PULMONARY–ALLERGY DRUGS ADVISORY COMMITTEE MEETING

15 MAY 2003

 

 

 

XOLAIRä (Omalizumab)

TABLE OF CONTENTS

 

Page

1...... executive summary........................................................................................    10

1.1...... Proposed Indication....................................................................................    10

1.2...... Efficacy.........................................................................................................    10

1.3...... Safety............................................................................................................    12

1.4...... Conclusions..................................................................................................    12

2...... Overview of Allergic disease................................................................    15

2.1...... IgE Biology and Allergic Disease..............................................................    15

2.2...... Rationale for Anti‑IgE..................................................................................    16

2.2.1..... Serum IgE Production and Distribution in Healthy Subjects....    17

2.2.2..... Association of Elevated Serum IgE and Asthma......................    17

2.3...... Allergic Asthma............................................................................................    18

2.4...... Changes in Inflammatory Cells and Mediators following Treatment with Omalizumab    ....................................................................................................................... 19

3.            Pharmacology………………………………………………………..............    22

3.1...... Description and Characterization of Omalizumab...................................    22

3.2...... In Vitro Activity..............................................................................................    23

3.3...... In Vivo Activity..............................................................................................    24

3.3.1..... Nonclinical In Vivo Activity............................................................    24

3.3.2..... Clinical In Vivo Activity..................................................................    24

3.4...... Omalizumab Pharmacokinetics and IgE Pharmacodynamics...............    26

3.4.1..... Pharmacokinetics.........................................................................    26

3.4.2..... IgE Pharmacodynamics...............................................................    27

3.4.3..... Determination of Therapeutic Target for Free IgE Suppression             28

3.4.4..... Dosing Regimens.........................................................................    30

3.5...... Phase III Pharmacokinetic/Pharmacodynamic Results...........................    32

4...... SUMMARY OF Clinical trials........................................................................    33

5...... Clinical efficacy.............................................................................................    37

5.1...... Pivotal Studies.............................................................................................    37

5.1.1..... Design and Patient Population...................................................    38

5.1.2..... Efficacy..........................................................................................    43

5.1.3..... Robustness of Primary Endpoint Results...................................    52

TABLE OF CONTENTS (cont’d)

 

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5...... Clinical efficacy (cont’d)

5.2...... Supportive Studies Providing Additional Efficacy Data..........................    55

5.2.1..... Study Q0694g...............................................................................    56

5.2.2..... Study 010.......................................................................................    59

5.2.3..... Study 011.......................................................................................    61

5.2.4..... Study IA04.....................................................................................    63

5.2.5..... Study Q2143g (ALTO).................................................................    66

5.3...... Analysis of Asthma Related Clinical Outcomes Among All Controlled Studies               69

5.4...... Analysis of Asthma Exacerbations among Patients Using Concomitant Asthma Medications ....................................................................................................................... 71

5.5...... Baseline Asthma Severity in Placebo‑Controlled Trials..........................    72

5.6...... Clinical Efficacy Summary and Conclusions............................................    73

6...... Clinical safety.................................................................................................    76

6.1...... Introduction and Overview...........................................................................    76

6.2...... Phase IIb/III Studies......................................................................................    78

6.2.1..... Demographics and Baseline Characteristics...........................    78

6.2.2..... Patient Disposition (Phase IIb/III Studies)..................................    83

6.2.3..... Drug Exposure (Phase IIb/III Studies).........................................    83

6.2.4..... Adverse Events (Phase IIb/III Studies)........................................    83

6.2.5..... Suspected Drug-Related Adverse Events.................................    94

6.2.6..... Deaths and Other Serious Adverse Events...............................    96

6.2.7..... Summary of Adverse Events.......................................................    99

6.2.8..... Laboratory Safety Tests (Phase IIb/III Studies).......................... 100

6.3...... Summary of Phase I/II Studies.................................................................... 107

6.4...... Uncontrolled Studies................................................................................... 108

6.4.1..... Study Q2195g............................................................................... 108

6.4.2..... Study 010 (Pediatric Allergic Asthma)....................................... 109

6.5...... Ongoing Studies.......................................................................................... 109

6.5.1..... Serious Adverse Events (Ongoing Studies).............................. 109

6.5.2..... Deaths (Ongoing Studies)........................................................... 110

TABLE OF CONTENTS (cont’d)

 

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6...... Clinical safety (cont’d)................................................................................... 110

6.6...... Special Topics (Phase I/II/III Studies)......................................................... 110

6.6.1..... Neoplasms.................................................................................... 110

6.6.2..... Injection‑Site Reactions (Phase IIb/III Placebo-Controlled Studies)                    115

6.6.3..... Anti-Omalizumab Antibodies....................................................... 115

6.6.4..... Safety of Re-Treatment (Study 006 Ext)..................................... 115

6.6.5..... Pregnancy...................................................................................... 116

6.7...... Drug–Drug, Drug–Demographic, and Drug–Disease Interactions (Phase IIb/III Studies)           ....................................................................................................................... 116

6.7.1..... Summary of Adverse Events in Population Subgroups............ 116

6.7.2..... Safety of Omalizumab in Patients 12–17 Years Old................. 118

6.8...... Long-Term Adverse Events (Phase IIb/III Studies)................................... 119

6.9...... Drug-Abuse, Overdose, and Withdrawal Effects..................................... 119

6.10... Clinical Safety:  Summary and Conclusions............................................. 120

7...... Benefits and risks.......................................................................................... 122

7.1...... Background.................................................................................................. 122

7.2...... Benefits of Omalizumab in Allergic Asthma.............................................. 123

7.3...... Safety of Omalizumab in Allergic Asthma................................................. 124

7.3.1..... Specific Safety Issues.................................................................. 124

7.4...... Assessment of Risk and Benefit of Omalizumab for Allergic Asthma... 125

