( Genentech, Inc., Novartis Pharmaceuticals Corp.) September 2003 Indication The FDA recently approved Omalizumab on June 20, 2003 for adults and adolescents (12 years of age and above) 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 (ICS). Safety and efficacy have not been established in other allergic conditions i. Although not approved by the FDA for the management of seasonal and perennial allergic rhinitis, studies have proven omalizumab to be safe and effective in reducing nasal and ocular symptoms ii,, iii iv. There may be off-label use of omalizumab in the management of food hypersensitivity. Omalizumab has also demonstrated efficacy in food allergies, specifically peanut or nut allergies. The threshold required to elicit an allergic response to peanut protein is significantly increased with administration of omalizumab v. Pharmacology Omalizumab is the first biotechnology product designed to treat patients with a subtype of asthma that is related to allergies. It is a recombinant humanized IgE monoclonal antibody that inhibits the binding of IgE to its high affinity receptor on mast cells and basophils. This prevents the release of histamine and other mediators of the allergic response when allergens bind. Epidemiology According to the Asthma and Allergy Foundation of America, asthma is a chronic lung disease that is estimated to affect more than 17 million people in the United States. No precise definition of allergic asthma (AA) appears to exist and there are no well-accepted epidemiologic data assessing the prevalence of this subtype of asthma. However, Genentech defines AA as an IgE-mediated disease that, in susceptible individuals, causes recurrent episodes of wheezing, breathlessness, chest tightness and cough, particularly at night and in the early morning. Efficacy Omalizumab has been evaluated in the treatment of patients with allergic asthma in four randomized, double-blind placebo-controlled, multicenter trials. All four of these trials are summarized in the evidence table. Clinical trial 008 and 009 Trials 008 and 009 enrolled patients 12 to 7 years old, with moderate to severe persistent asthma for at least one year and a positive skin test reaction to a perennial aeroallergen. All patients had moderate to severe asthma that was not controlled with ICS and short acting beta-agonists. At the start of the study, their pre-study ICS was converted to an equivalent beclomethasone diproprionate (BDP) dose. Other medications were not allowed for maintenance therapy. Most patients (over 70%) were on an intermediate dose of ICS, and less than 11% were on a high dose of ICS vi. Patients remained on a stable dose of ICS for the first sixteen weeks of each trial and were tapered off the ICS during weeks 17-28 until either complete discontinuation or the lowest possible dose that did not worsen asthma symptoms.
The primary endpoint was exacerbations of asthma. An exacerbation was defined as a worsening of asthma control requiring use of oral or intravenous corticosteroids or doubling of the baseline BDP dose. While the percent of patients experiencing an exacerbation was significantly reduced, effect size in absolute terms was small, producing a NNT of 12 and respectively during the stable ICS phase. Duration of exacerbations was significantly reduced. Xolair users were also significantly less likely to have an exacerbation and more likely to have a reduction in the ICS dosage during the ICS reduction phase. Clinical trial 010 Trial 010 was conducted in young children, age 5-12 years old, who were well controlled on low to medium dose ICS, primarily to evaluate safety in this population. More patients (55% vs 39%) were able to reduce ICS therapy vii. Reduction in asthma exacerbations was not significant in the stable steroid phase, but was in the ICS reduction phase. Further assessment on its efficacy in children is needed. Clinical trial 011 Subjects enrolled in this trial were patients (age 12-75) with severe AA. Subjects were on higher doses of ICS, and 95 of the 341 enrolled subjects were also using oral steroids at baseline. Subjects were converted to an equivalent fluticasone dose. There was a modest but statistically greater reduction in ICS dosage with Xolair (0%) vs placebo (50%) during the steroid reduction phase (weeks 17-32) viii. There was no difference in reduction in oral corticosteroid use. There was also no difference in asthma exacerbations in the stable steroid (weeks 1-1) phase