Selectivity and Specificity Are the Keys to Cost-Effective Use of Omalizumab for Allergic Asthma

Omalizumab (Xolair) was approved by the U.S. Food and Drug Administration (FDA) on June 20, 2003, for subcutaneous (SC) treatment of adults and adolescents (aged 12 years and older) (a) who have moderate or severe persistent asthma, (b) who have a positive skin test or in vitro reactivity to a perennial aeroallergen, and (c) whose symptoms are inadequately controlled with inhaled corticosteroids. It is associated with off-label (unapproved use) for seasonal allergic rhinitis.

ss Selectivity and Specificity Are the Keys to Cost-Effective Use of Omalizumab for Allergic Asthma Omalizumab (Xolair) was approved by the U.S. Food and Drug Administration (FDA) on June 20, 2003, for subcutaneous (SC) treatment of adults and adolescents (aged 12 years and older) (a) who have moderate or severe persistent asthma, (b) who have a positive skin test or in vitro reactivity to a perennial aeroallergen, and (c) whose symptoms are inadequately controlled with inhaled corticosteroids. 17 It is associated with off-label (unapproved use) for seasonal allergic rhinitis.
Omalizumab was the first humanized therapeutic antibody approved by the FDA for treatment of asthma and the first approved therapy designed to target immunoglobulin E (IgE). Omalizumab labeling includes the results of 3 clinical trials involving 1,368 allergic asthma patients who were randomized to receive either subcutaneous weight-adjusted doses of omalizumab or placebo every 2 or 4 weeks. 18 Doses were determined based on patients' body weight and IgE level. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment (stable-steroid phase) and tapered during a further 12-week treatment period (steroid-reduction phase).
So, how does omalizumab stack up by the measures of efficacy, safety, and cost? Efficacy compared with placebo is not inspiring. In the 2 multicenter clinical trials, 86% to 88% of 542 omalizumab patients experienced no exacerbations of asthma at 16 weeks during the stable steroid phase versus 70% to 77% of patients who received placebo. During the 12-week steroid reduction phase, 79% to 84% of omalizumab patients experienced no exacerbations compared with 68% to 70% of placebo patients. 19,20 By the measure of at least 50% reduction in symptom score, the response ratio was 50% at 20 weeks for high-dose omalizumab (5.8 mcg per kilogram [kg] of body weight per nanogram of IgE per milliliter [mL]), 47% for low-dose (2.5 mcg per kg per nanogram of IgE per ml) patients, and 45% for placebo. 21 In this third multicenter clinical trial involving 317 allergic asthma patients who required inhaled or oral corticosteroids (or both), Milgrom et al., for the rhuMAb-E25 Study Group, found that 30% of high-dose patients, 28% of low-dose patients, and 45% of patients who received placebo experienced exacerbations of asthma. Treatment with oral corticosteroids for exacerbations of asthma was required in 13% of patients in the high-dose group, 16% in the low-dose group, and 28% in the placebo group. The absolute improvement in forced expiratory volume in 1 second (FEV1) at 12 weeks in the study by Milgrom et al. was 1.9% in the high-dose group, 2.1% in the low-dose group, and 1.0% in the placebo group.
In their review of omalizumab in this issue of JMCP, Belliveau and Lahoz found that the drug is not only expensive (generally in the range of $15,000 to $44,000 per patient per year depending upon the dose) but also that severe injection site reactions are reported to occur in 12% of patients. 22 Safety concerns also arise from other adverse events commonly reported in the clinical trials, such as viral infections (23%), upper respiratory infections (20%), sinusitis (16%), headache (15%), and pharyngitis (11%).
Added to the direct cost of the drug is the indirect cost, including patient and caregiver time. Administration of this drug is complicated and time consuming for patients and health care professionals. While it generally requires 15 to 20 minutes of frequent swirling to dissolve the product prior to injection (omalizumab is a fragile protein and therefore the vial cannot be shaken), some vials may take longer than 20 minutes to dissolve completely, and the omalizumab should not be injected if the contents of the vial do not dissolve completely within 40 minutes. While anaphylaxis within 2 hours of the first or subsequent administration of omalizumab is rare (in fewer than 0.1% of patients without other identifiable allergic triggers), patients should be observed after injection of omalizumab, and medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available. 20 For a drug that is not much more effective than placebo, has side effects, is not simple to administer, and has a cost generally in the range of $1,000 to $3,000 per month, there is an obvious need to identify the patient selection criteria to determine the subset of moderate-to-severe allergic asthma patients who would be most likely to respond favorably to treatment with omalizumab. As pointed out by Belliveau and Lahoz, high utilization of medical care resources might help to justify the high direct cost of the drug.
Bousquet et al. provide additional guidance by pooling the results from the 2 principal multicenter clinical trials (Study 1 and Study 2) with omalizumab. 23 Of the 1,070 allergic asthma patients who were symptomatic regardless of moderate-to-high doses of inhaled beclomethasone dipropionate (BDP, mean dose of 75 mcg per day), 542 patients received omalizumab and 528 patients received placebo, administered at a 4-weekly subcutaneous dose of at least 0.016 mg per kg of IgE (IU/mL) for 16 weeks in addition to stable BDP therapy. Univariate logistic regression was performed to explore baseline variables predictive of best response, and 4 aspects of response were assessed (reduced symptom scores, reduced use of rescue medication, improved lung function, improved quality of life [QoL]) as well as a composite definition of response (response in at least 1 of these 4 aspects with no asthma exacerbation during 16 weeks of treatment). For the composite measure of response, the factor most predictive was a history of emergency asthma treatment in the past year (P = 0.015), 67% for omalizumab versus 42% for placebo; for those without a history of emergency asthma treatment, the response rate with omalizumab was 63% versus 54% for placebo. High BDP dose (≥800 mcg per day) was also a predictive factor (P = 0.037) in response to treatment with omalizumab (65%) compared with 40% for placebo; for those treated with <800 mcg per day of BDP, 63% of omalizumab patients had a clinically significant response to treatment versus 55% for placebo. A low FEV1 (≤65%) was not predictive (P = 0.072) of response to omalizumab (60%, versus 40% for placebo).