7.5...... Benefit/Risk Conclusions............................................................................ 126

reference List.......................................................................................................... 127

 

TABLES AND FIGURES

Table 1:......... List of Abbreviations........................................................................      14

Table 2:......... Omalizumab Effects on Cells and Cellular Effectors of Inflammation     20

Table 3:......... Detailed Specifications of Omalizumab........................................      22

Table 4:......... Serum Free IgE and Clinical Responses in Phase I and II Studies        29

TABLE OF CONTENTS (cont’d)

 

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TABLES AND FIGURES (cont’d)

Table 5:......... Omalizumab (mg) Administered by SC Injection Every 4 Weeks for Adults and Adolescents (³12 Years Old) with Allergic Asthma.....................      31

Table 6:......... Omalizumab (mg) Administered by SC Injection Every 2 Weeks for Adults and Adolescents (³12 Years Old) with Allergic Asthma.....................      32

Table 7:......... Phase I/II Completed Studies.........................................................      34

Table 8:......... Phase IIb/III Completed Studies.....................................................      35

Table 9:......... Phase III Ongoing Studies (18 July 2002).....................................      37

Table 10:....... Demographic and Baseline Characteristics in Placebo‑Controlled Pivotal Studies (All Randomized Patients)..................................................................... 42

Table 11:....... Patient Disposition in Placebo‑Controlled Pivotal Studies (All Randomized Patients)...........................................................................................................      43

Table 12:....... Asthma Exacerbations per Patient during the Double‑Blind Stabilization Phase in the Pivotal Studies (All Randomized Patients)...................................      44

Table 13:....... Asthma Exacerbations per Patient during the Double‑Blind Steroid‑Reduction Phase in the Pivotal Studies (All Randomized Patients).........................      45

Table 14:....... Beclomethasone Dipropionate Dose Reduction in Pivotal Studies (All Randomized Patients)............................................................................................      48

Table 15:....... Selected Secondary and Exploratory Variables at the End of the Stabilization Phase (Week 16) in Pivotal Adult Studies (All Randomized Patients)..      49

Table 16:....... Between‑Treatment Comparisons of the Change from Baseline (LS Mean) in the AQLQ Scores in Adequate and Well‑Controlled Pivotal Adult Studies (All Randomized Patients)............................................................................................      50

Table 17:....... Patients (%) with Clinically Important Changes from Baseline (³0.5) in the AQLQ Scores in Allergic Asthma Studies 008 and 009 (All Randomized Patients)    ........................................................................................................... 51

TABLE OF CONTENTS (cont’d)

 

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TABLES AND FIGURES (cont’d)

Table 18:....... Robustness of Primary Efficacy Results in Stable Steroid Phase of Studies 008 and 009 (All Randomized Patients)......................................................      54

Table 19:....... Robustness of Primary Efficacy Results in Steroid Reduction Phase of Studies 008 and 009 (All Randomized Patients)...............................................      55

Table 20:....... Efficacy and QOL Results (Supportive Study Q0694g)...............      58

Table 21:....... Efficacy Results (Supportive Study 010).......................................      60

Table 22:....... Efficacy Results (Supportive Study IA04)......................................      65

Table 23:....... Rate of Protocol‑Defined Asthma Exacerbations Using Methods 1 and 2:  Safety Population.........................................................................................      68

Table 24:....... Asthma‑Related Outpatient Medical Visits ER Visit, and Hospitalization Results for Studies 008C/Ext, 009C/Ext, 010C/Ext, 011C, IA04, and Q2143g Pooled      ........................................................................................................... 70

Table 25:....... Asthma Exacerbation Risk and Rates by Baseline Asthma Medications in Studies IA04 and Q2143g (ALTO)...............................................................      72

Table 26:....... Patients Enrolled in Phase I–III Completed Studies by Indication (As of 18 July 2002)...........................................................................................................      77

Table 27:....... Patient Demographics and Baseline Characteristics in Phase IIb/III AA Adolescent/Adult Controlled Studies (All Safety Analyzable Patients)               79

Table 28:....... Asthma‑Related Medical History and Baseline Disease Characteristics in Phase IIb/III AA Adolescent/Adult Controlled Studies (All Randomized Patients)     80

Table 29:....... Patient Demographics and Baseline Characteristics in All Phase IIb/III Controlled Studies (All Safety
Analyzable Patients)........................................................................      81

Table 30:....... Concomitant Medication Use in Phase IIb/III AA Adolescent/Adult Controlled Studies
(All Randomized Patients)..............................................................      82

TABLE OF CONTENTS (cont’d)

 

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TABLES AND FIGURES (cont’d)

Table 31:....... Adverse Events in the Most Frequently Affected Body Systems (≥5% in Any Group) in Phase IIb/III Allergic Asthma Adolescent/Adult Controlled Studies (All Safety Analyzable Patients)........................................................................      84

Table 32:....... Most Common Adverse Events (³3% in Any Group) in Phase IIb/III Allergic Asthma Adolescent/Adult Controlled Studies
(All Safety Analyzable Patients).....................................................      85

Table 33:....... Adverse Events in the Most Frequently Affected Body Systems (³5% in Any Group) in All Phase IIb/III Controlled Studies
(All Safety Analyzable Patients).....................................................      87

Table 34:....... Most Common Adverse Events (³3% in Any Group) in All Phase IIb/III Controlled Studies (All Safety Analyzable Patients)....................................... 89    

Table 35:....... Overall Frequency and Severity of Skin Rash in All Phase IIb/III Controlled Studies (All Safety Analyzable Patients)............................................................      90

Table 36:....... Urticarial Reactions by Severity Grade in All Phase IIb/III Controlled Studies (All Safety Analyzable Patients)........................................................................      91

