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Background Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab. Objective This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. Methods Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240 mg every 2 weeks for 10 weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24 weeks after the first dose. Results QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV 1 (allergen PC 15 ) that was maximal and approximately 3-fold greater than that of omalizumab ( P = .10) and 16-fold greater than that of placebo ( P = .0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC 15 (2-fold to 500-fold change). QGE031 was well tolerated. Conclusion QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma. [ABSTRACT FROM AUTHOR]

Airway hyperresponsiveness (AHR) to direct (histamine and methacholine) and indirect (exercise, cold air, hyperventilation, AMP) challenges is a universal and defining feature of asthma. One component of AHR is transient or inducible and occurs after allergen exposure, for example, and improves occasionally rapidly after inhaled corticosteroids or environmental control. This transient airway hyperresponsiveness is more marked to the indirect stimuli. There are convincing data linking this component of AHR to airway inflammation; however, the precise mechanisms linking airway inflammation and hyperresponsiveness of the airway smooth muscle are not clear. The other component of AHR is more persistent and is relatively refractory to environmental control and inhaled corticosteroids. This is likely secondary to structural airway changes, which are collectively referred to as airway remodeling, and which are a result of the chronic (rather than the acute) effects of airway inflammation. This persistent AHR is best reflected by airway hyperresponsiveness to direct stimuli such as methacholine. The mechanisms are also uncertain, but reduced airway caliber, increased airway wall thickness, increased airway smooth muscle mass, and perhaps contractility likely all play a role. [Copyright &y& Elsevier]

Methacholine tests are widely used as a diagnostic aid for asthma. Their strength has been reputed to be the high sensitivity and very infrequent occurrence of false-negative test results (ie, high negative predictive value). There are 2 commonly used methods that have been outlined by the American Thoracic Society. These methods were thought to give equivalent results. However, in 3 investigations in which we have compared the 2 methods, we have demonstrated a marked lack of comparability. In subjects with borderline to mild airway responsiveness (tidal breathing, methacholine PC20 >2 mg/mL), the 5 deep inhalations required of the dosimeter method produce marked bronchoprotection in some subjects with asthma. The result of this bronchoprotection is that in 55 subjects with asthma, 50% of those whose tidal breathing PC20 value was greater than 2 mg/mL and 25% of the total had negative methacholine challenge results. This indicates that the standardized dosimeter method has an unacceptable loss of diagnostic sensitivity. We recommend that the dosimeter method not be performed as outlined by the American Thoracic Society and that methacholine should be administered by means of submaximal inhalations or tidal breathing. [Copyright &y& Elsevier]

Background: The early asthmatic response (EAR) to inhaled allergen results from IgE-mediated release of multiple mast-cell mediators, including leukotrienes and histamine, both of which cause bronchoconstriction. Combination therapy directed at blocking the effects of both mediators might protect against the EAR better than either therapy alone. Objective: We sought to evaluate the effect of desloratadine and montelukast, administered alone and in combination, on the EAR to inhaled allergen. Methods: Ten adults with mild-to-moderate atopic asthma participated in a randomized, 4-way crossover study design comparing placebo, 5 mg of desloratadine, 10 mg of montelukast, and the combination administered at 26 hours and 2 hours before each allergen challenge conducted at least 7 days apart. The primary end point was the concentration of allergen that resulted in a 20% decrease in FEV1 (PC20). Results: The geometric mean allergen PC20 (mean log ± SEM) for combination therapy, montelukast, desloratadine, and placebo was 697 U/mL (2.8433 ± 0.3253), 338 U/mL (2.5295 ± 0.2979), 123 U/mL (2.0883 ± 0.2102), and 104 U/mL (2.0166 ± 0.2553), respectively (n = 9; P < .00001, ANOVA). Montelukast increased the allergen PC20 4.8-fold, and combination therapy increased the allergen PC20 8.9-fold. The effect of the combination was greater than that with montelukast alone (P < .02). Desloratadine treatment was no different than placebo. Conclusions: The early response to inhaled allergen was unchanged after desloratadine therapy and partially inhibited with montelukast therapy. The combination of desloratadine and montelukast provided superior efficacy to either blocker administered alone. Investigations into the possible mechanisms of the enhanced inhibition are necessary. [Copyright &y& Elsevier]