M. Blogg

Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations

BACKGROUND Physicians have questioned whether omalizumab can be discontinued or the dose reduced after clinical improvement is seen in patients with severe asthma. OBJECTIVES To examine the relationships among omalizumab, free IgE, and clinical outcomes in a randomized, placebo-controlled trial in patients with severe persistent allergic asthma following a posology based on pretreatment total IgE and body weight. METHODS A pharmacokinetic-pharmacodynamic binding model was used to calculate free IgE, omalizumab, and total IgE concentrations during the 28-week treatment and 16-week follow-up of the INvestigation of Omalizumab in seVere Asthma TrEatment (INNOVATE) study. These were plotted against the mean changes in the total asthma symptom score, morning peak expiratory flow, and rescue medication use for physician-defined treatment responders and nonresponders. RESULTS The model accurately fitted omalizumab and free and total IgE, allowing reconstruction of the entire time course for each patient. Free IgE was rapidly suppressed below the 50 ng/mL (20.8 IU/mL) target, although there was a notable period before clinical measures stabilized. After treatment cessation, free IgE and omalizumab returned toward baseline and, after a delay, asthma symptoms re-emerged. Model-derived omalizumab and free IgE concentrations correlated well with changes in clinical outcomes, particularly in omalizumab-treated responders. Asthma symptoms exhibited different correlations during response onset compared with response offset (hysteresis), indicative of physiological time delays between changes in IgE levels and pulmonary function. CONCLUSION Omalizumab and free IgE correlated well with clinical symptoms. Reducing omalizumab doses below those in the dosing table cannot be recommended; the resulting increase in free IgE would cause a deterioration in asthma control.

Omalizumab and the risk of malignancy: Results from a pooled analysis

BACKGROUND Since initial registration, the omalizumab clinical trial database has expanded considerably, with a doubling of patients exposed in the clinical trial environment. Previous pooled data (2003) from phase I to III studies of omalizumab showed a numeric imbalance in malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%). The previous analysis was based on limited available data, warranting further investigation. OBJECTIVE We sought to examine the incidence of malignancy using comprehensive pooled data from clinical trials of omalizumab-treated patients. METHODS This pooled analysis included data from 67 phase I to IV clinical trials. The prespecified primary analysis assessed the incidence of primary malignancy in 32 randomized, double-blind, placebo-controlled (RDBPC) trials. RESULTS There were 11,459 unique patients in all clinical trials (7,789 received omalizumab). The primary analysis identified malignancies in 25 patients (RDBPC trials): 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 (95% CI, 2.26-6.94) and 4.45 (95% CI, 2.22-7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39-2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified. CONCLUSIONS In this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials; the rate ratio was below unity. The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely.

Effectiveness of omalizumab in patients with inadequately controlled severe persistent allergic asthma: An open-label study