Table 37:....... Bleeding-Related Adverse Events Reported in ≥2 Patients in Any Treatment Group in Phase IIb/III Allergic Asthma Adolescent/Adult Controlled Studies (All Safety Analyzable Patients)........................................................................      93

Table 38:....... Bleeding-Related Adverse Events Reported in ≥2 Patients in Any Treatment Group in All Phase IIb/III Controlled Studies (All Safety Analyzable Patients)        94

Table 39:....... Most Common (≥1% in Any Group) Adverse Events Suspected to Be Related to Study Drug in Phase IIb/III Allergic Asthma Adolescent/Adult Controlled Studies (All Safety Analyzable Patients)........................................................................      95

Table 40:....... Frequency of Serious Adverse Events Other Than Asthma-Related Events in All Phase IIb/III Controlled Studies
(All Safety Analyzable Patients).....................................................      97

TABLE OF CONTENTS (cont’d)

 

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TABLES AND FIGURES (cont’d)

Table 41:....... Serious Adverse Events Reported by at Least 4 Patients in the AA Controlled Studies...........................................................................................................      98

Table 42:....... Serious Adverse Events Reported by at Least 4 Patients in All Controlled Studies    ........................................................................................................... 98

Table 43:....... Shift Analyses for Platelet Counts in Phase IIb/III AA Adolescent/Adult Controlled Studies (All Safety
Analyzable Patients)........................................................................   101

Table 44:....... Shift Analyses for Platelet Counts in All Phase IIb/III Controlled Studies (All Safety Analyzable Patients)........................................................................   102

Table 45:....... Shift Analysis for Platelets in All Phase IIb/III Controlled Studies Patients Aged 12–17 Years.................................................................................................   104

Table 46:....... Shift Analysis for Platelets in All Phase IIb/III Controlled Studies Patients Aged 6–11 Years.................................................................................................   105

Table 47:....... Patients (%) with Serious Adverse Events by IMN Body System (Ongoing Studies)   ........................................................................................................... 110

Table 48:....... Summary of Malignant Neoplasms in All Phase I–III Completed Studies (All Safety Analyzable Patients)........................................................................   112

Table 49:....... Various Malignancy Rates in All Completed, Placebo‑Controlled Studies (Phase I–III)...........................................................................................................   113

Table 50:....... Various Malignancy Rates in All Completed Studies..................   114

Table 51:....... Pregnancies.....................................................................................   116

 

Figure 1:........ Omalizumab Mechanism of Action................................................        7

Figure 2:........ Serum Omalizumab, Free and Total IgE Concentration–Time Profiles in AA Patients Study 008..........................................................................................      25

Figure 3:........ Free IgE Reductions in Patients with AA (Phase III) Using AA Dosing Table (Studies 008, 009, 010, 011).........................................................................      33

Figure 4:........ Study Design of Pivotal Studies 008 and 009..............................      39

TABLE OF CONTENTS (cont’d)

 

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TABLES AND FIGURES (cont’d)

Figure 5:........ Time to First Asthma Exacerbation Pivotal Study 008................      46

Figure 6:........ Time to First Asthma Exacerbation Pivotal Study 009................      47

 

 

APPENDICES

Appendix A:..... Proposed Package Insert............................................................   131

Appendix B:..... Animal and Other Nonclinical Data.............................................   152

 

1.         executive summary

The purpose of this background package is to provide information on Xolairä (omalizumab) and its proposed use in the management of allergic asthma (AA) to the Pulmonary–Allergy Drugs Advisory Committee members and consultants. 

Omalizumab represents a novel approach to the treatment of AA whereby immunoglobulin E (IgE) binding to the FceRI is blocked in atopic asthmatic patients using a humanized monoclonal antibody.  The clinical development of omalizumab was performed jointly by Novartis Pharma AG (East Hanover, NJ) and Genentech, Inc. (South San Francisco, CA) and represents over 10 years of clinical development.

The original Biologic License Application (BLA) included 17 completed trials and was submitted in June 2000.  A BLA amendment was submitted in December 2002 and included data from an additional nine completed clinical trials as well as a newly integrated summary of safety.

 

1.1       Proposed indication

The proposed indication for omalizumab is as maintenance therapy for the prophylaxis of asthma exacerbations and control of symptoms in adults and adolescents (³12 years old) with moderate to severe allergic asthma that is inadequately controlled despite the use of inhaled corticosteroids (ICSs).

 

1.2       Efficacy

Primary support for the use of omalizumab in AA is based on the results of pivotal Studies 008 and 009.  These studies were of identical design:  two Phase III, 7‑month, randomized, double‑blind, parallel‑group, placebo‑controlled, multicenter trials, each with a 5‑month blinded extension period, that assessed the efficacy, safety, tolerability, steroid reduction, pharmacokinetics, and pharmacodynamics of subcutaneous (SC) omalizumab.  The patients studied were symptomatic adolescents and adults (12–75 years old) with moderate to severe AA requiring daily treatment with ICSs and short‑acting b‑agonists.  Study 008 was conducted in the United States (U.S.), and Study 009 was an international study (40% of patients were in the U.S.).

The prospectively defined, primary intent‑to‑treat (ITT) analyses of both of these trials in a total of 1071 patients demonstrated that omalizumab significantly reduced the frequency of protocol‑defined asthma exacerbations requiring initiation of intravenous (IV) or oral CSs or a doubling of beclomethasone dipropionate (BDP) from baseline, per patient, compared with placebo.  Relative reductions of 48%–58% during the stable steroid phase and 41%–52% during the steroid reduction phase were observed in the mean number of asthma exacerbations per patient in the studies comparing omalizumab with placebo.  The patients randomized to these trials had ongoing asthma symptoms at baseline despite moderate to high doses of inhaled BDP (420–1680 mg) and use of inhaled albuterol (3–4 puffs per day).  The reduction in asthma exacerbations was seen in the context of less rescue medication use during the stable steroid phase. 

