Dermatology

 

 

Omalizumab: A New Treatment
for the Management of Asthma

Volume VII, Number 1 | January/February 2004
Bridgette L. Sims, Pharm.D. Candidate

Print this Content

Return to Pharmacotherapy Update Index

Introduction

Asthma is a chronic disease with three different components: bronchoconstriction, inflammation of the airways, and airway remodeling. Acute symptoms are usually caused by bronchospasms due to the hyperresponsiveness of the airways. The chronic components of the inflammatory process include inflammatory cells (e.g., basophils, T cells, mast cells, neutrophils, eosinophils, macrophages, and epithelial cells), mast cell degranulation, denudation of the epithelium, and collagen deposits in the subbasement membrane.1 The chronic inflammation results in dyspnea, wheezing, coughing, and chest tightness. Airway remodeling is a new mechanism involved in the pathophysiology of asthma. Previously, it was thought that the symptoms and inflammation of asthma were reversible. However, airways adapt and repair in response to the inflammation which may result in fibrosis. In some asthmatic patients, airflow restriction and structural changes observed in the airways secondary to chronic inflammation may be irreversible. This results in the obstruction of airways, similar to that observed with chronic obstructive pulmonary disease (COPD).

In allergic asthma, IgE antibodies are formed against common aeroallergens such as cats, dogs, dust mites, and mold. There are two components involved in the development of allergic asthma. One involves atopy, which is a genetic predisposition to an IgE response to aeroallergens. The second component is the ability to develop IgE antibodies due to an imbalance between T-helper 1 (Th-1) and T-helper 2 (Th-2) cytokines. In allergic inflammation, Th-2 cytokines, which are expressed to a greater extent than Th-1 cytokines, produce interleukin (IL)-4, -5, -6, -9, and -13, that can mediate allergic inflammation.1,2 When atopic asthmatics come in contact with these common aeroallergens, IgE is released and binds to basophils and mast cells. The activation of basophils and mast cells stimulates the release of histamine, leukotrienes, granulocyte-macrophage colony-stimulating factor (GM-CSF), type II interferon (IFN-γ), interleukin (IL)-1, -2, -3, -4, and -5, and tumor necrosis factor (TNF-α). The release of these mediators causes smooth muscle contraction and bronchoconstriction.

The current classification of asthma severity is based on symptoms and lung function tests (See Table 1), while the current treatment for asthma is based on severity (See Table 2).2,3

Table 1: Asthma Severity Classification
Classification Symptoms Lung Function
Step 1:
Mild-Intermittent

Daytime < 2 times per week
 
Nighttime < 2 times per month
 
Brief exacerbations
 
Asymptomatic between exacerbations
 
Intensity of exacerbations varies

PEF Variability < 20%
 
FEV1 > 80%
 
PEF > 80%
Step 2:
Mild-Persistent
Daytime > 2 times per week but < 1 time per day
 
Nighttime > 2 times per month
 
Exacerbations may affect activity
PEF Variability range of 20%-30%
 
FEV1 > 80%
 
PEF > 80%
Step 3:
Moderate-Persistent
Daytime symptoms daily
 
Nighttime symptoms > 1 time per week
 
Exacerbations affect activity
 
Exacerbations > 2 times per week
 
Exacerbations last days
 
Daily use of inhaled short-acting ß2-agonists

PEF Variability > 30%

FEV1 > 60% but < 80%

PEF > 60% but < 80%

Step 4:
Severe-Persistent
Daytime symptoms continual
 
Nighttime symptoms frequent
 
Symptoms limit physical activity
 
Exacerbations frequent
PEF variability > 30%
 
FEV1 < 60%
 
PEF < 60%

 

PEF = peak expiratory flow, FEV1 = forced expiratory volume in 1 second
Adapted from National Asthma Education and Prevention Program. NIH. 1997;97-4051:iii-86.
Kelly HW, et al. Pharmacology: a Pathophysiologic Approach 5th ed. New York: McGraw-Hill; 2002. p. 475-510.

