Robert Maykut

Treatment of chronic autoimmune urticaria with omalizumab

BACKGROUND Approximately 45% of patients with chronic urticaria have an IgG autoantibody directed to the alpha-subunit of the high-affinity IgE receptor (chronic autoimmune urticaria, CAU) leading to cutaneous mast cell and basophil activation. Treatment of allergic asthma with omalizumab produces rapid reduction in free IgE levels and subsequent decrease in Fc epsilon RI expression on mast cells and basophils. If this occurs in CAU, cross-linking of IgE receptors by autoantibody would be less likely, reducing cell activation and urticaria/angioedema. OBJECTIVE To investigate the efficacy of omalizumab in patients with CAU symptomatic despite antihistamine therapy. METHODS Twelve patients with CAU, identified by basophil histamine release assay and autologous skin test, with persistent symptoms for at least 6 weeks despite antihistamines, were treated with placebo for 4 weeks followed by omalizumab (>or=0.016 mg/kg/IU mL(-1) IgE per month) every 2 or 4 weeks for 16 weeks. Primary efficacy variable was change from baseline to the final 4 weeks of omalizumab treatment in mean Urticaria Activity Score (UAS, 0-9 scale). Changes in rescue medication use and quality of life were assessed. RESULTS Mean UAS declined significantly from baseline to the final 4 weeks of omalizumab treatment (7.50 +/- 1.78 to 2.66 +/- 3.31, -4.84 +/- 2.86, P = .0002). Seven patients achieved complete symptom resolution. In 4 patients, mean UAS decreased, but urticaria persisted. One patient did not respond. Rescue medication use was reduced significantly, and quality of life improved. No adverse effects were reported or observed. CONCLUSION This exploratory proof of concept study suggests omalizumab is an effective therapy for CAU resistant to antihistamines.

The eXpeRience registry: The ‘real-world’ effectiveness of omalizumab in allergic asthma

Omalizumab has demonstrated therapeutic benefits in controlled clinical trials. Evaluation of outcomes in real-world clinical practice is needed to provide a complete understanding of the benefits of omalizumab treatment. eXpeRience was a 2-year, international, single-arm, open-label, observational registry that evaluated real-world effectiveness, safety and use of omalizumab therapy in 943 patients with uncontrolled persistent allergic asthma. Effectiveness variables (physicians Global Evaluation of Treatment Effectiveness [GETE], and change from baseline in exacerbation rate, symptoms, rescue medication use, and oral corticosteroid [OCS] use) were evaluated at pre-specified time-points. Safety data were also recorded. By physicians GETE, 69.9% of patients were responders to omalizumab after 16 (±1) weeks. The proportion of patients with no clinically significant exacerbations increased from 6.8% during the 12-month pre-treatment period to 54.1% and 67.3% at Months 12 and 24, respectively. Symptoms and rescue medication use at Month 24 were reduced by >50% from baseline. Maintenance OCS use was lower at Month 24 (14.2%) compared with Month 12 (16.1%) and baseline (28.6%). Overall, omalizumab had an acceptable safety profile. The results from eXpeRience indicate that omalizumab was associated with improvements in outcomes in patients with uncontrolled persistent allergic asthma; these improvements were consistent with the results of clinical trials.

Persistency of response to omalizumab therapy in severe allergic (IgE-mediated) asthma

To cite this article: Bousquet J, Siergiejko Z, Świebocka E, Humbert M, Rabe KF, Smith N, Leo J, Peckitt C, Maykut R, Peachey G. Persistency of response to omalizumab therapy in severe allergic (IgE‐mediated) asthma. Allergy 2011; 66: 671–678.

Response of Older Patients with IgE-Mediated Asthma to Omalizumab: A Pooled Analysis

Asthma in older adults is under-recognized and possibly associated with allergic triggers. We conducted a pooled analysis of omalizumab double-blind, placebo-controlled trials to evaluate efficacy in older adults. Data for the total study population and subjects aged ≥ 50 years with moderate-severe allergic asthma were examined. We used Poisson regression to analyze the number of asthma exacerbations and logistic regression to evaluate treatment effectiveness. Symptom scores and total rescue medication puffs were evaluated by analysis of covariance. Omalizumab reduced the risk of clinically significant asthma exacerbations, led to a significantly greater response in patient/investigator-reported global effectiveness, improved asthma symptom scores, and reduced rescue medication use in adults ≥50 years with moderate-severe allergic asthma.