or the steroid reduction phase. An exacerbation was defined as a worsening of symptoms requiring initiation of systemic steroids, a more stringent definition than those used in trials 008 and 009. These results suggest that the benefit of omalizumab may be limited in patients with severe asthma. Warnings Pregnancy category B Discontinue therapy if severe hypersensitivity reaction to omalizumab occurs Safety and efficacy has not been established in patients less than 12 years of age Omalizumab has not been shown to alleviate asthma exacerbations acutely and should not be used for the treatment of acute bronchospasm or status asthmaticus Systemic or inhaled corticosteroids should not be abruptly discontinued after initiation of omalizumab Adverse Effects The most severe adverse reactions present were malignancies, 20 out of 4127 (0.5%) in Xolair vs 5 out of 223 (0.2%) in placebo, and anaphylaxis in 3 patients (<0.1%) i. The difference in malignancy between omalizumab and placebo arms was not statistically significant. Types of malignancies varied including breast, prostate, non-melanoma skin, parotid and melanoma. Since most of these patients were followed for less than one year, long term malignancy risks are not known at this time, however the manufacturer is planning to conduct Phase IV studies to evaluate ix. Anaphylactic reactions occurred within 2 hours of omalizumab administration without other identifiable triggers. Reactions included urticaria and throat and/or tongue edema. Therefore, omalizumab subcutaneous injections should be performed at a physician s office in order to monitor for hypersensitivity reactions. 2
Xolair is generally well tolerated; the most frequent adverse events are included in table 1 below. Table 1. Frequent adverse events encountered by patients. Adverse Event Rate (%) Injection site reaction 45% Viral infection 23% Upper respiratory infection 20% Sinusitis 1% Headache 15% Pharyngitis 11% Dosage Omalizumab 150 to 375mg is administered SC every 2 or 4 weeks. Because the solution is slightly viscous, the injection may take 5-10 seconds to administer. Doses and dosing frequency are determined by serum total IgE level and body weight measured before the start of treatment. See the dose determination charts below for appropriate dose assignment. Doses of more than 150 mg are divided among more than one injection site to limit injections to not more than 150mg per site. Table 2. Omalizumab doses (milligrams) administered by SQ Injection every 2 weeks for adults and adolescents (12 years of age and older) with asthma. ADMINISTRATION EVERY 4 WEEKS Pre-treatment Body Weight (kg) Serum IgE (IU/mL) 30-0 > 0-70 > 70-90 > 90-150 >30-100 150 150 150 300 > 100-200 300 300 300 > 200-300 300 > 300-400 > 400-500 SEE TABLE 3 > 500-00 Table 3. Omalizumab doses (milligrams) administered by SQ Injection every 2 weeks for adults and adolescents (12 years of age and older) with asthma. ADMINISTRATION EVERY 2 WEEKS Pre-treatment Body Weight (kg) Serum IgE (IU/mL) 30-0 > 0-70 > 70-90 > 90-150 >30-100 SEE TABLE 2 > 100-200 225 > 200-300 225 225 300 > 300-400 225 225 300 > 400-500 300 300 375 > 500-00 300 375 DO NOT DOSE > 00-700 375 3
Dosage adjustments Serum total IgE may remain elevated for up to one year after omalizumab discontinuation. Therefore, IgE levels from initial dose determination should be used to determine omalizumab dosing following a treatment interruption of less than one year. If therapy has been interrupted for greater than one year, then IgE levels may be re-tested for dose determination. Dose adjustments should be made following significant changes in body weight based on tables 2 and 3. Cost The suggested AWP by the manufacturer is $541.25 per vial. Since omalizumab dosing is based on patient weight and baseline IgE level, the number of vials needed for treatment may range from one to six vials per month. This translates to $541.25 to $3,247.50 per month or $,495 to $38,970 per year. It must be administered in a physician s office so that patients may be monitored for anaphylaxis. Omalizumab will only be available through five regional specialty distributors. Conclusions Omalizumab is a new treatment option for allergic asthma with a novel mechanism of action. More research is needed to clarify its role in therapy. The only study focusing on severe asthmatics showed limited benefit. For patients with moderate asthma being treated with low to moderate doses of ICS plus as needed