In the second phase of the pivotal studies (Weeks 16–28), a protocol‑mandated steroid reduction showed that a significantly greater median reduction of BDP occurred in the omalizumab group compared with the placebo group.  At the same time, patients in the omalizumab group had fewer asthma exacerbations than those in the placebo group despite having received lower doses of inhaled steroids and lower doses of rescue medication (albuterol).  In addition, a significantly higher proportion of omalizumab‑treated patients completely discontinued BDP compared with placebo‑treated patients.  Patients treated with omalizumab showed significant reductions in asthma symptoms and rescue medication use and an improved quality of life (QOL) compared with patients treated with placebo.  During the extension periods of both pivotal studies, omalizumab‑treated patients had fewer asthma exacerbations despite their sustained decreased use of ICSs.  Subsequent studies have also demonstrated reductions in asthma exacerbations in omalizumab-treated patients, compared with control, receiving other concomitant asthma medications such as long‑acting b‑agonists (LABAs) and leukotriene receptor antagonists (LTRAs).

 

1.3       Safety

The omalizumab safety database includes 6252 patients, of which 4265 have been treated with omalizumab.  Overall, the frequency of adverse events was similar in the omalizumab and placebo/control groups.  No pattern could be found in the adverse event data that suggested medically significant toxicity to a major organ system.  Serum sickness was not observed, and there was no evidence of immune-complex disease in omalizumab‑treated patients.  Urticaria occurred with similar frequency in the omalizumab‑treated and control patients.  Serious adverse events were uncommon and occurred in equal frequencies in the omalizumab and placebo groups.  Anaphylaxis, anaphylactoid reactions, and other hypersensitivity adverse events occurred at similar frequencies in the omalizumab and placebo/control groups.

As part of the ongoing, nonclinical safety studies, thrombocytopenia occurred in cynomolgus monkeys at drug serum concentrations roughly 3‑ to 19‑fold higher than anticipated serum concentrations in clinical patients receiving the highest dose of omalizumab.  A careful review of the clinical laboratory and safety database showed no evidence of drug-induced effects of omalizumab on platelet levels or bleeding adverse events in humans. 

A small number of malignant neoplasms were observed in the clinical program, with a slightly higher incidence in omalizumab‑treated patients than control patients (5.9 vs. 3.6 events per 1000 patient‑years).  These malignancies did not have unusual clinical presentations, represented a broad range of organ systems and histologies, and the majority had an onset within 6 months of initiation of study drug, suggesting that they were unrelated to omalizumab treatment. 

 

1.4       ConclusionS

Twenty‑six clinical trials in 6252 patients (4265 treated with omalizumab) collectively demonstrated that omalizumab is safe and effective.  Omalizumab is beneficial to patients with moderate to severe asthma who are still symptomatic despite use of existing anti‑inflammatory or ICS treatment.  The benefits of reduced asthma exacerbations, improved asthma control, steroid reduction, and the potential for preventing severe asthma‑related sequelae significantly outweigh the potential risks associated with this product. 

The abbreviations used in this document are defined in Table 1.

 

 

 

 

 

2.         overview of Allergic disease

2.1       IgE biology and allergic disease

The causal role of immunoglobulin E in allergic disease is well established (Ishizaka and Ishizaka 1967; Johansson and Bennich 1967).  The allergic cascade is initiated when IgE, bound to high‑affinity FcRI receptors on the surface of basophils and mast cells, is cross‑linked by an allergen that results in the degranulation of these effector cells and the release of inflammatory mediators, such as histamine and leukotrienes (see Figure 1).  Existing strategies to treat allergic diseases have limitations and consist of attempts either to desensitize the atopic individual to a given allergen or ameliorate an ongoing allergic reaction.  Treatments that selectively inhibit IgE activity are a logical approach to managing the allergic response.  One such strategy uses omalizumab, a recombinant humanized IgG₁ monoclonal anti‑IgE antibody that binds to IgE at the same epitope as FcRI and is thus non‑anaphylactogenic (Heusser and Jardieu 1997).

 

Figure 1

Omalizumab Mechanism of Action

 

 

2.2       rationale for anti‑ige

Because of the prominent role of mast cell IgE antibodies in the release of pro‑inflammatory mediators, several strategies have been conceived and tested to eliminate the IgE‑derived signal to mast cells.  The basic rationale is to reduce IgE and to minimize the allergic response.  The approach taken here is to develop a monoclonal antibody directed at the FCeRI (high‑affinity) receptor‑binding site on human IgE.  This receptor is situated on the CH3 domain of the molecule.  Humanization of a murine antibody was effected by inserting the mouse complementarity‑determining region on to the consensus sequence of human IgG₁ using site‑directed mutagenesis.  The advantages of this approach were that this antibody could inhibit the binding of IgE to the mast cell and reduce the potential for antigen‑specific degranulation.  In addition, the design of this molecule makes it impossible for the anti‑IgE to bind to IgE that is already bound to the high-affinity receptor.  This important design makes the molecule non‑anaphylactogenic and is thus very different from previously developed antibodies targeting anti-IgE.

 

2.2.1   Serum IgE Production and Distribution in Healthy Subjects

IgE‑producing plasma cells are located primarily in lymphoid tissue adjacent to the respiratory tract, with the highest concentration of these plasma cells in tonsil and adenoid tissue.  IgE produced by these cells may appear in local mucosal exocrine secretions or may enter the systemic circulation, eventually becoming distributed on mast cells and basophils throughout the body.  Serum IgE concentrations increase slowly after birth and reach adult levels at approximately 6 years old (Kjellman et al. 1976).