Uncontrolled asthma among children: impairment in social functioning and sleep.

Objective. To evaluate asthma symptom frequency, severity, and control among children with asthma and to evaluate the impact on social functioning and sleep impairment. Patients and Methods. Using a cross-sectional design, adult caregivers of children aged 6–12 years with moderate to severe asthma (severity based on National Asthma Education and Prevention Program guidelines) were surveyed about the childs symptoms, treatment, activity limitation, and sleep impairment. Asthma was categorized as uncontrolled if the caregiver reported any of the following of the child: experienced >2 days/week with symptoms, were awakened at night by symptoms during the preceding 4 weeks, had activity limited by a health problem, or used short-acting beta-agonist for rescue >5 times/week. Asthma not meeting any of these criteria was categorized as controlled. Social functioning and sleep impairment were assessed using questions adapted from the SleepLearnPlay instrument. Children with uncontrolled and controlled asthma were compared using t tests for continuous variables and Fishers exact test for categorical variables. Multiple comparison adjustment using the Bonferroni procedure was made for social functioning and sleep impairment measures. Results. A total of 473 caregivers completed the survey; 360 were caregivers of children with uncontrolled asthma and 113 of children with controlled asthma. Compared with controlled asthma, a greater proportion of children with uncontrolled asthma showed avoidance across all nine social activities assessed. Children with uncontrolled asthma were significantly more likely to wake up at night with symptoms (p <.0001) and use a rescue inhaler at night (p <.0001), experience difficulty waking up in the morning (p = .0001) and getting out of bed (p = .0039), and be overly tired all day (p <.0001). Conclusions. Uncontrolled asthma impacted functioning and sleep of children to a significantly greater degree than well-controlled asthma. Proper treatment and disease management to improve symptom control can reduce this impact on the lives of children.

Oral corticosteroid sparing with omalizumab in severe allergic (IgE-mediated) asthma patients

Abstract Background: Long-term oral corticosteroid (OCS) therapy and related adverse events are associated with a significant burden on patients and healthcare resources. Methods: This subgroup analysis of a randomized, open-label, parallel-group study evaluated the OCS-sparing effect of omalizumab (OMA) added to optimized asthma therapy (OAT), compared with OAT alone. Patients (12–75 years) with severe allergic asthma, uncontrolled despite GINA 2004 Step 4 therapy, received OMA or OAT for 32 weeks. The change from baseline in OCS use by Week 32 in patients requiring maintenance OCS at baseline was assessed in terms of percent OCS dose change and numbers of patients with reduced/stopped or maintained/increased OCS. Results: Eighty-two patients were receiving maintenance OCS at baseline (OMA/OAT n = 59, OAT n = 23). Change from baseline in mean maintenance OCS dose at Week 32 was significantly greater in the OMA/OAT group compared with the OAT group (−45% vs. + 18.3%, p = 0.002). In the OMA/OAT group, 37 patients (62.7%) reduced/stopped OCS use at Week 32, compared with seven patients (30.4%) receiving OAT (p = 0.013). Improvements in other efficacy outcomes were seen at Week 32 in the OMA/OAT group, irrespective of OCS use. An investigator global evaluation of treatment effectiveness at Week 16 was an effective predictor of persistent treatment response at 32 weeks for the majority of OMA/OAT patients (93%), also irrespective of OCS use. Conclusion: In this open-label study of patients with severe allergic asthma, OMA/OAT therapy reduced maintenance OCS use, compared with OAT alone. Improvements in efficacy measures were observed in the OMA/OAT group, irrespective of OCS change. Clinicaltrials.gov identifier: NCT00264849.

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.

Uncontrolled persistent allergic asthma in practice: eXpeRience registry baseline characteristics.

