New asthma guidelines emphasize control, regular monitoring

Omalizumab is cost-beneficial in properly selected patients

The current wholesale acquisition cost of omalizumab is $532 for one 150-mg vial (David Zito, personal communication). The cost of treatment varies based on body weight and IgE level but may range from a wholesale cost of $6,388 to $38,326 per year.

However, as asthma severity increases, both direct and indirect medical expenditures increase substantially.^47,48 Annual costs are approximately four times higher for severe asthma compared with mild asthma⁴⁹; not only are treatment and exacerbation costs higher, but indirect costs are also disproportionately greater. Annual costs for severe asthma are significantly greater if the disease is inadequately controlled.⁵⁰ For these reasons, an intervention that leads to improved outcomes for severe, poorly controlled asthma carries the potential for the greatest cost-utility for society, as it can lower direct costs by reducing the frequency and severity of exacerbations, in addition to reducing indirect medical expenditures on the basis of increased productivity and fewer days of missed work or school. The cost of omalizumab in quality-adjusted life years compares favorably with that of biologicals used in managing rheumatoid arthritis, Crohn disease, and multiple sclerosis.⁵⁰

Adverse effects of omalizumab

In pivotal trials,^43,44 omalizumab was associated with a substantial rate of local reactions. The rate of anaphylaxis was slightly less than 1 in 1,000, and this has been confirmed by surveillance data recorded since approval of the drug in 2003. Based on the observed risk of anaphylaxis, in July 2007, the US Food and Drug Administration added a black-box warning to the omalizumab label and stipulated that a medication guide should be provided for patients.⁵¹ The warning indicates that health care providers administering omalizumab should be prepared to manage anaphylaxis and that patients should be closely observed for an appropriate period after omalizumab administration.

The package insert also describes a numerical, but not statistically significant, increase in the rate of malignancy in patients receiving omalizumab.⁴² Malignancy developed in 0.5% of patients receiving omalizumab, compared with 0.2% of patients who received placebo. Because these malignancies were diagnosed over a shorter period than the time required for oncogenesis (ie, 6 months in 60% of cases), and because a heterogeneous variety of tumors was observed, there is reason to doubt these tumors were causally associated with omalizumab.

Postmarketing surveillance studies are in progress that will provide more definitive data on the potential relationship between malignancy and omalizumab exposure.

Omalizumab: Guideline recommendations

The EPR3 guidelines¹ state that omalizumab is the only adjunctive therapy to demonstrate efficacy when added to high-dose inhaled corticosteroids plus long-acting beta agonists in patients with severe, persistent, allergic asthma and that evidence does not support use of the following agents, which in some cases are approved for managing other conditions and have been advocated for management of severe, refractory asthma: methotrexate, soluble interleukin (IL)-4 receptor, anti-IL-5, anti-IL-12, cyclosporine A, intravenous immune globulin, gold, troleandomycin, and colchicine. The data supporting use of macrolides were characterized as “encouraging but insufficient to support a recommendation.”

The strength of evidence for the use of omalizumab for patients in steps 5 and 6 who fulfill the criteria for its use (see above) was classified in the EPR3 guidelines¹ as category B. The guidelines also say that omalizumab may be considered for adjunctive therapy in properly selected patients in step 4, as a means to avoid higher doses of inhaled corticosteroids, but that additional studies are needed to establish its utility for such patients. This recommendation was classified as category D because of the lack of published comparator trials.

ALLERGEN IMMUNOTHERAPY FOR PATIENTS WITH ASTHMA

Many patients with asthma have clinically relevant, IgE-mediated (allergic) potential to inhaled allergens.¹ For patients with persistent asthma (steps 2–6 in Table 5), allergic reactions can contribute to airway inflammation, provoke symptoms, and lead to more use of medications. For this reason, identification and management of clinically relevant allergy merits consideration.⁵²

The EPR3 guidelines¹ recommend considering allergen immunotherapy for patients with mild or moderate persistent asthma (steps 2–4) who have a clinically relevant component of allergy to inhaled substances.

Changing the immune response

Allergen immunotherapy entails the incremental administration of inhalant allergens by subcutaneous injection for the purpose of inducing immune system changes in the host response. The goal of immunotherapy is to protect against allergic reactions that can be expected to occur with ongoing exposure to clinically relevant allergens.⁵³

The immunologic changes that develop with allergen immunotherapy are complex.^53,54 Successful immunotherapy results in generation of a population of CD4+/CD25+ T lymphocytes producing IL-10, transforming growth factor beta, or both. Allergen immunotherapy has been shown to block the immediate- and late-phase allergic response; to decrease recruitment of mast cells, basophils, and eosinophils on provocation or natural exposure to allergens in the skin, nose, eye, and bronchial mucosa; to blunt the seasonal rise in specific IgE; and to suppress late-phase inflammatory responses in the skin and respiratory tract. However, the efficacy of immunotherapy in relation to these immunologic changes is not completely understood.⁵⁴