Omalizumab Protects against Allergen- Induced Bronchoconstriction in Allergic (Immunoglobulin E-Mediated) Asthma

Abstract

Background: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels. Methods: Asthmatic adults (18–65 years; body weight 40–150 kg) were divided into groups according to screening IgE (group 1: 30–300 IU/ml; group 2: 700–2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12–14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FE_NO) was an exploratory endpoint. Results: Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6–16. Omalizumab completely suppressed FE_NO increases after ABP in both groups. Conclusions: Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.

The Effect of Omalizumab on Eosinophilic Inflammation of the Respiratory Tract in Patients with Allergic Asthma

“…Zielen et al [27] in their study reported that omalizumab therapy at 8 and 16 week significantly inhibited post-allergenic bronchial contraction within 30 min. following the provocation and reduced the FeNO (fractional nitric oxide concentration in exhaled breath) level measured 24 hours after bronchial provocation with an allergen, which implies inhibition of eosinophilic influx to the allergic reaction site in the late phase.…”

“…Neutralization of free IgE by omalizumab and its effect on the expression and function of FceRI are reflected in clinical phenomena, such as inhibition of early [26,27] and late phase of allergic reaction [28,29] and also a decrease in the severity of chronic allergic inflammation.…”

Revision of omalizumab dosing table for dosing every 4 instead of 2 weeks for specific ranges of bodyweight and baseline IgE

“…For the omalizumab-IgE model, it started with single-dose data in atopic but otherwise healthy volunteers (MenoTetang and Lowe, 2005) through the addition of two Japanese and three Caucasian studies (Hayashi et al, 2007), then further intermediate incarnations Slavin et al, 2009) to the form used for the expansion of the EU dosing table in January 2010 (EMA Xolair Ò Summary of product information, 2013). For the DTR, the PK-PD model referenced data from 9 studies (Busse et al, 2001;Holgate et al, 2004;Humbert et al, 2005;Kornmann et al, 2014;Lanier et al, 2009;Milgrom et al, 2001;Riviere et al, 2011;Soler et al, 2001;Zielen et al, 2013).…”

“…These were: (i) a randomized, double-blind, placebo-controlled study demonstrating the protective effects of omalizumab against allergen-induced bronchoconstriction in patients (aged 18-65 years) with allergic asthma and baseline IgE up to 2000 IU/mL (Zielen et al, 2013); and (ii) a multicenter, open-label, parallel-group study evaluating omalizumab at high doses in patients (aged 18-55 years) with IgE/bodyweight combinations outside the initially approved dosing regimen (Kornmann et al, 2014) . Finally, a single-dose parallel-group bioequivalence study investigated the use of omalizumab (150 and 300 mg sc) in atopic (total IgE above normal levels [30-300 IU/mL]) but otherwise healthy volunteers (Riviere et al, 2011).…”

“…Five studies were identified (Kornmann et al, 2014;Milgrom et al, 2001;Saini et al, 1999Saini et al, , 2011Zielen et al, 2013), and their data pooled to confirm the safety profile of high dose omalizumab, especially in terms of adverse events (AEs). Additionally, a cumulative search with a cut-off date of 30 June 2011 was conducted in the global postmarketing safety database to identify patients who had received P900 mg/month of omalizumab.…”