Marc Massanari

Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma

BACKGROUND Although specific immunotherapy is a valuable treatment option for patients with allergic asthma, the potential for systemic allergic reactions has limited its use, especially for patients with symptomatic disease. OBJECTIVE To evaluate omalizumabs effect on the tolerability of specific immunotherapy in patients with symptomatic persistent asthma not adequately controlled with inhaled corticosteroids. METHODS This multicenter, double-blind, parallel-group study randomized patients to treatment with omalizumab or placebo, after which they received specific immunotherapy to at least 1 of 3 perennial aeroallergens (cat, dog, and house dust mite) according to a 4-week, 18-injection cluster regimen, followed by 7 weeks of maintenance therapy. The primary efficacy variable, a systemic allergic reaction after immunotherapy, was analyzed by using the Cochrane-Mantel-Haenszel test. RESULTS A total of 248 randomized patients (126 omalizumab, 122 placebo) received at least 1 dose of immunotherapy and were evaluated for efficacy. Patients receiving omalizumab experienced significantly fewer systemic allergic reactions to immunotherapy than those receiving placebo (17/126 [13.5%] vs 32/122 [26.2%]; P = .017; 95% CI, 2.91% to 22.56%) and had fewer respiratory-related (grade 3) systemic allergic reactions (6 vs 24, respectively). Grade 4 reactions were reported in 2 patients in each group. More omalizumab patients were able to reach the target maintenance immunotherapy dose (110 [87.3%] vs 88 [72.1%], respectively; P = .004). CONCLUSION Use of omalizumab in patients whose asthma was symptomatic despite use of inhaled corticosteroids was associated with fewer systemic allergic reactions to specific immunotherapy and enabled more patients to achieve the target immunotherapy maintenance dose.

Effects of omalizumab on markers of inflammation in patients with allergic asthma

Asthma is a chronic inflammatory disease of the airways in which immunoglobulin E (IgE) plays a key role by activating a variety of inflammatory cells through interactions with FcɛRI and FcɛRII receptors. The role of IgE in allergic inflammation provided the rationale for developing omalizumab, a humanized monoclonal anti‐IgE antibody, for patients with moderate‐to‐severe or severe allergic asthma. The reductions in circulating levels of IgE resulting from omalizumab treatment leads to reductions in FcɛRI expression on mast cells, basophils and dendritic cells. This combined effect results in attenuation of several markers of inflammation, including peripheral and bronchial tissue eosinophilia and levels of granulocyte macrophage colony stimulating factor, interleukin (IL)‐2, IL‐4, IL‐5 and IL‐13. By blocking IgE binding to its receptors and diminishing dendritic cell FcɛRI receptor expression, omalizumab may also reduce allergen presentation to T cells and the production of Th2 cytokines. The anti‐inflammatory effects of omalizumab may, therefore, explain the reductions in asthma exacerbations and symptoms seen in clinical trials in patients with moderate‐to‐severe or severe, persistent, inadequately controlled allergic asthma.

Effect of omalizumab on peripheral blood eosinophilia in allergic asthma

Eosinophilia is an established marker of asthma-related inflammation. We assessed the effect of omalizumab on peripheral blood eosinophil counts using a pooled analysis of data from five randomized, double-blind, placebo-controlled studies in patients with moderate-to-severe persistent allergic asthma receiving moderate-to-high-dose inhaled corticosteroids (omalizumab, n=1136; placebo, n=1100). Relationships between omalizumab, peripheral blood eosinophils, serum free IgE concentrations and clinical outcomes were explored. Baseline mean eosinophil counts were similar in each treatment group. Post-treatment eosinophil counts were significantly reduced from baseline in the omalizumab group (p<0.0001) but were not significantly different in the placebo group. Greater reductions in eosinophil counts were observed in patients who had post-treatment free IgE levels <50ng/mL. Three studies included steroid-stable and steroid-reduction phases. At the end of each phase in these studies, a significantly greater reduction in eosinophil counts was achieved in the omalizumab group compared with the placebo group (p<0.0001). A consistent pattern of improved clinical outcomes/decreased eosinophils and worsened clinical outcomes/increased eosinophils was observed for both omalizumab and placebo treatment groups. The findings from our analysis of a large patient population are consistent with earlier reports of the inhibitory effect of omalizumab on eosinophils.