Editorial Subjects-In This Issue and in Previous Issues
On February 7, 2005, the National Institute for Clinical Excellence announced that its nearly 3-year-old plan to evaluate omalizumab for uncontrolled asthma was being suspended since omalizumab had not been approved for marketing in the United Kingdom. 24 Sin et al. concluded in their systematic review and meta-analysis that the precise role of monoclonal anti-IgE antibody therapy with omalizumab in the management of chronic asthma was not clear. 25 All 4 clinical trials were short-term-the longest in duration of omalizumab treatment at full dose was 28 weeks-so the value of omalizumab beyond 7 months of therapy is not known. What is more certain is that omalizumab has been tested only in patients with severe allergic asthma treated with inhaled corticosteroids, with allergy skin test results that are positive for at least 1 or 2 perennial (and common) allergens, and who have elevated serum IgE levels, ≥30 IU/mL. Second, Salvi and Babu pointed out in a follow-up to the first published clinical trial results for omalizumab in December 1999 26 that (a) acute anaphylaxis can occur in the absence of IgE in laboratory animals; (b) humanized monoclonal antibody can significantly reduce concentrations of free IgE in patients with allergic rhinitis without improving symptom scores; (c) the role of IgE in the pathogenesis of asthma is not known; (d) corticosteroids and beta-agonists, the most effective drugs for asthma treatment, improve symptoms while increasing IgE serum levels; (e) the increased concentration of IgE in allergic asthma may be a phenomenon unrelated to the disease; and (f) symptom scores for the patients treated with omalizumab were only slightly better than those for placebo; and (g) the first clinical trial results with omalizumab did not include any objective measures of asthma such as the standard tests of lung function (FEV1 and peak expiratory flow). 27 From an evidence-based perspective, there is a distinct lack of evidence to support the use of omalizumab even in severe allergic asthma patients and, therefore, insufficient support to develop useful clinical criteria for a prior authorization/medical exception process for health plan coverage of omalizumab therapy. On the other hand, the dilemma for managed care organizations in setting selective and specific criteria for the appropriate use of omalizumab may be moot since most patients do not use the drug beyond a few months. An analysis of pharmacy claims with dates of service from January 1, 2003, through October 32, 2005, showed that 36% of omalizumab patients used the drug for 2 months or less, 64% used the drug for 6 months or less, and only 2% of patients received omalizumab for 12 months or more. 28