg group (mean change 043 L [SE 005]; mean difference 026 [011-040; p=00008]) compared with placebo (018 L [SE 005]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per L subgroup (overall population: 200 mg every 2 weeks, p<00001; 300 mg every 2 weeks, p<00001; <300 eosinophils per L: 200 mg every 2 weeks, p=00034; 300 mg every 2 weeks, p=00086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-705%), the subgroup with at least 300 eosinophils per L (712-807%), and the subgroup with fewer than 300 eosinophils per L (599-676%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%).Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting 2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.Sanofi-Genzyme and Regeneron Pharmaceuticals.


Castro M.,University of Washington | Zangrilli J.,Teva Pharmaceuticals | Wechsler M.E.,National Jewish Health | Bateman E.D.,University of Cape Town | And 6 more authors.
The Lancet Respiratory Medicine | Year: 2015

Background: Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma. Methods: We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12-75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (3·0 mg/kg) or placebo every 4 weeks for 1 year by computerised central randomisation. Patients and investigators were masked to treatment assignment during the study. Each patient received a specific volume of study drug (reslizumab or matching placebo) on the basis of the patient's body weight and randomly assigned treatment group. Additionally, the sponsor's clinical personnel involved in the study were masked to the study drug identity until the database was locked for analysis and the treatment assignment revealed. The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat. We assessed safety outcomes in the patients who had received one or more dose of the drug. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT01287039 (study 1) and NCT01285323 (study 2). Findings: Study 1 was done between April 12, 2011, and March 3, 2014 and study 2 between March 22, 2011, and April 9, 2014. Of 2597 patients screened, 953 were randomly assigned to receive either reslizumab (n=477 [245 in study 1 and 232 in study 2]) or placebo (n=476 [244 and 232]). In both studies, patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations (study 1: rate ratio [RR] 0·50 [95% CI 0·37-0·67]; study 2: 0·41 [0·28-0·59]; both p<0·0001) compared with those receiving placebo. Common adverse events on reslizumab were similar to placebo. The most common adverse events were worsening asthma symptoms (127 [52%] for placebo and 97 [40%] for reslizumab in study 1; 119 [51%] for placebo and 67 [29%] for reslizumab for study 2), upper respiratory tract infections (32 [13%] and 39 [16%]; 16 [7%] and eight [3%]), and nasopharyngitis (33 [14%] and 28 [11%]; 56 [24%] and 45 [19%]). Two patients in the reslizumab group had anaphylactic reactions; both responded to standard treatment at the study centre and resolved, and the patients were withdrawn from the study. Interpretation: These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy. Funding: Teva Branded Pharmaceutical Products R&D. © 2015 Elsevier Ltd.


PubMed | University of Washington, National Jewish Health, Teva Pharmaceuticals, Ghent University and 5 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Respiratory medicine | Year: 2015

Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma.We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12-75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per L or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (30 mg/kg) or placebo every 4 weeks for 1 year by computerised central randomisation. Patients and investigators were masked to treatment assignment during the study. Each patient received a specific volume of study drug (reslizumab or matching placebo) on the basis of the patients body weight and randomly assigned treatment group. Additionally, the sponsors clinical personnel involved in the study were masked to the study drug identity until the database was locked for analysis and the treatment assignment revealed. The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat. We assessed safety outcomes in the patients who had received one or more dose of the drug. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT01287039 (study 1) and NCT01285323 (study 2).Study 1 was done between April 12, 2011, and March 3, 2014 and study 2 between March 22, 2011, and April 9, 2014. Of 2597 patients screened, 953 were randomly assigned to receive either reslizumab (n=477 [245 in study 1 and 232 in study 2]) or placebo (n=476 [244 and 232]). In both studies, patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations (study 1: rate ratio [RR] 050 [95% CI 037-067]; study 2: 041 [028-059]; both p<00001) compared with those receiving placebo. Common adverse events on reslizumab were similar to placebo. The most common adverse events were worsening asthma symptoms (127 [52%] for placebo and 97 [40%] for reslizumab in study 1; 119 [51%] for placebo and 67 [29%] for reslizumab for study 2), upper respiratory tract infections (32 [13%] and 39 [16%]; 16 [7%] and eight [3%]), and nasopharyngitis (33 [14%] and 28 [11%]; 56 [24%] and 45 [19%]). Two patients in the reslizumab group had anaphylactic reactions; both responded to standard treatment at the study centre and resolved, and the patients were withdrawn from the study.These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy.Teva Branded Pharmaceutical Products R&D.