BACKGROUND In a 1-year, randomized, open-label study in patients with moderate-to-severe allergic (immunoglobulin E (IgE)-mediated) asthma, adding omalizumab to best standard care (BSC) significantly improved efficacy outcomes compared with BSC alone (control). We assessed the efficacy of omalizumab in the subgroup of patients with inadequately controlled severe persistent allergic asthma despite high-dose inhaled corticosteroids (ICS) plus a long-acting beta(2)-agonist (LABA), which reflects the European Union (EU) label population. METHODS Efficacy outcomes included annual asthma exacerbation rate, annual asthma deterioration-related incident (ADRI) rate, % predicted forced expiratory volume in 1 s (FEV(1)), asthma symptoms (Wasserfallen score) and quality of life (Mini Asthma Quality of Life Questionnaire (Mini-AQLQ)), which were compared in the omalizumab and control groups. Outcomes were also determined for omalizumab-treated patients judged to have responded to therapy (> or = 0.5-point improvement in Mini-AQLQ overall score at 27 weeks). RESULTS In total, 164 patients (omalizumab, n=115; control, n=49) were receiving high-dose ICS plus a LABA. Annual asthma exacerbation rate was significantly reduced by 59% in the omalizumab group vs. control (1.26 vs. 3.06; P<0.001). ADRI rate was significantly reduced by 40% in the omalizumab group compared with control (5.61 vs. 9.40; P<0.05). Significant improvements were also seen in % predicted FEV(1) (71% vs. 60%; P<0.001), change from baseline in asthma symptom scores (-6.7 vs. 0.5; P<0.05) and Mini-AQLQ overall score (1.32 vs. 0.17; P<0.001). In omalizumab-treated patients, 71/102 (70%) were judged to have responded to therapy. In these Mini-AQLQ-assessed responders, exacerbation rate was reduced by 64% vs. control (1.12 vs. 3.06; P<0.001), ADRI rate was reduced by 50% vs. control (4.71 vs. 9.40; P<0.01). Percent predicted FEV(1) (73% vs. 60%; P<0.001), change from baseline in asthma symptom scores (-8.1 vs. 0.5; P<0.001) and Mini-AQLQ overall score (1.81 vs. 0.17; P<0.001) were also further significantly improved vs. control. CONCLUSIONS Adding omalizumab to BSC is efficacious in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA (EU label population), with further efficacy observed in patients judged to have responded to therapy which may more accurately illustrate the actual benefit of omalizumab therapy in clinical practice. The naturalistic setting of this study confirms the benefits observed in double-blind randomized clinical trials.

Omalizumab in children with inadequately controlled severe allergic (IgE-mediated) asthma

Abstract Background: Many children with severe persistent allergic (IgE-mediated) asthma remain inadequately controlled despite treatment with high-dose inhaled corticosteroids (ICS) plus a long-acting β2-agonist (LABA). Research and design methods: This pre-specified analysis of a randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of omalizumab in children (6–<12 years) with perennial allergen sensitivity, and history of asthma exacerbations and symptoms despite treatment with ICS (fluticasone ≥500 µg · day−1 or equivalent) plus a LABA. Patients received omalizumab (75–375 mg once or twice a month by subcutaneous injection, as determined from dosing tables) or placebo over 52 weeks (24-week fixed-steroid then 28-week adjustable-steroid phases). Results: Out of 246 randomized patients (omalizumab, n = 166; placebo, n = 80), efficacy was analysed in 235 (omalizumab, n = 159; placebo, n = 76). Over the 24-week fixed-steroid phase, omalizumab reduced the rate of clinically significant asthma exacerbations (worsening symptoms requiring doubling of baseline ICS dose and/or systemic steroids) by 34% versus placebo (0.42 vs 0.63, rate ratio 0.662; P = 0.047). Over 52 weeks, the exacerbation rate was reduced by 50% (P < 0.001). Omalizumab had an acceptable safety profile, with no statistically significant (P < 0.05) differences in adverse events observed between omalizumab and placebo. Conclusion: Add-on omalizumab is well-tolerated and reduces exacerbations in children (6–<12 years) with severe persistent allergic asthma, inadequately controlled despite high-dose ICS plus a LABA. It should be noted that the sample size was not based on providing statistical power in the severe subgroup, and no corrections were made for multiple comparisons; however, outcomes consistently favoured omalizumab. Trial registration: ClinicalTrials.gov identifier: NCT00079937.

Relationship between pretreatment specific IgE and the response to omalizumab therapy

Background:  Omalizumab, an anti‐IgE antibody, has proven efficacy in patients with moderate‐to‐severe and severe persistent allergic (IgE‐mediated) asthma. While previous analyses have had some limited success in predicting which patients will gain greatest benefit based on pretreatment baseline characteristics, it remains important to try to improve this predictability.