Table 2: Treatment Guidelines for Asthma
Classification Short-Term Treatment Long-Term Treatment Additional Treatment
Step 1:
Mild-Intermittent
Short-acting inhaled ß2-agonist
 
Use of rescue inhaler > 2 times per week consider long-term treatment
None needed None needed
Step 2:
Mild-Persistent
Short-acting inhaled ß2-agonist
 
Use of rescue inhaler daily or increased frequency need additional long-term treatment
Inhaled low doses of corticosteroids, cromolyn sodium (Intal®), or nedocromil (Tilade®)
 
Sustained-release theophylline, zafirlukast (Accolate®) or zileuton (Zyflo®)

 

None needed
Step 3:
Moderate-Persistent
Short-acting inhaled ß2-agonist
 
Use of rescue inhaler daily or increased frequency need additional long-term treatment
Inhaled medium dose corticosteroids OR
 
Inhaled low-medium dose corticosteroids plus long-acting inhaled ß2-agonist
Medium-high dose inhaled corticosteroids AND
 
Long-acting inhaled ß2-agonist, sustained-release theophylline, or long-acting ß2-agonist tablets
Step 4:
Severe-Persistent
Short-acting inhaled ß2-agonist
 
Use of rescue inhaler daily or increased frequency need additional long-term treatment
High dose inhaled corticosteroid AND
 
Long-acting inhaled ß2-agonist, sustained-release theophylline, or long-acting ß2-agonist tablets
Long-term oral corticosteroids

Adapted from: National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. NIH 1997;97-405:iii-86.
Kelly HW, Sorkness CA. Asthma In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, et al. editors. Pharmacology: A Pathophysiologic Approach 5th ed. New York: McGraw-Hill; 2002. p. 475-510.

Omalizumab

The Food and Drug Administration (FDA) approved omalizumab (Xolair®; Genentech/Novartis) in June of 2003.

Indications

Omalizumab is FDA-approved for use in moderate-persistent to severe-persistent asthma. Eligible patients for therapy need to be >12 years of age, have a positive skin test to a perennial aeroallergen (e.g., dust mites, cats, dogs, and mold), and be symptomatic with inhaled corticosteroids. An unlabeled use of omalizumab is for the treatment of allergic rhinitis, and it is also being studied for use in patients with peanut allergies.

Pharmacology and Pharmacokinetics

Omalizumab is an IgG monoclonal antibody that inhibits IgE from binding to the surface of basophils and mast cells.4 This removes and deactivates free, circulating IgE and any IgE that has detached from cell surface receptors. Decreasing and eliminating IgE prevents the activation of basophils and mast cells, thus, preventing allergic mediated early- and late-phase hyperresponsiveness of asthma.5

The bioavailability of omalizumab is 62% after subcutaneous administration. It reaches a peak concentration within 7 to 8 days after subcutaneous administration and has a half-life of approximately 26 days. Omalizumab is eliminated by the liver through the reticuloendothelial system.4

Selected Clinical Trials

Omalizumab has been studied in both pediatric and adult patients (See Tables 3 and 4). The trials mainly focus on the reduction of asthma exacerbations, the ability to decrease or eliminate inhaled corticosteroids, and the ability to increase the quality of life in asthmatic patients.

In several of the trials described, patients were only taking inhaled corticosteroids.6-8 In a study by Milgrom and colleagues (1999), patients were allowed to use inhaled corticosteroids or both inhaled and oral corticosteroids.9 There were, however, no trials that allowed patients to be treated with long-acting inhaled ß2-agonists. The current guidelines for asthma recommend that patients with moderate-persistent to severe-persistent asthma should be maximized on inhaled corticosteroids with either a long-acting inhaled or oral ß2-agonist or theophylline. Additionally, in severe-persistent asthma, long-term oral corticosteroids can be added to maximize treatment.2 Thus, none of the trials maximized patients on the accepted current standards of practice. Since the study by Milgrom (1999) included treatment that was more similar to the standards, its results may be more applicable to practice.9

Table 3. Selected Pediatric Omalizumab Clinical Trials6,7
Study Patients and Baseline Treatment Omalizumab Study Treatment Primary Endpoints Results
Milgrom et al.6
RDBPC
n = 334
 
Age: 6-12 years
 
Well controlled with inhaled corticosteroids (doses equivalent to 168 to 420 mcg/day of BDP) and bronchodilators
Inhaled BDP and OMX SC 0.016 mg/kg/IgE (IU/mL) for 28 weeks or placebo
OMZ n=225
 
Placebo n=109
 
Steroid-stable phase: BDP dose kept constant for 16 weeks
 
Steroid-reduction phase: BDP dose reduced over 8 weeks to minimum tolerated dose: Minimum dose maintained for 4 additional weeks
BDP does reduction, symptoms, spirometry, AE Median BDP dose reduction of 100% with OMZ vs. 66.7% with placebo (p=0.001)
 
