Effect of Anti-IgE in Non-Allergic Asthma
Effect of Anti-IgE in Non-Allergic Asthma
The purpose of this study is to find out if omalizumab is effective in treating non-allergic
 asthma. The US Food and Drug Administration has approved the use of omalizumab to treat
 moderate to severe allergic asthma.
Asthma is a chronic inflammatory disease of the lower airways. The inflammatory process is
 associated with changes in airway hyperresponsiveness (irritability), and airflow limitations
 caused by bronchoconstriction, edema, and mucous plugging. Mast cells, basophils,
 eosinophils, activated T-lymphocytes, macrophages, neutrophils, and airway epithelial cells
 all play a role in this inflammatory process by releasing mediators directly responsible for
 local inflammation and by releasing mediators that encourage a further influx of inflammatory
 cells (Expert Panel Report 2, 1997). These cells and their products eventually produce a
 state of chronic allergic inflammation leading to increased vascular leakage, mucous
 secretion, smooth muscle hyperresponsiveness, and nerve activation. Clinically, this process
 is characterized by intermittent shortness of breath, wheezing, coughing, and chest
 tightness.

 Although most asthmatics are atopic (allergic), non-atopic asthmatics exist and can develop
 equally severe disease. Non-allergic asthmatics have a trend towards higher than normal
 levels of the allergic antibody (IgE) though obviously they lack skin test specificity. When
 examining skin test reactivity and serum IgE as independent variables for asthma risk, there
 was a stronger association with serum IgE elevation than skin test reactivity. In fact, serum
 IgE tended to be high in asthmatics regardless of skin test reactivity.

 Omalizumab (Xolair®) is a recombinant humanized monoclonal antibody that binds specifically
 to the (FceRI) binding site on human IgE. The binding of omalizumab inhibits the ability of
 IgE to bind to basophils or mast cells.

 Omalizumab recently received FDA approval for the treatment of moderate to severe persistent
 allergic asthma in pediatric (12 years of age and above) and adult patients. The addition of
 omalizumab to standard asthma therapies has been found to reduce asthma exacerbations and
 decrease both inhaled corticosteroid dose and rescue medication use. (Busse, 2001). In a
 phase III double blinded placebo controlled trial involving 525 severe allergic asthmatics,
 omalizumab treated patients had fewer exacerbations during both a steroid stable phase and
 steroid reduction phase than did placebo controls (Busse, 2001). The median reduction in
 steroid dose during reduction phase was 75% and 50% in the omalizumab and placebo groups
 respectively. In a similarly designed steroid reduction study involving 6 to 12 year-old
 moderate to severe allergic asthmatics, steroid reduction was possible in 100% of treated
 patient verses 66.7% of placebo treated patients (Milgrom, 2001). Other steroid reduction
 studies have had similar results (Buhl 2002, Soler 2001). Omalizumab has also been shown to
 improve quality of life in allergic asthmatics as measured by the Asthma Quality of Life
 Questionnaire (AQLQ). In adults, AQLQ demonstrated greater improvement at 16, 28 and 52 weeks
 in omalizumab treated patients than in placebo treated (Finn 2003). Similarly in pediatric
 populations, AQLQ improvement reached statistical significance in omalizumab treated patients
 (Lemanske 2002).

 Omalizumab has shown itself to be a promising new therapy for the treatment of moderate to
 severe allergic asthma. It is currently not indicated for patients with non-allergic asthma.
 The objective of this study will be to define the effects of omalizumab on cell surface FceRI
 expression and serum IgE of non-allergic asthmatics.
Inclusion Criteria:

 -  Males and non-pregnant, non-breastfeeding females 18 through 80 years of age

 -  Clinically acceptable ECG

 -  Diagnosis of moderate to severe persistent asthma

 -  History or presence of episodic symptoms of airflow obstruction (wheeze, chest
 tightness, cough, shortness of breath)

 -  Airflow obstruction is at least partially reversible

 -  FEV1 in the context of this study is <80%of predicted values at visit 1 with no
 short-acting ß agonist use within 6 hours of spirometry

 -  Improvement of at least 12% of predicted FEV1 value and at least 200 ml within 15 to
 30 minutes of inhaling nebulized albuterol (up to 5mg) or 2-4 puffs of albuterol (90
 mcg/actuation) demonstrated at study entry or documented in the last year.

 -  Subjects must be able to demonstrate proper technique for use of the MiniWright peak
 flow meter

 -  Subjects must have a negative skin test to the 5 common perennial aeroallergens (D.
 farinae, D. pteronyssinus, cat, dog, and cockroach) at prick puncture with an adequate
 histamine control.

 -  Subjects must have negative RAST to the same 5 common perennial aeroallergens .

 -  Serum total IgE must be 30-700 IU/ml.

 -  Normal EKG at baseline

 -  Females must be: Surgically sterile (hysterectomy, bilateral oophorectomy, bilateral
 tubal ligation), OR postmenopausal (at least 1 year since last menses), OR using one
 of the following medically acceptable forms of birth control throughout the duration
 of the study:

 -  Systemic contraceptives

 -  Diaphragm with intravaginal spermicide

 -  Cervical cap

 -  Intrauterine device

 -  Condom with intravaginal spermicide

 -  Females in certain categories (not sexually active, vasectomized partner) will be
 admitted at the discretion of the investigator on a case-by-case basis. Accepted cases
 will be documented on the Female Enrollment Form and kept with the informed consent
 document.

 -  Females, excluding those more than 1 year postmenopausal or who are surgically
 sterile, must have a negative urine pregnancy test at Visit 1 and other visits
 specified in this protocol. If a subject becomes pregnant during the study
 participation, they will be discharged from the study and followed until termination
 of the pregnancy or delivery is complete.

 Exclusion Criteria:

 -  Respiratory tract infection within 14 days prior to Visit 1

 -  Chronic bronchitis, COPD, emphysema and other chronic lung diseases

 -  Receiving immunotherapy other than maintenance therapy

 -  Current smokers

 -  Current use of Xolair®

 -  Recent history of drug or alcohol abuse (within 3 years prior to Visit 1)

 -  Pregnant or likely to become pregnant during the study

 -  Breast-feeding

 -  History of hypersensitivity to albuterol, or Xolair, or to drugs with similar chemical
 structures

 -  Treatment with any investigational drug in the last 30 days before enrollment into the
 study (Visit 1)

 -  Clinically relevant cardiovascular, hepatic, neurologic, psychiatric, endocrine, or
 other major systemic disease making the protocol or interpretation of the study
 results difficult

 -  Site staff members or their immediate families are not eligible to enroll