Bachert C.,Ghent University | Maspero J.,Allergy and Respiratory Research Unit
Journal of Asthma | Year: 2011

Background and aims. Allergic rhinitis (AR) and asthma share common mediators, cytokines, and chemokines from mast cells and basophils that are central to the complex cascade of events involved in the inflammatory response. Histamine is the salient mediator released after immunologic challenge, initiating multiple pathologic processes of the allergic reaction that result in bronchial smooth muscle contraction, vasodilation, mucus hypersecretion, and edema. The recent identification of a fourth histamine receptor has reinforced clinical interest in the pleiotropic effects of histamine and the relative roles of histamine receptors in mediating immune and inflammatory responses. Material and methods. A comprehensive literature search was conducted for the following terms, alone or in combination: allergic rhinitis, asthma, antihistamines, histamine, and histamine receptors, and for the second-generation antihistamines azelastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mizolastine, and rupatadine. Clinical trials were included that reported results for patients with AR and comorbid asthma who were treated with second-generation antihistamines. The search dates ranged from 1995 through 2010. Clinical studies that were not placebo controlled or double blinded were excluded from this review. Results. A total of 14 clinical trials of second-generation nonsedating antihistamines were included in this review. Conclusion. H1-antihistamines have been shown to attenuate the symptoms associated with early- and late-phase allergic reactions. Cumulative clinical evidence indicates that H1-antihistamines may have a beneficial effect on asthma symptoms and improve quality of life. Scientific significance. Mechanistic and clinical data suggest that the potential of H1-antihistamines to alleviate comorbid asthma symptoms in AR patients should be further investigated. © 2011 Informa Healthcare USA, Inc.


Glossop P.A.,Sandwich Laboratories | Watson C.A.L.,Sandwich Laboratories | Price D.A.,Sandwich Laboratories | Price D.A.,Pfizer | And 26 more authors.
Journal of Medicinal Chemistry | Year: 2011

A novel tertiary amine series of potent muscarinic M 3 receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M 3 receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans. © 2011 American Chemical Society.


Millan D.S.,Worldwide Medicinal Chemistry | Bunnage M.E.,Worldwide Medicinal Chemistry | Burrows J.L.,Sandwich | Butcher K.J.,Worldwide Medicinal Chemistry | And 14 more authors.
Journal of Medicinal Chemistry | Year: 2011

This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD. © 2011 American Chemical Society.


Maspero J.F.,Allergy and Respiratory Research Unit | Jardim J.R.,University of Sao Paulo | Aranda A.,Hospital Auxilio Mutuo | Tassinari C.P.,Central University of Venezuela | And 4 more authors.
World Allergy Organization Journal | Year: 2013

Background In 2011 the Latin America Asthma Insight and Management (LA AIM) survey explored the realities of living with asthma. We investigated perception, knowledge, and attitudes related to asthma among Latin American asthma patients. Methods Asthma patients aged ≥12 years from four Latin American countries (Argentina, Brazil, Mexico, Venezuela) and the Commonwealth of Puerto Rico responded to questions during face-to-face interviews. A sample size of 2,169 patients (approximately 400 patients/location) provided an accurate representation of asthma patients' opinions. Questions probed respondents' views on topics such as levels of asthma control, frequency and duration of exacerbations, and current and recent use of asthma medications. Results A total of 2,169 adults or parents of children with asthma participated in the LA AIM survey. At least 20% of respondents experienced symptoms every day or night or most days or nights. Although 60% reported their disease as well or completely controlled, only 8% met guideline criteria for well-controlled asthma. 47% of respondents reported episodes when their asthma symptoms were more frequent or severe than normal, and 44% reported seeking acute care for asthma in the past year. Asthma patients in Latin America overestimated their degree of asthma control. Conclusions The LA AIM survey demonstrated the discrepancy between patient perception of asthma control and guideline-mandated criteria. Additional education is required to teach patients that, by more closely following asthma management strategies outlined by current guidelines more patients can achieve adequate asthma control. ©2013 Maspero et al.


PubMed | Allergy and Respiratory Research Unit
Type: Journal Article | Journal: The World Allergy Organization journal | Year: 2014

In 2011 the Latin America Asthma Insight and Management (LA AIM) survey explored the realities of living with asthma. We investigated perception, knowledge, and attitudes related to asthma among Latin American asthma patients.Asthma patients aged 12 years from four Latin American countries (Argentina, Brazil, Mexico, Venezuela) and the Commonwealth of Puerto Rico responded to questions during face-to-face interviews. A sample size of 2,169 patients (approximately 400 patients/location) provided an accurate representation of asthma patients opinions. Questions probed respondents views on topics such as levels of asthma control, frequency and duration of exacerbations, and current and recent use of asthma medications.A total of 2,169 adults or parents of children with asthma participated in the LA AIM survey. At least 20% of respondents experienced symptoms every day or night or most days or nights. Although 60% reported their disease as well or completely controlled, only 8% met guideline criteria for well-controlled asthma. 47% of respondents reported episodes when their asthma symptoms were more frequent or severe than normal, and 44% reported seeking acute care for asthma in the past year. Asthma patients in Latin America overestimated their degree of asthma control.The LA AIM survey demonstrated the discrepancy between patient perception of asthma control and guideline-mandated criteria. Additional education is required to teach patients that, by more closely following asthma management strategies outlined by current guidelines more patients can achieve adequate asthma control.

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