Abstract Background: Medical registries can be used to assess and monitor the effectiveness and safety of approved therapy, and provide insights into how quality of care can be optimized. Methods: The post-marketing, non-interventional, observational registry (eXpeRience) aims to collect data on the treatment effectiveness and safety of omalizumab in ‘real-world’ practice. The baseline characteristics of patients with uncontrolled allergic asthma receiving omalizumab therapy and included in the first interim analysis of this observational registry are reported. Results: A total of 294 patients were included in the first interim analysis. Of these patients, 271 (92.2%) were active in the registry at the time of reporting. At baseline, the mean duration of allergic asthma was approximately 19 years, with over 87% of patients testing positive for a perennial allergen. Mean % predicted FEV1 and serum total IgE levels were 62.4% and 316.7 IU/mL, respectively. Asthma was uncontrolled for approximately 62% of patients, while around 23% were partly controlled. The majority of patients were being treated with multiple asthma controller medications, including inhaled-corticosteroids, long-acting β2-agonists and leukotriene receptor antagonists, and 28% of patients were also receiving maintenance oral corticosteroids. Concomitant diseases were present in many patients, the most common being perennial allergic rhinitis (42.5%). Conclusions: Demographic and disease characteristics highlight the unmet clinical need in patients with uncontrolled allergic asthma. Future analyses from this study will further determine the real-life effectiveness and safety of omalizumab.

One-year safety and efficacy of tobramycin powder for inhalation in patients with cystic fibrosis.

This is an integrated analysis of data from patients with cystic fibrosis (CF) aged 6–21 years who were treated with up to seven cycles of tobramycin powder for inhalation (TIPTM) over a period of at least 1 year. Safety and key efficacy endpoints were analyzed. Results: The improvement in lung function and decrease in sputum P. aeruginosa (Pa) density from baseline were sustained over the 1‐year treatment period. The number of adverse events (AEs) was low and did not increase with additional cycles of TIP treatment. Some increase in tobramycin minimum inhibitory concentration (MIC) was observed, but there was no significant increase in emergence of resistant strains based on the parenteral breakpoint for tobramycin. Conclusion: Efficacy of TIP was maintained for up to seven cycles. Long‐term treatment with TIP was generally safe and well tolerated with no increase in AEs. Pediatr Pulmonol. 2016;51:372–378.

Asthma in pediatric patients: Unmet need and therapeutic options

Asthma is a chronic inflammatory disease of the airways that is characterized by airway hyperresponsiveness and intermittent reversible airway obstruction. The severity of the disease and degree of impairment in lung function have been correlated with higher serum immunoglobulin E (IgE) levels in some patients. Asthma usually begins at an early age and is the most common chronic childhood disease in the United States as well as a major cause of disability. The prevalence of asthma has increased considerably in recent decades. In 2007 alone, there were an estimated 22.9 million Americans with asthma, including 1.2 million children aged <5 years and 5.6 million aged 5 to 17 years. This increase in prevalence has been attributed at least in part to an increase in atopic sensitization. The Third National Health and Nutrition Examination Survey estimates that atopy is responsible for 55% of the prevalence of asthma in children and adolescents aged 6 to 19 years. Atopy may play an even greater role in persistent asthma, affecting 88% of 1041 children aged 5 to 13 years with mild to moderate persistent asthma and 91% of 6to 17-year-olds with moderate to severe persistent asthma (T. Haselkorn, PhD, unpublished data, October 2009). Symptoms of asthma can range from mild to seriously debilitating, and the disease has been categorized into 4 severity levels: intermittent, mild persistent, moderate persistent, and severe persistent. A subset of asthma patients with the most severe disease represents approximately 5% to 10% of the total asthma population. Severe asthma was reported among 0.5% of all 10-yearolds and among 4.5% of current asthma patients, based on data from the 10-year follow-up of the Environment and Childhood Asthma study conducted in Norway. More recently, the prevalence of severe asthma among children aged 6 to 7 years has been reported to be 4.9% globally and 7.1% in North America in phase 3 of the International Study of Asthma and Allergies in Childhood. Therapeutic advancements over the years have produced a number of well-tolerated asthma medications that have proven to be effective in most patients; however, poor asthma control remains common in children. In some children, this may be because of inadequate treatment resulting from a poor understanding of asthma and its management, and/or nonadherence. Several guidelines based on expert opinion and currently available clinical evidence have been published for improving the management of asthma in pediatric patients. Unfortunately, there remain a number of children whose severe asthma is not well controlled despite appropriate therapy. These children with severe uncontrolled asthma constitute an understudied population. The objective of this review is to provide a summary of the epidemiology, burden, and management of childhood asthma, with a focus on patients having more severe uncontrolled disease.