Recent asthma exacerbations predict future exacerbations in children with severe or difficult-to-treat asthma

BACKGROUND Children with severe/difficult-to-treat asthma experience high morbidity including frequent severe exacerbations. More knowledge is required to identify predictors of these exacerbations to reduce their occurrence. OBJECTIVE To investigate the risk of future severe exacerbations (FSEs) in children with severe/difficult-to-treat asthma and recent severe exacerbations (RSEs). METHODS We analyzed the occurrence and association of RSE (defined as 1 or more corticosteroid bursts during the 3 months before each of 3 annual visits) and FSE (defined as 1 or more corticosteroid bursts 6 or 12 months later) in children age 6 to 11 years in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens 3-year observational study. Repeated measures logistic regression analysis assessed the risk of FSE adjusted for demographics and clinical variables. RESULTS In a multivariable model, FSE at 6 months was most strongly predicted by RSE (odds ratio [OR], 3.08; 95% CI, 2.21-4.28) and having 3 to 4 allergic triggers (OR, 2.05; 95% CI, 1.31-3.20). Race (OR, 1.77; 95% CI, 1.25-2.51) and being very poorly controlled according to the impairment component of the National Heart, Lung, and Blood Institute guidelines (OR, 1.59; 95% CI, 1.14-2.23) also significantly predicted FSE. CONCLUSION Recent severe asthma exacerbations are an important independent predictor of FSE in children with severe/difficult-to-treat asthma and should be considered when establishing asthma management plans.

Effect of omalizumab on the need for rescue systemic corticosteroid treatment in patients with moderate-to-severe persistent IgE-mediated allergic asthma: a pooled analysis

ABSTRACT Background: Allergic asthma is an immunoglobulin E (IgE)-mediated disease characterized by frequent exacerbations following exposure to relevant allergens that leads to the development of chronic airway inflammation. Omalizumab, an anti-IgE antibody, reduces asthma exacerbation and hospitalization rates in patients with IgE-mediated allergic asthma. We investigated the effect of omalizumab on asthma outcomes in a retrospective pooled analysis of data from phase III clinical trials in patients (≥ 12 years) with moderate-to-severe persistent IgE-mediated allergic asthma. Methods: Systemic corticosteroid bursts and physician and patient overall assessments of asthma control were assessed in patients who received add-on omalizumab or current asthma therapy (control). The association of physician and patient overall assessments with the number of steroid bursts were also evaluated. Results: The analysis encompassed 4308 patients with moderate-to-severe persistent IgE-mediated allergic asthma (93% met GINA 2002 criteria for severe persistent asthma) from seven clinical trials. The number of systemic corticosteroid bursts was significantly lower in omalizumab-treated patients than in the control group (relative risk [95% CI]: 0.57 [0.48–0.66], p < 0.001). In addition, 58.5% of omalizumab recipients had complete/marked improvement in asthma control according to the physicians overall assessment (responders) vs. 36.9% in the control group ( p < 0.001). Similarly, 64.2% of omalizumab patients vs. 43.9% of control patients had complete/marked improvement according to the patients overall assessment ( p < 0.001). There were statistically significant associations between systemic corticosteroid bursts and physician (Goodman–Kruskal gamma [95% CI]: 0.32 [0.26–0.38]) and patient (gamma [95% CI]: 0.29 [0.23–0.36]) overall assessments. This pooled analysis has limitations as it was not pre-specified. Conclusions: Omalizumab therapy reduced the need for systemic corticosteroid bursts and improved effectiveness of asthma treatment as judged by both physicians and patients.