Immunogenicity and safety of omalizumab in pre-filled syringes in patients with allergic (IgE-mediated) asthma

Abstract Background: Omalizumab, a humanised anti-immunoglobulin E monoclonal antibody for treatment of uncontrolled moderate-to-severe or severe persistent allergic asthma, was developed as a lyophilised powder for reconstitution. A liquid formulation in pre-filled syringes has now been developed. The purpose of this study was to assess the immunogenicity and safety of this liquid formulation. Methods: In this multinational, open-label, single-arm study, patients (≥12 years) with moderate-to-severe allergic asthma were treated for 24 weeks with the liquid formulation of omalizumab (75 or 150 mg in a pre-filled syringe) at 2 or 4 week intervals. Immunogenicity was assessed by measurement of human anti-therapeutic antibody (ATA) levels. Safety was assessed by monitoring adverse events (AEs), haematology, blood chemistry, urine analysis and vital signs. Results: A total of 155 patients were enrolled in the study. No patient had a confirmed positive ATA test result. Most frequent individual AEs were asthma (17.4%), sinusitis (17.4%) and upper respiratory tract infection (11.6%). Fourteen patients (9.0%) had serious AEs and there was one death (not treatment related). There were no cases of anaphylaxis according to Sampson criteria. Most patients remained within normal ranges for haematology and biochemistry laboratory variables. Conclusions: Omalizumab in pre-filled syringes was not associated with immunogenicity. This novel formulation, which does not require reconstitution, had a safety profile consistent with the lyophilised formulation. A limitation of this study is that efficacy of omalizumab in the treatment of asthma was not specifically addressed herein. Clinicaltrials.gov identifier: NCT00500539.

Omalizumab reduces the rate of asthma deterioration-related incidents in patients with poorly controlled allergic asthma*

34 Omalizumab Reduces the Rate of Asthma Deterioration-Related Incidents in Patients with Poorly Controlled Allergic Asthma J. G. Ayres ], R. Niven 2, G. Ayre 3, M. Blogg 3, H. Fox3; ]Chest Research Unit, Heartlands Hospital, Birmingham, UNITED KINGDOM, 2North West Lung Research Centre, Manchester, UNITED KINGDOM, 3Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: To evaluate the efficacy of omalizumab (Xolair| a monoclonal anti-immunoglobulin E antibody, for reducing the rate of asthmadeterioration related incidents (ADRIs) in patients with poorly controlled allergic asthma. METHODS: In a 52-week, open-label study, 312 patients (aged 12-75 yrs) receiving _>400 mcg/d (pediatric) or _>800 mcg/d (adult) inhaled beclomethasone dipropionate or equivalent for poorly controlled, moderate-to-severe allergic asthma were randomized (2:1) to current asthma therapy (CAT) with or without subcutaneous omalizumab (at least 0.016 mg/kg/IgE [IU/mL) per 4 wks). The primary efficacy variable was the annualized rate of ADRIs, ie, >1 of the following events due to asthma: course of oral steroids or antibiotics, missed school/work attendance, unscheduled physician visit, or emergency room visit/hospitalization. RESULTS: Baseline characteristics were comparable for the two groups (omalizumab, n=206; CAT alone, n=106), with 99% of patients being treated according to GINA step 3/4. Among evaluable patients, treatment with omalizumab significantly reduced the mean rate of ADRIs vs CAT alone (4.92 and 9.76 per patient-year, respectively; p<0.001). The percentage of patients who remained ADRl-free was increased for omalizumab-treated patients vs CAT alone (36% [69/191] and 20% [18/89], respectively; p=0.008). These results were paralleled by significantly improved lung function and fewer exacerbations for those treated with omalizumab, which proved safe and well tolerated. CONCLUSIONS: The findings of this naturalistic study indicate that add-on therapy with omalizumab is effective in reducing the rate of ADRIs in patients with moderate-to-severe allergic asthma who remain poorly controlled despite conventional treatment. Funding: Novartis Pharma AG and Genentech lnc 535 Fluticasone Propionute (FP) CFC Delivered via Valved Holding Chamber with Facemask for 12 Weeks Improved Asthma Control in Children Aged 24-47 Months with Asthma