short-acting beta-agonists, other therapeutic options would appear to be more cost-effective. Current literature has found that adult asthma patients with moderate to severe asthma, can significantly improve lung function and reduce asthma symptoms with the addition of a long acting bronchodilator, such as salmeterol or doubling the ICS dose x, xi, xii. This conventional way of managing asthma may be more cost-effective in managing patients uncontrolled on a medium dose ICS and rescue beta-agonist than the addition of omalizumab. Immunotherapy has also been shown to improve asthma symptoms and may be an option for some patients with allergic asthma. Research in patients with severe allergic seasonal asthma would appear to be warranted. Studies administering this agent during peak allergen exposure would especially be of interest. Studies comparing omalizumab with other traditional treatment options are also needed. 4
Evidence Table Study Design Demographics Drug Regimen N Outcome Response Rate (%) ARR (%) NNT 008 RCT, DB, MC, PG Caucasian 89% Mean age 39 yrs (12-74) Moderate-to-severe AA Albuterol for rescue Mean BDP dose (mcg/d) Control 58 Experimental 570 range 20-80 (1wks) (12wks) 525 Asthma 2 0 endpoint Reduction in BDP 1. 23.3 p = 0.0009 2. 14. 1. 32.3 p = 0.004 2. 21.3 1. 19 2. 40 8.7 11 21 12 9 5 009 RCT, DB, MC Caucasian 91% Mean age 40 yrs (12-7) Moderate-to-severe AA 1yr Salbutamol for rescue Positive skin-prick test Mean BDP dose (mcg/d) Control 772 Experimental 79 range 98-358 (1wks) (12wks) 54 Asthma 2 o endpoint Reduction in BDP 1. 30.5 p < 0.001 2. 12.8 1. 29.8 p < 0.001 2. 15.7 1. 19 p < 0.001 2. 44 17.7 14.1 25 7 4 010 RCT, DB, MC, PG Caucasian 7% Mean age 9 yrs (5-12) Duration of AA 1 yr Albuterol (salbutamol) for rescue Positive skin-prick test Well controlled on ICS Control 27 Experimental 284 range 20-129 (1wks) (1wks) 334 Reduction in BDP 2 o endpoint Asthma 1. 39 p = 0.004 2. 55 1. 22.9 p = 0.093 2. 15. 1. 38.5 p < 0.001 2. 18.2 1 20.3 5 011 RCT, DB MC, PG Caucasian 83% Mean age 43 yrs (12-75) Severe AA Positive skin-prick test Mean ICS dose (mcg/d) Control 1387 Experimental 1432 Rescue beta 2 agonist range 19-1055 (1wks) (1wks) 341 Reduction in ICS 2 o endpoint 1. Reduction in oral corticosteroid 100% 2. Asthma 1. 15 p = 0.003 2. 21 1. 42 p = 0.75 2. 42 1. 15 p = 0.85 2. 1 1. 27 p = 0.50 2. 22 17 RCT randomized controlled trial, DB double blind, MC multicentre, PG parallel group, SQ subcutaneous, AA- allergic asthma, BDP beclomethasone diproprionate, ICS inhaled corticosteroid, Sx- symptom, not significant 5
References i Genentech. Xolair (omalizumab) Prescribing Information. Available at http://www.fda.gov/cber/label/omalgen02003lb.pdf. Accessed July 29, 2003. ii Casale TB. et. al. Safety of Readministration of rhumab-e25 in Seasonal Allergic Rhinitis (SAR). Ann Allergy Asthma Immunol 2000: 84: A70 iii Chervinsky P., Busse W., Casale T. Xolair in the Treatment of Perennial Allergic Rhinitis. J Allergy Clin Immunol 2001; 107: S13. iv Busse W., Nayak, Chervinsky P. Omalizumab (Xolair) Improves Perennial Allergic Rhinitis in Patients Who Were Previously Unresponsive to Treatment with Nasal Steroids or Immunotherapy. J Allergy Clin Immunol 2001; 107: A1. v Leung DYM, Sampson HA, Yunginger JW, Burks AW, Schneider LC, Wortel CH, et al. Effect of Anti-IgE Therapy in Patients with Peanut Allergy. N Eng J Med 2003; 348: 98-93. vi http://www.fda.gov/ohrms/dockets/ac/03/slides/3952s1_02_fda-kaiser_files/frame.htm#slide0002.htm. Access July 29, 2003. vii Milgrom Henry MD, Berger William MD, et. al. Treatment of Childhood Asthma with Anti-Immunoglobulin E Antibody (Omalizumab). Pediatrics. 2001; 108(2): 1-10. viii http://www.fda.gov/ohrms/dockets/ac/03/briefing/3952b1_03_fda-xolair-efficacy.pdf. Accessed July 29, 2003. ix The Pink Sheet. Genentech Xolair Average Cost is $10,000 a Year; mid-july Launch Planned. June 2003. x Greening, Andrew P. et.al. Added Salmeterol Versus Higher-dose Corticosteroid in Asthma Patients with Symptoms on Existing Inhaled Corticosteroid. The Lancet. 1994; 344: 219-224. xi Faurschou P., Steffensen I., Jacques L. Effect of Addition of Inhaled Salmeterol to the Treatment of Moderate-to-Severe Asthmatics Uncontrolled on High-Dose Inhaled Steroids. Eur Respir J. 199; 9: 1885-1890. xii Woolock, A., Lundback B., Ringdal N., Jacques L. Comparison of Addition of Salmeterol to Inhaled Steroids with Doubling of the Dose of Inhaled Steroids. Am J Respir Crit Care Med. 199; 153: 1481-1488.