BDP completely withdrawn in 55% receiving OMZ vs. 39% receiving placebo (p=0.004)
 
Steroid stable phase:
Asthma exacerbations occurred in 15.6% receiving OMZ vs. 22.9% receiving placebo (p=0.095)
 
Steroid reduction phase:
Asthma exacerbations occurred in 18.2% receiving OMZ vs. 38.5% receiving placebo (p<0.001)
 
No statistical difference in symptom scores or spirometry
 
No serious AE
Lemanske et al.7
RDBPC
Same as Milgrom et al.6 Same as Milgrom et al.6 Mean change from baseline in asthma-related QOL scores End of steroid-stable phase:
No statistical difference in PAQLQ scores between groups
 
End of steroid-reduction phase:
-Greater mean change from baseline in activities scores (p<0.05) and symptoms scores (p<0.05) with OMZ vs. placebo
-No statistical difference in emotions scores between groups
-The overall mean score change from baseline was statistically significant with OMZ vs. placebo (p<0.05)
 
End of study:

Greater proportion of OMZ patients achieved a clinical improvement in asthma-related QOL

AE=Adverse event
BDP=beclomethasone dipropionate or equivalent inhaled steroid
DBPC=double-blind, placebo-controlled, n=number of patients in study group
OMZ=omalizumab
PAQLQ=Pediatric Asthma Quality of Life Questionnaire
QOL=Quality of Life
RDBPC=randomized, double-blind, placebo-controlled trial
SC=subcutaneous

Table 4. Selected Adult Omalizumab Clinical Trials
Study Patients and
Baseline Treatment
Omalizumab Study Treatment Primary Endpoints Results
Busse et al.8
DBPC parallel trial
n=525 patients
 
Age: 12-75 years
 
Inhaled corticosteroids (doses equivalent to 168 to 420 mcg/day of BDP)
Inhaled BDP and OMZ SC 0.016 mg/kg/igE (IU/mL) for 28 weeks or placebo
OMZ n=268
 
Placebo n=257
 
Steroid-stable phase: dose kept constant for 16 weeks
 
Steroid-reduction phase: dose reduced over 12 weeks to minimum tolerated dose
Number of exacerbations during steroid stable and reduction phases, steroid dose reduction
Steroid-stable phase:
> 1 exacerbations in 14.6% OMZ patients vs. 23.3% placebo patients (p=0.009)
 
Steroid-reduction phase:
Fewer OMZ patients with exacerbations vs. placebo (21.3% vs. 32.3%, respectively; p=0.004)
 
More OMZ patients achieved a > 50% reduction in steroid dose (72.4% vs. 54.9%, respectively; p<0.001)
Milgrom et al.9
RDBPC
n=317 patients
 
Age: 11-50 years
 
Inhaled corticosteroids (triamcinolone 200 mcg BID or equivalent)
 
OR
 
Oral prednisone 20 mg daily or 40 mg every other day and inhaled corticosteroids
High dose
(5.8 mcg/kg/IgE [ng/mL]) or low dose (2.5 mcg/kg/IgE [ng/mL]) IV
OMZ for 20 weeks or placebo

 
OMZ:
-High-dose n=106
-Low-dose n=106
 
Placebo n=105
 
Steroid-stable phase: dose kept constant for 12 weeks
 
Steroid-reduction phase: dose reduced over 8 weeks to minimum tolerated dose
Improvements in asthma symptoms scores at 12 weeks Range: 1 (none) to 7 (very great deal)
 
Baseline mean: 4
High dose OMZ
Mean symptom score 2.8+ 0.1 (p=0.008 vs. placebo)
 
Reduction in oral steroid dose > 50% in 78% of patients (p=0.04 vs. placebo)
 
Reduction in inhaled steroid dose > 50% in 51% of patients (p=0.07 vs. placebo)

Low dose OMZ
Mean symptom score 2.8+ 0.1 (p=0.005 vs. placebo)
 
Reduction in oral steroid dose > 50% in 57% of patients (p=0.23 vs. placebo)
 
Reduction in inhaled steroid dose > 50% in 49% of patients (p=0.12 vs. placebo)

Placebo
Mean symptom score 3.1+ 0.1
 
Reduction in oral steroid dose > 50% in 33% of patients
 
Reduction in inhaled steroid dose > 50% in 38% of patients

BDP=beclomethasone dipropionate or equivalent inhaled steroid
DBPC=double-blind, placebo-controlled
n=number of patients in study group
OMZ=omalizumab
RDBPC=randomized, double-blind, placebo-controlled trial
SC=subcutaneous

