Yamo Deniz

Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma.

SUMMARY Objective: Omalizumab (Xolair*), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit. * Xolair is a registered trade name of Novartis Pharma AG, Basel, Switzerland and Genentech, South San Francisco, California, USA Data sources: Published articles and data on file (Novartis PharmaAG, Genentech). Results: Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50ng/ml (20.8 IU ml−1) or less (target 25 ng ml−1 (10.4IU ml−1)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patients weight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150–375 mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators. Conclusions: The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.

Total serum IgE levels in a large cohort of patients with severe or difficult-to-treat asthma

BACKGROUND Limited data are available on levels of IgE in large cohorts of patients with severe or difficult-to-treat asthma. OBJECTIVE To examine IgE levels and disease in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS From January 2001 to October 2001, 4,923 patients were screened for inclusion in the study. Of these, 4,756 patients 6 years or older with severe or difficult-to-treat asthma were enrolled and completed a baseline study visit. Total serum IgE levels were measured at the baseline visit and are summarized by geometric means. RESULTS The mean total IgE level of the population is 106.6 IU/mL (95% confidence interval, 101.5-112.0 IU/mL). Children (6-12 years old) and adolescents (13-17 years old) have higher mean IgE levels than adults (> or =18 years old) (P < .001). Males have a higher mean IgE level than females (P < .001). IgE levels are higher among nonwhite patients than white patients (P < .001). Current smokers have higher IgE levels than past smokers or never smokers (P < .001). Among children, patients with severe asthma have a higher mean IgE level (280.2 IU/mL) than patients with moderate (145.8 IU/mL) or mild (137.8 IU/mL) asthma (P < .001). Among adults, patients with childhood-onset asthma have higher IgE levels (124.3 IU/mL [n = 1,348]) than patients with adult-onset asthma (65.7 IU/mL [n = 1,956]) (P < .001). CONCLUSION In patients with severe or difficult-to-treat asthma from the TENOR study, higher total IgE levels were observed in males, children, smokers, nonwhite racial/ethnic groups, and adults with childhood-onset disease. In addition, IgE levels are associated with asthma severity among younger patients.

Asthma in older adults: observations from the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study

BACKGROUND The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) was a 3-year, multicenter, observational study of 4,756 patients 6 years or older with severe or difficult-to-treat asthma by physician evaluation. More than 280 pulmonologist and allergist sites across the United States participated. OBJECTIVE To compare health care utilization (HCU), medication use, asthma control, and quality of life (QoL) in older (> or =65 years; n = 566) and younger (18-64 years; n = 2,912) adult patients in TENOR. METHODS Patients had to be under a physicians care for at least 1 year and have high medication use or HCU in the past year. Heavy smokers (> or =30 pack-years) and patients with cystic fibrosis were excluded. RESULTS Although older patients in TENOR had worse lung function as measured by decreased percent predicted forced expiratory volume in 1 second (FEV1) (P < .001), they had significantly lower HCU compared with younger patients. They also had higher use of inhaled corticosteroids and better QoL than younger patients. Older patients reported fewer problems controlling their asthma (P < .001) but reported worse communication with their physicians (P = .02). CONCLUSIONS Older patients in TENOR appeared to do better than younger patients, despite having worse lung function. Older patients in TENOR may have received more aggressive care than older asthmatic patients in other studies, based on a higher use of inhaled and oral corticosteroids. Whether differences in treatment or disease influenced other physiologic or inflammatory outcomes that contribute to the disconnect between HCU and FEV1 awaits further study.

Allergen skin tests and free IgE levels during reduction and cessation of omalizumab therapy

BACKGROUND The recombinant humanized anti-IgE antibody omalizumab rapidly reduces serum free IgE concentrations and alleviates allergic airway disease. It is not known whether stopping or reducing the dose of omalizumab maintains adequate suppression of free IgE levels and IgE-mediated mast cell activation. OBJECTIVE To determine the effects of omalizumab on serum free IgE and immediate allergen skin test reactivity during initial therapy followed by treatment reduction and cessation. METHODS Forty patients with perennial allergic rhinitis were randomized to receive 0.015 or 0.030 mg/kg/IU/mL open-label intravenous omalizumab every 2 weeks for 28 weeks, followed by 0.0015 or 0.0050 mg/kg/IU/mL every 2 weeks for 18 weeks. Serum free IgE levels were measured and titrated dust mite allergen skin tests conducted throughout. RESULTS At day 98, serum free IgE concentrations were decreased by 96% to 99%, and wheal-and-flare reactions to skin tests were markedly suppressed. After reduced omalizumab doses (day 322), serum free IgE and allergen skin test reactivity increased significantly. On complete discontinuation of therapy (day 378), serum free IgE levels and skin test reactivity returned to baseline levels. Patients with lower initial levels of IgE had significantly less suppression of skin test reactivity. CONCLUSION Omalizumab reduced serum free IgE and immediate skin test reactivity to allergen during initial, high-dose administration. These effects were not fully maintained during dose reduction and returned to baseline after cessation of chronic treatment.

Safety and tolerability of omalizumab (Xolair), a recombinant humanized monoclonal anti-IgE antibody.

Omalizumab (Xolair®) is a humanized monoclonal antibody designed to bind specifically to immunoglobulin (Ig)E. It is indicated in the United States for the treatment of adolescent and adult patients (≥12 yr) with moderate-to-severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen, and whose symptoms are inadequately controlled with inhaled corticosteroids. Omalizumab was evaluated in an extensive clinical development program that included 12 controlled phase IIB/III clinical trials with more than 5243 patients who were appropriate for inclusion in the safety analysis (all ages in all controlled studies). In these studies, omalizumab had an adverse event profile comparable to that of the control group (i.e., placebo or standard therapy). Data presented in this article supports omalizumab as a safe and well-tolerated agent for the treatment of IgE-mediated asthma.

Effects of omalizumab, a humanized monoclonal anti-IgE antibody, on nasal reactivity to allergen and local IgE synthesis

BACKGROUND Treatment with omalizumab has been shown to reduce serum free IgE concentrations and to have beneficial effects on allergic airway disease. However, its effect on IgE synthesis is unknown. OBJECTIVE To determine whether omalizumab therapy affects nasal reactivity to allergen and local IgE production. METHODS Nineteen patients with perennial allergic rhinitis were treated with intravenous omalizumab every 2 weeks for 26 weeks in an open-label study. Serum free and total IgE concentrations were measured at baseline and every 2 weeks throughout the study. Nasal challenge to dust mite allergen was performed at baseline and after 12 and 24 weeks of treatment. Nasal lavage fluid obtained before and after each nasal challenge was evaluated for mite-specific antibodies, plaque-forming cells, and productive epsilon messenger RNA (mRNA). RESULTS During treatment, serum free IgE concentrations were decreased by 97% to 99%, and the nasal response to allergen challenge was significantly reduced on days 80 and 164. The postchallenge increase in nasal lavage mite specific IgE was significantly reduced by treatment with omalizumab on day 168. IgE plaque-forming cells and productive epsilon mRNA were not significantly affected by omalizumab treatment. CONCLUSIONS Omalizumab treatment markedly reduced serum free IgE and the clinical response to nasal allergen challenge. However, the absence of an effect on IgE-secreting B cells and epsilon mRNA in nasal lavage fluid suggests that omalizumab treatment for 6 months does not significantly modulate synthesis of nasal IgE.