Adding Omalizumab to the Therapy of Adolescents With Persistent Uncontrolled Moderate—Severe Allergic Asthma

Objective. This study aimed to evaluate the effectiveness of omalizumab among adolescents with moderate—severe allergic asthma inadequately controlled with inhaled corticosteroids. Patients and methods. Data from patients 12 to 17 years of age were pooled from 5 placebo-controlled registration trials of omalizumab. Impact on asthma control was assessed by need for rescue bursts of oral corticosteroids, lung function, symptom scores, and unscheduled office visits. Results. In adolescents (n = 146), addition of omalizumab decreased mean number of rescue bursts (0.3 vs 0.9) versus placebo; relative risk 0.47 (95% confidence interval [CI], 0.22-0.99; P = .047). At study conclusion, mean forced expiratory volume in 1 second increased 268 mL (13.8%) in omalizumab-treated subjects versus 98 mL (5.5%) for placebo (least squares mean treatment difference 146 mL [95% CI, 19.4-272.6; P = .024]). Omalizumab significantly improved asthma symptom scores and reduced unscheduled office visits. Conclusion. Omalizumab added to baseline therapy improves measures of asthma control in adolescents with persistent moderate—severe allergic asthma.

Effectiveness of omalizumab in reducing corticosteroid burden in patients with moderate to severe persistent allergic asthma

BACKGROUND Asthma guidelines advocate maintaining asthma control while minimizing corticosteroid exposure. OBJECTIVE To assess the reduction in corticosteroid burden during long-term treatment and the corresponding impact of this reduction on asthma control, lung function, and inflammation in patients with moderate to severe allergic asthma. METHODS We conducted a pooled analysis (N = 1,071) of 2 similarly designed, randomized, double-blind, placebo-controlled omalizumab trials and their extension phases. Each study included a 16-week steroid-stable phase, a 12-week steroid-reduction phase, and a 24-week extension phase. Patients received subcutaneous omalizumab (minimum, 0.016 mg/kg/IU (IgE/mL) every 4 weeks) or placebo every 2 or 4 weeks. Outcomes included change from baseline in inhaled corticosteroid dose, number of oral corticosteroid bursts, and other clinical measures, including asthma exacerbations and change in asthma quality-of-life score (questionnaire), lung function, and eosinophil count. RESULTS The median reduction from baseline in inhaled corticosteroid dose (beclomethasone dipropionate equivalent dose) by the completion of the extension phase was greater for the omalizumab group than for the placebo group (-420.0 vs -252.0 μg/d; P < .001). During that time, omalizumab-treated patients required fewer oral corticosteroid bursts overall for treatment of acute exacerbations (mean, 0.2 vs 0.3; relative risk, 0.56; 95% confidence interval, 0.41 to 0.76; P < .001) and demonstrated greater improvements in measures of asthma control. CONCLUSION The addition of omalizumab to baseline therapy in patients 12 years or older with moderate to severe persistent allergic asthma resulted in a durable reduction in the overall steroid burden and improvement in other clinical measures of asthma control.

A retrospective randomized study of asthma control in the US: Results of the CHARIOT study

ABSTRACT Background: The third version of the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report (EPR-3): Guidelines on the Diagnosis and Management of Asthma emphasizes the need to use asthma control rather than patient severity to base adjustments to treatment and ultimately improve patient outcomes. The objectives of the current study were to assess control of patients with moderate-to-severe asthma, examine the natural history of the disease, practice patterns and resource utilization in specialty community practices according to recently reviewed NAEPP guidelines. Research design and methods: This analysis represents a retrospective, multicenter, randomized study of 1009 patient charts in sixty United States allergy and pulmonary medicine community practices. The proportion of patients with controlled and uncontrolled asthma over 12 months, prevalence and characteristics of atopy, past asthma history, pulmonary function, medications and treatment patterns, patient and clinical practice characteristics were analyzed. Main outcome measures: The primary outcome of interest was asthma control. Results: A total of 365 male and 644 female patients with moderate-to-severe persistent asthma (mean 43.2 ± 17.1 years) were enrolled. 81.9% of patients were uncontrolled according to recent NAEPP guidelines. Importantly, a greater percentage of patients with moderate asthma vs. severe persistent asthma were uncontrolled (p < 0.0114). Atopy was detected in 92% of patients. Patients with early onset of asthma were associated with control (p < 0.0433). Atopic symptoms, such as allergic rhinitis (p < 0.0130) and rhinosinusitis (p < 0.0476), were associated with uncontrolled asthma. Uncontrolled patients were also associated with more medications (a mean of 4.05 ± 1.87 medications) than were controlled patients (a mean of 3.40 ± 1.37 medications (p < 0.0001), although the temporal relationship of this association was not recorded. Limitations may have included patient and/or study site selection bias and difficulty in the process of operationalizing the definitions of control and disease severity. Since the current study only examined patients from specialty practices, the results may not be generalizable to the overall asthma population. Conclusions: Greater than 80% of asthma patients from specialty practices were uncontrolled with regard to asthma symptoms. Atopic symptoms, such as allergic rhinitis and rhinosinusitis, in addition to a greater number of medications, were associated with uncontrolled asthma. Moreover, patients designated as having asthma of moderate severity were associated with being uncontrolled more than were those with severe asthma (p < 0.0114), which suggests that the former population may not have received adequate assessment of impairment or risk, with subsequent changes in treatment for control of symptoms.