Adverse Drug Reactions

Some of the most common adverse drug reactions of omalizumab include: injection site reactions, viral infections, upper respiratory tract infection, sinusitis, headache, and pharyngitis. Additional adverse drug reactions are described in Table 5.10,11

Table 5. Reported Adverse Drug Reactions of Omalizumab
System Adverse Reactions
Respiratory Pharyngitis, upper respiratory tract infection, sinusitis, pneumonia, asthma exacerbation
CNS Fatigue, pain, headache, dizziness
Local Injection site reactions (swelling, redness)
Dermatologic Pruritus, dermatitis, urticaria, rash
Musculoskeletal Leg pain, fracture, arm pain, arthralgia
Gastrointestinal Vomiting, gastroenteritis, diarrhea
Otic Earache
Miscellaneous Anaphylaxis, malignancy, eye edema, rhinitis

Adapted from: Lexi-Drugs® online. Omalizumab monograph. Accessed 14 August 2003.
Omalizumab package insert. 1 DNA Way, CA:Genentech Inc.; June 2003.
Food and Drug Administration Center for Biologics Evaluation and Research. Briefing document on safety BLA STN 103976/0 Rockville, MD: The Department of Health & Human Services; 2003.

Drug-Drug Interactions

Currently, there are no known drug-drug interactions with omalizumab. During the investigation of omalizumab, no formal drug interaction studies were conducted. The assessment of the concurrent use of omalizumab and allergen immunotherapy has also not been investigated.4

Pregnancy and Lactation

Omalizumab is classified as a pregnancy risk category B.1 A category B drug has either not demonstrated fetal risk in animal-reproduction studies and has no controlled studies in pregnant women or animal studies have shown an adverse effect but the adverse effect in the first trimester has not been confirmed in controlled studies in women and there is no risk in later trimesters.12 Fetal and neonatal growth was not impaired in animal studies. There are no controlled-trials that have evaluated omalizumab in pregnant women. IgG molecules will cross through the placenta, therefore, it is recommended that omalizumab should not be used during pregnancy. Omalizumab should only be used if it is imperative to treatment and the benefit outweighs the risk. Since omalizumab is an IgG antibody and there is evidence that IgG can pass into breast milk, omalizumab may be expected to be present in breast milk. The extent that omalizumab is passed into human milk is unknown, thus, it is unknown whether the infant will absorb a quantity of omalizumab that would be harmful. The adverse effects of omalizumab on infants have not been determined. The use of omalizumab in nursing women should be done cautiously or avoided if possible.4

Monitoring Parameters

It is important to obtain baseline IgE levels and pulmonary function tests including peak flow and FEV1. IgE levels should not be used during treatment to monitor a patient's response since omalizumab and IgE form complexes that increase serum total IgE levels, and available assays only report total levels.13 During treatment, it is important to monitor how often a patient is symptomatic along with pulmonary function tests. IgE levels should not be repeated until at least one year after omalizumab is discontinued since total IgE levels remain elevated for one year after the discontinuation of therapy.10

Dosage and Administration

The dose and frequency of omalizumab are based on body weight in kilograms (kg) and the serum total IgE level (IU/mL) obtained before initiation of treatment. If large fluctuations in weight occur, the dose of omalizumab should be adjusted accordingly. Generally, the average dose is between 150 to 375 mg every 2 or 4 weeks. Omalizumab is administered by subcutaneous injection, with the maximum dose per injection site being 150 mg. If a dose greater than 150 mg is needed, it can be split and administered at multiple injection sites. If a dose greater than 450 mg is needed, the dose can be split in half and administered every 2 weeks instead of every 4 weeks. Specific dosing recommendations are outlined in Table 6.10

Table 6. Omalizumab Doses in Milligrams Administered Every 2 to 4 Weeks
Pre-treatment
serum IgE (IU/mL)
Body Weight (kg)
  30-60 >60-70 >70-90 >90-150
> 30-100 150 q4 weeks 150 q4 weeks 150 q4 weeks 300 q4 weeks
>100-200 300 q4 weeks 300 q4 weeks 300 q4 weeks 225 q2 weeks
>200-300 300 q4 weeks 225 q2 weeks 225 q2 weeks 300 q2 weeks
>300-400 225 q2 weeks 225 q2 weeks 225 q2 weeks 300 q2 weeks
>400-500 300 q2 weeks 300 q2 weeks 375 q2 weeks Do Not Use
>500-600 300 q2 weeks 375 q2 weeks Do Not Use Do Not Use
>600-700 375 q2 weeks Do Not Use Do Not Use Do Not Use

q=every
Adapted from: Omalizumab package insert. 1 DNA Way, CA:Genentech Inc.; June 2003