Data on the distribution of IgE levels in the healthy, non‑allergic population are limited.  IgE levels of non‑asthmatics in the Tucson Epidemiological Study of White Non-Mexican‑Americans ranged from a geometric mean of 43 IU/mL in patients 6–34 years old to 26 IU/mL in patients 35–54 years old to 18 IU/mL in patients ³55 years old (Burrows et al. 1989).  When all ages were combined, the geometric mean IgE level of the population was 32.1 IU/mL.  These levels were consistent with results from a sample of Caucasian patients from the southern United States that reported an overall geometric mean IgE level of 32 IU/mL in healthy controls, including children and adults (Witting et al. 1980).  In studies of non‑allergic adults only, the geometric mean levels of IgE were somewhat lower than those reported in the Tucson and southern states studies, which included both allergic and non‑allergic healthy adults. 

Serum IgE levels were related to age (Burows et al. 1989).  Peak IgE levels occurred during childhood, usually between 8 and12 years old and decreased thereafter.

 

2.2.2   Association of Elevated Serum IgE and Asthma

Higher serum IgE levels in asthmatic adults and children compared with non‑asthmatic adults and children have been demonstrated in studies from San Diego (Criqui et al. 1990), Charlottesville, Virginia (Pollart et al. 1989), Paris, France (Annesi et al. 1992), Tucson, Arizona (Burrows et al. 1989), and the southern United States (Wittig et al. 1980).  Although asthma patients had higher IgE levels than healthy control patients on average, there was considerable overlap in the distribution of IgE in these populations (Wittig et al. 1980).  Mean IgE levels were higher in all age strata in patients with asthma compared with those without asthma (Burrows et al. 1989).  In the data from the Tucson Epidemiological Study, asthma was almost always associated with a higher IgE level.  In this study, the geometric mean IgE level for asthmatics was 224 IU/mL for those 6–34 years old, 117 IU/mL for those 35–54 years old, and 56 IU/mL for those ³55 years old (Burrows et al. 1989).  The prevalence of asthma increased gradually as the age specific Z scores of IgE level increased regardless of smoking or atopic status (Burrows et al. 1982; Burrows et al. 1989; Burrows et al. 1991).  Similarly, the prevalence of asthma rose as the age‑ and sex‑standardized serum IgE level rose (Burrows et al. 1991).

 

2.3       Allergic Asthma

Asthma is a common disease for which there is no known cure, no effective means of prevention, and most cases are secondary to allergies.  Allergic asthma is defined as asthma with co‑existing evidence of allergy.  A good medical history is usually sufficient to make this diagnosis with confidence.  For the majority of patients with mild and moderate disease, available therapies result in acceptable control of symptoms.  These therapies are less effective for patients with more severe disease who are likely to continue to suffer from persistent symptoms of asthma and intermittent exacerbations.  Although the proportion of patients who fall into this category is small, the absolute number of poorly controlled individuals represents a significant unmet medical need because the asthma population is large (Tattersfield 1997).

In 1995, the prevalence of self-reported asthma in the United States was 56.8 per 1000 persons, an increase of 75% from the figures reported in the early 1980s.  This translates into an estimated 14.9 million patients with a diagnosis of asthma in the preceding 12 months, causing over 1.5 million emergency room (ER) visits, approximately 500,000 hospitalizations, and more than 5500 deaths (Mannino et al. 1998; Mannino et al. 2002).  Although significant, hospitalizations are relatively infrequent.  The most common complaint in patients who are poorly controlled despite appropriate treatment is recurrent exacerbations.  These exacerbations may be mild, requiring only the use of intermittent short‑acting b-agonists.  The exacerbations studied in the omalizumab clinical program were more severe, resulting in frequent wakening at night and treatment with systemic or increased doses of ICSs.  If untreated, episodes of this type could result in unscheduled visits to the physician or ER.

 

2.4       Changes in inflammatory cells and mediators following treatment with omalizumab

Asthma is a chronic, inflammatory disease of the airways in which many cells, cellular by‑products, and IgE play a role.  Bronchial biopsy specimens, sputum, and fluid obtained by bronchoalveolar lavage have shown that significant inflammation is present in early asthma and is also present in patients with only a short duration of symptoms and mild disease  (Beasley et al. 1993; Laitinen et al. 1993; Sont et al. 1996).  Chronic inflammation is thought to lead to an increase in airway smooth muscle (hyperplasia and hypertrophy), increased bronchial glands, edema formation, development of irreversible changes in lung function, and increased bronchial responsiveness to a variety of stimuli (Fahy 2000).

Current therapies for the treatment of allergic disease largely seek to control the inflammatory response by avoidance of allergens triggering Type I immediate hypersensitivity reactions and through the use of mast cell stabilizers (chromones), antihistamines, LTRAs, and CSs.  The identification of IgE by Johansson and Bennick (1967) and Ishizaka and Ishizaka (1970) and the description of its capacity to bind with high affinity to FceRI receptors on mast cells and basophils (Ishizaka and Ishizaka 1970; Presta et al. 1993) opened up the possibility of targeting this interaction for therapy of allergic diseases.  By targeting IgE, the central humoral mediator of Type I immunopathology, omalizumab has demonstrated broad anti‑inflammatory activities in atopic disease (see Table 2).

 

 

As expected, initial bronchial challenge studies in patients with mild asthma (Studies Q0630g and Q0634g) showed that omalizumab reduced the early bronchoconstrictor response to allergens, widely recognized to be prompted by the activation of mast cells (Oettgen and Geha 1999).  Omalizumab also reduced the late response to allergens, an acute inflammatory response thought to be orchestrated by T cells and associated with the infiltration of eosinophils (Zweiman 1993).  In an accompanying editorial, Demoly and Bousquet (1997) concluded that because the asthmatic, late‑phase reaction is known to be associated with a bronchial inflammatory response, omalizumab treatment acts on the inflammation of the airways. 