Efficacy of omalizumab in cat-allergic patients with moderate-to-severe persistent asthma

Cat allergen (Fel d 1) is a pervasive and common trigger of exacerbations in sensitized patients with IgE-mediated asthma. This study was designed to evaluate the effect on asthma-related outcome measures of adding omalizumab to current treatment in patients with moderate-to-severe persistent asthma and cat allergen sensitivity. A pooled analysis was conducted of two double-blind, placebo-controlled, 28-week pivotal U.S. registration trials. In all patients, asthma was inadequately controlled with moderate-high dose inhaled corticosteroids. Patients were randomized to receive subcutaneous omalizumab (minimum, 0.016 mg/kg per IgE IU/mL every 4 weeks) or matched placebo. The effects of omalizumab on asthma-related outcomes were assessed for patients with cat allergen sensitivity (n = 811), identified by positive skin-prick test. The mean number of asthma exacerbations requiring treatment with systemic steroid bursts in cat allergen-sensitive patients was lower in those receiving omalizumab versus placebo (0.6 versus 1.3, respectively; relative risk = 0.50, p < 0.001). Compared with placebo, omalizumab treatment led to significantly lower asthma symptom scores (least squares means (LSMs) treatment difference [95% confidence interval {CI}]: -0.57 [-0.77, -0.37]; p < 0.001), less rescue medication use (LSMs treatment difference [95% CI]: -0.75 puffs of rescue beta-agonist per day [-1.04, -0.46]; p < 0.001), and improvement in forced expiratory volume in 1 second (LSMs treatment difference [95% CI]: 100.84 mL [51.86, 149.81]; p < 0.001). Patient and investigator global evaluations of treatment effectiveness paralleled these outcomes. Omalizumab improved asthma control by reducing exacerbations and decreasing symptoms in cat-allergic patients with moderate-to-severe persistent IgE-mediated asthma.

Measurement of fractional exhaled nitric oxide in real-world clinical practice alters asthma treatment decisions

BACKGROUND Assessment of asthma using clinical measures alone often fails to detect underlying airway inflammation. Fractional exhaled nitric oxide (FeNO) is a recognized biomarker of type 2 airway inflammation in asthma. Measurement of FeNO is instrumental in the assessment and management of patients with corticosteroid-sensitive asthma. OBJECTIVE To determine the impact of measuring FeNO on asthma management in real-world clinical practices. METHODS Clinicians from 337 US practices performed a clinical assessment and recorded treatment plans before and after measuring FeNO in 7,901 patients with asthma. Airway inflammation was classified as low, intermediate, or high according to the clinicians usual procedures, including clinical examination, spirometry, and symptoms. Clinicians recorded asthma medication plans, indicating medications to be initiated, continued, or stopped. FeNO measurement was performed, followed by documentation of any change(s) in the treatment plans based on the FeNO value (eg, initiating new medications or changing the dose of or discontinuing existing medications). RESULTS Clinical assessment was concordant with FeNO measurement in only 56% of cases, matching FeNO more frequently in patients with low inflammation (64%) vs high inflammation (34%). After FeNO measurement, clinicians modified their treatment plan in 31% and altered prescriptions for inhaled corticosteroids in 90% of cases. Inhaled corticosteroids were initiated or their dose increased in 66% of patients with high inflammation but discontinued or their dose decreased in only 9% of patients with low inflammation. CONCLUSION Measurement of FeNO enabled clinicians to assess underlying airway inflammation, leading to a significant revision of their treatment plans compared with real-world clinical assessment of asthma alone.