Cost

The average wholesale price (AWP) for a 150 mg vial of omalizumab is $541. For dosing every 4 weeks, the price will range approximately from $541 to $1,000 (for 150 mg and 300 mg, respectively). For one year of treatment with these doses, the cost will range from $10,000 to $16,000. For dosing every 2 weeks, the price will range from $800 to $1,400 (for 225 mg and 375 mg, respectively). The total price for a month of treatment with dosing every two weeks is $1,600 to $2,700. For a year of treatment with these doses, the cost will range from $20,000 to $32,000.14

Summary

Omalizumab is a new agent indicated for the treatment of uncontrolled, moderate-persistent to severe-persistent allergic asthma. The available studies did not evaluate the efficacy of omalizumab in patients who were maximized on appropriate drug therapy based on the disease severity. Studies need to be conducted in patients with severe-persistent asthma who are still symptomatic with inhaled high-dose corticosteroids, a long-acting ß2-agonist, long-term oral corticosteroids, and even additional treatments.

In the study populations evaluated, there have been improvements in terms of decreased exacerbations, improved quality of life, and decreased doses of inhaled and oral corticosteroids.6-9

It is currently not known where omalizumab fits into the treatment guidelines for asthma; however, it is not considered a first-line agent in the treatment of allergic asthma. It should be reserved as either a second- or third-line agent after combined inhaled corticosteroids and a long-acting ß2 agonist. Omalizumab is currently under formulary review.

Return to Pharmacotherapy Update Index

References

  1. Busse WW, Boushey HA, Buist S, Clark NM, Kelly HW, Lemanske RF, et al. National asthma education and prevention program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics — 2002. J Allergy Clin Immunol 2002;110(5s):1A-S219.
  2. National Asthma Education and Prevention Program. Expert panel report 2: Guidelines for the diagnosis and management of asthma. NIH 1997;97-4051: iii-86.
  3. Kelly HW, Sorkness CA. Asthma. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, et al, editors. Pharmacotherapy: a Pathophysiologic Approach 5th ed. New York: McGraw-Hill; 2002. p. 475-510.
  4. Omalizumab package insert. 1 DNA Way, CA:Genentech Inc.; June 2003.
  5. Woodruff PG, Fahy JV. Asthma: prevalence, pathogenesis, and prospects for novel therapies. JAMA 2001;286(4):395-398.
  6. Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 2001;108(2):e36.
  7. Lemanske RF, Nayak A, McAlary M, Everhard F, Fowler-Taylor A, Gupta N. Omalizumab improves asthma-related quality of life in children with allergic asthma. Pediatrics 2002;110(5):e55.
  8. Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allerg Clin Immunol 2001;108(2):184-190.
  9. Milgrom H, Fick RB, Su JQ, Reimann JD, Bush RK, Watrous ML, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 1999;341(26):1966-1973.
  10. Lexi-Drugs® online. Omalizumab monograph. Accessed 14 Aug 2003.
  11. Food and Drug Administration Center for Biologics Evaluation and Research. Briefing document on safety BLASTN 103976/0. Rockville, MD: The Department of Health & Human Services; 2003.
  12. Briggs GG, Freeman RK, Yaffe SJ, editors. A reference guide to fetal and neonatal risk drugs in pregnancy and lactation 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. v11-xxiv.
  13. Rambasek TE, Lang DM, Kavuru MS. Omalizumab: where does it fit into current asthma management? Cleve Clin J Med 2004;71:251-61.
  14. Xolair®. Cardinal wholesaler, Inc. Accessed 22 Aug 2003.
 
Bookmark this Chapter
Copyright © 2000-2014 The Cleveland Clinic Foundation. All Rights Reserved.
Center for Continuing Education | 9500 Euclid Avenue, KK31, Cleveland, OH 44195
Copyright © 2000-2014 The Cleveland Clinic Foundation. All Rights Reserved.
Center for Continuing Education | 9500 Euclid Avenue, KK31, Cleveland, OH 44195