Treatment with omalizumab reduced the number of eosinophils in sputum relative to pretreatment baseline values (Study 012) and decreased airway hyperresponsiveness (Studies Q0634g and 012), indicating that treatment with omalizumab has a long‑term, anti‑inflammatory effect (Barnes 1999).  In Study 012, treatment with omalizumab reduced the number of eosinophils in sputum relative to pretreatment and reduced the number of eosinophils in submucosal compartments on endobronchial biopsy.  There was also a trend in reducing the number of eosinophils/mm₂ in endobronchial biopsies in submucosal compartments.  In exploratory analyses of induced sputum, bronchial biopsies, and bronchoalveolar lavage, omalizumab produced effects on cytokines, chemokines, inflammatory mediators, and mast cells, suggesting that it positively influences a range of anti-inflammatory processes compared with placebo.

Additionally, omalizumab treatment was found to decrease the percentage of eosinophils and the concentrations of eosinophil cationic protein (a marker of degranulation) in induced sputum samples collected on the day after airway allergen challenges (Fahy et al. 1997).  Clinical trials of omalizumab in mild (Studies Q0630g and Q0634g) and moderate to severe asthmatics (Study Q0694g) have shown significant reductions in circulating blood eosinophils.  Eosinophilia of airway lumen fluids and whole blood is a cardinal feature of the asthmatic inflammatory state. 

In addition to the previously cited effects on eosinophils, omalizumab appears to affect another inflammatory cell.  In a study of severe asthmatics who were poorly responsive to CSs, treatment with high‑dose omalizumab (0.014 mg/kg/IU/mL every 2 weeks) resulted in a decrease in sputum neutrophil cell count (-9% vs. +4.4% in omalizumab vs. placebo, respectively) that was confirmed by a commensurate fall in neutrophil myeloperoxidase (Busse et al. 1998).  It is increasingly recognized that the neutrophil is a prominent inflammatory cell that plays an important pathogenic role in patients with chronic severe asthma  (Fahy et al. 1995).

Nonspecific bronchial hyperresponsiveness to a wide variety of nonspecific stimuli (exercise, cold air, hypertonic saline, methacholine) is a consequence of airway inflammation.  Boulet et al. (1997) reported that following omalizumab treatment of mild asthmatics, methacholine PC₂₀ improved significantly.  Fahy et al. (1997) confirmed and extended this observation by describing a significant improvement following the inflammatory stimulus of aeroallergen challenge.

These observations strongly suggest that omalizumab affects mast cells and basophils, as well as eosinophils.  An important finding has been the discovery that treatment with omalizumab causes down‑regulation of FceRI expression on human basophils (Genentech Study Q0673g) and presumably mast cells, from a median of ~220,000 to 8300 receptors per cell (MacGlashan et al. 1997a).  Furthermore, the responsiveness of the cells to stimulation with dust mites (D. Farinae) was reduced by ~90% with omalizumab treatment (Study Q0673g).  Human basophil release of pro‑inflammatory histamine was reduced 90% after 3 months of omalizumab treatment (MacGlashan et al. 1997a).  The inflammatory wheal and flare skin responses also significantly decreased with omalizumab treatment.

 

3.         pharmacology

3.1       Description and characterization of omalizumab

Omalizumab is a recombinant, humanized construct of murine antibody MaE11 directed against human IgE (Presta et al. 1993).  The murine antibody was humanized using an established methodology developed by Genentech.  The critical amino acids responsible for the binding of the murine monoclonals to IgE were engrafted onto a human IgG₁ subclass framework to yield a humanized antibody with the properties of the selected murine monoclonal (see Table 3 for detailed specifications of omalizumab).

 

 

Nonclinical pharmacology studies were conducted prior to entry into the clinic and provided confidence that omalizumab was unlikely to precipitate anaphylaxis by cross‑linking IgE on effector cells.  Given that omalizumab was designed to form complexes with circulating or non‑receptor bound IgE, omalizumab:IgE complexes were characterized biochemically in vitro and ex vivo.  The potential for interaction of omalizumab and omalizumab:IgE with complement was evaluated.  Additional studies conducted with omalizumab have increased understanding of the mechanism of action of this humanized monoclonal anti‑IgE antibody in the treatment of allergic diseases.

 

3.2       In vitro Activity

Omalizumab was characterized as a non‑anaphylactogenic antibody because:

·        Epitope mapping studies demonstrated that omalizumab and MaE11 bind to the same site on IgE as FceRI.

·        Omalizumab did not recognize IgE on FceRI‑bearing cells.

·        Omalizumab did not induce spontaneous histamine release from IgE‑loaded human basophils.

Characterization of omalizumab:IgE complexes demonstrated the following:

·        Omalizumab formed complexes with IgE that were predominantly heterotrimers.  Hexamers were the largest size form observed with a maximum molecular weight of 1 million.  The size and composition of the complexes were dependent on the molar ratio of the two molecules.

·        Complexes formed in vivo were similar to those studied in vitro.

·        Neither omalizumab or omalizumab:IgE complexes bound C1q or generated C3a.  Omalizumab did not mediate complement‑dependent cytotoxicity.

Characterization of omalizumab as an inhibitor of IgE:FceRI interaction demonstrated the following:

·        Omalizumab competitively inhibited IgE:FceRI interaction, consistent with the epitope mapping of omalizumab and FceRI to the same site on IgE.

·        Omalizumab was able to trap IgE as it dissociated from the FceRI in vitro and may therefore aid in off‑loading IgE from receptors in vivo.

·        Omalizumab inhibited histamine release from cells sensitized with ragweed‑specific IgE.

·        Omalizumab also blocked histamine release and contraction of human and cynomolgus monkey lung strips after passive sensitization with ragweed‑specific IgE.

Omalizumab reduced high‑affinity receptor expression in vitro and in vivo by decreasing free IgE  (MacGlashan et al. 1997b; MacGlashan et al. 1997a; Saini et al. 1999).  Treatment with omalizumab reduced FceRI on human basophils such that histamine release was reduced or eliminated in response to antigen challenge.

Omalizumab inhibited IgE synthesis in vitro; however, no significant effect on IgE synthesis was observed clinically (Study Q0673g; Corren et al. 1998).  There are no data to suggest that administration of omalizumab and the resultant decreased levels of free IgE caused a positive feedback signal to increase synthesis as IgE levels returned to baseline when omalizumab therapy was withdrawn.

 

3.3       In vivo Activity

3.3.1   Nonclinical In Vivo Activity

Omalizumab administration did not result in anaphylaxis in non‑human primates.

No evidence of immune complex disease has been observed in the nonclinical or clinical setting after administration of omalizumab.  Omalizumab demonstrated pharmacological activity in a non‑human primate model of hypersensitivity to ragweed.  Skin test reactivity was reduced in cynomolgus monkeys sensitized to ragweed after administration of omalizumab.  Studies in cynomolgus monkeys demonstrated that clearance of IgE was reduced because of its incorporation in omalizumab:IgE complexes, resulting in increased concentrations of serum total IgE postdose (Fox et al. 1997).

 

3.3.2   Clinical In Vivo Activity

a.   Response of Serum IgE to Anti‑IgE

Total IgE.  Total IgE concentrations increased after administration of omalizumab (see Figure 2).  This increase was consistent with reduced clearance of IgE because of its incorporation into omalizumab:IgE complexes (Fox et al. 1997).  The percentage increase in total IgE concentrations was very similar across sex, age, indication, and race subgroups.  The increases in total IgE usually reached a plateau or steady‑state level approximately
60–90 days after initiation of a multiple dose regimen.  Total IgE concentrations returned to baseline values after drug was eliminated.  No rebound increase in total IgE after drug washout was observed in the clinical studies.

 

Figure 2

Serum Omalizumab, Free and Total IgE Concentration–Time Profiles in AA Patients Study 008

Omalizumab was dosed at 150 to 300 mg SC every 4 weeks.

 

Free IgE.  Serum free IgE decreased in a dose‑ and baseline IgE–dependent manner across all of the studies.  The dose–response relationship was generally sigmoidal, with incremental decreases in free IgE requiring large increases in omalizumab concentrations.  Average maximal decreases during the pivotal Phase III trials were 84%–99%.  Free IgE concentrations also returned to baseline values after drug washout.  No rebound increase in free IgE after drug washout has been observed in any of the clinical studies.  Age, race, sex, and indication did not have an impact on the relationship between omalizumab concentration and suppression of serum free IgE.

 

3.4       Omalizumab pharmacokinetics and ige pharmacodynamics

3.4.1   Pharmacokinetics

Omalizumab pharmacokinetics in humans are summarized as follows:

·        Omalizumab is absorbed slowly, reaching maximum concentrations
3–10 days postdose.

·        Omalizumab elimination is also slow (SC terminal t_1/2 = 22 ± 8.7 days).  Slow clearance of omalizumab is consistent with proposed recycling of IgG₁ class immunoglobulins via the FcRn receptor system.

·        Estimates of mean bioavailability (F) range from 53% to 71%.  Bioavailability estimates were comparable for adults, adolescents, and children.

·        Drug exposure (AUC, C_max, C_ss, min) increased in proportion to dose at therapeutic dose levels.

·        Omalizumab pharmacokinetics were comparable upon retreatment for a second ragweed season ~1 year after initial dosing (seasonal allergic rhinitis [SAR] patients).

·        Differences in age, sex, race, and indication do not appear to result in clinically important changes in omalizumab pharmacokinetics.

a.   IgG, IgE, and Complex Pathways

The disposition of omalizumab is determined by its IgG₁, framework, and specific binding to IgE.  Omalizumab is recycled via the FcRn system and cleared from circulation via specific binding and complex formation with its target ligand, free serum IgE.  Serum omalizumab clearance is dependent upon omalizumab concentrations, serum free IgE concentrations, and their relative ratios.  The omalizumab:IgE complexes are believed to clear via interactions with Fcg receptors at rates that are generally faster than IgG clearance.  IgE is removed by binding to its high-affinity receptor, FceRI, and by non‑specific protein clearance.  IgE removal is usually rapid, with half‑lives of a few days.  Formation of complexes with omalizumab will shift IgE clearance from its rapid, high-affinity receptor pathway to the slower complex clearance, the Fcg receptor pathway.  This apparent reduction in IgE clearance results in elevation in serum total IgE levels after omalizumab treatment.  Relative clearance of free omalizumab, free IgE, and complexes is summarized as:

Free IgE clearance > > omalizumab:IgE clearance > omalizumab clearance

At dose levels used in the Phase III studies, omalizumab is in 10- to 30‑fold excess relative to IgE, and the proportion of omalizumab:IgE complexes is small relative to free drug.  Clearance of omalizumab at doses proposed for marketing will therefore be dominated by the slow, free IgG clearance process.  IgG clearance is relatively slow, with a terminal half‑life of 20–30 days.  Data for omalizumab at doses >0.5 mg/kg demonstrate similar terminal half‑lives (18–40 days).

 

3.4.2   IgE Pharmacodynamics

IgE pharmacodynamics in humans are summarized as follows:

·        Serum free IgE concentrations decline in a dose- and baseline IgE-dependent manner within 1 hour postdose.

·        Average decreases in serum free IgE in Phase III trials were 84%–99% of baseline.

·        Omalizumab forms complexes of limited size with IgE.  Nonclinical studies demonstrated clearance of omalizumab:IgE complexes via the Fcg‑receptor bearing cells in the liver and reticuloendothelial system at rates approximately 4–6 times faster than those observed for free omalizumab.

·        Studies in cynomolgus monkeys demonstrated that clearance of IgE was reduced because of its incorporation in omalizumab:IgE complexes, resulting in increased concentrations of serum total IgE postdose.  Serum total IgE was increased an average of 4‑fold postdose in clinical studies.  The fold‑increases in serum total IgE were inversely related to baseline IgE concentrations. 

·        Following discontinuation of omalizumab, increases in total IgE and decreases in free IgE were reversible, with no rebound in IgE levels after drug washout (approximately 9 months after the last dose).

·        Upon retreatment approximately 1 year after initial dosing, baseline IgE values and the extent of free IgE suppression were comparable to initial dosing.

Serum free IgE concentrations from the Phase III trials were assessed for possible variability because of demographic effects.  Comparisons were made for the 300 mg every 4 weeks dosing groups and produced consistent serum free IgE concentrations across age, sex, and race subgroups.

 

3.4.3   Determination of Therapeutic Target for Free IgE Suppression

a.   Clinical Endpoints, Serum Free IgE, and Minimum Effective Dose

The mechanism of action for omalizumab is via complexing serum free IgE.  Therefore, the major question for dosing strategy development was the extent of serum free IgE reduction necessary for clinical benefit and the omalizumab doses and regimen required to obtain the targeted free IgE reduction.

The initial target for serum free IgE reduction was based on in vitro studies quantifying the number of high‑affinity IgE receptors on effector cells (mast cells, basophils) and the minimum amount of IgE necessary to cross‑link receptors.  The number of cell surface IgE cross‑links required for histamine release is approximately 100–1000 (MacGlashan et al. 1997a).  Approximately 1 ng/mL of antigen‑specific free IgE is sufficient for receptor cross‑linking and histamine release.  If it is assumed that antigen‑specific IgE is £10% of total IgE, the target minimal level of total IgE to prevent receptor cross‑linking is approximately 10 ng/mL. 

Exploratory analyses of a variety of clinical response data from early Phase I and II studies suggested clinical benefit at serum free IgE concentrations of
<10–30 ng/mL; a majority of patients benefited from concentrations of <50 ng/mL (see Table 4).

 

 

Based on the in vitro data and the exploratory clinical endpoint response analyses, doses that would result in average free IgE concentrations of £25 ng/mL were recommended for the Phase III trials, with the majority of patients at free IgE levels of <50 ng/mL (see Figure 3).

The doses and dosing regimen necessary to achieve the targeted free IgE suppression were estimated based upon:  1) the ratio of drug to IgE necessary to maintain suppression; 2) the dose of drug necessary to maintain average serum concentrations at or above the minimum drug to IgE ratio; and 3) the dosing frequency necessary to ensure adequate serum concentrations with an acceptable number of visits and injections.  The ratio of serum omalizumab (nM) to serum IgE (nM) necessary to maintain suppression was estimated to be 16–21 to 1 using in vitro analyses of free IgE suppression in serum from atopic patients.  Observed serum free IgE suppression versus omalizumab to IgE ratio from Study 006 suggested that a drug excess of 15–20 to 1 was necessary for reduction of serum free IgE into the target clinical range.

Early Phase I and II studies used dosing adjusted only for body weight (mg/kg).  Dosing on a milligram per kilogram basis ensured that serum levels of omalizumab were comparable across all body weights but did not ensure that the serum IgE levels would be suppressed to a comparable extent in every patient, as treated atopic AA patients have a wide range of baseline serum IgE concentrations (approximately 20–1700 IU/mL, approximately
48–4100 ng/mL).  Results from the early studies suggested that dosing incorporating baseline serum IgE‑antigen load would produce more consistent IgE suppression and possibly result in more consistent clinical responses.  Adjustment of doses by baseline serum IgE would also ensure a consistent omalizumab to IgE ratio.  Doses included adjustment for body weight since the target population was to include both children and adults and the body weight range could extend from approximately 20–150 kg.  Body weight was used as a surrogate for serum volume, and adjustment for body weight was to ensure consistent serum omalizumab concentrations across the entire target population.

Evaluation of results from Study Q0694g plus retrospective calculations of individualized doses from other Phase II historical studies with omalizumab and related molecules suggested that the minimum effective dose administered as an SC bolus equivalent biweekly was approximately 0.008 mg/kg/[IU/mL] (baseline IgE) and 0.016 mg/kg/[IU/mL] every 4 weeks.

 

3.4.4   Dosing Regimens

Omalizumab dosing is based on the theoretical premise that lowering the amount of IgE available for binding to the effector cells of the allergic inflammatory cascade is a pre-requisite for efficacy.  In vitro studies demonstrated that reduction in serum free IgE to <10 ng/mL was required to prevent IgE receptor cross linking and degranulation.  It should be noted that there is wide variability in the number of occupied receptors necessary for degranulation.  This varies with the individual being tested and the antigen used in the system.  Some basophils degranulate with only 100 occupied receptors whereas others may need as many as 2500 receptors to be occupied.  Based on clinical response (Phases I and II), 25 ng/mL was the average serum free IgE level associated with clinical benefits.  Targeting a reduction of serum free IgE to an average level of 25 ng/mL ensures that ³95% of patients would achieve a level of below 50 ng/mL, which has consistently been shown to be of therapeutic benefit during the Phase III development.  The minimum dose of omalizumab required to maintain an average serum free IgE level below 25 ng/mL was 0.016 mg/kg every 4 weeks.  The omalizumab-dosing table, based on individual serum IgE level and body weight, ensures that each patient receives a dose of at least 0.016 mg/kg every 4 weeks (see Tables 5 and 6). There has been no evidence that reducing the serum free IgE to lower levels is associated with increased therapeutic benefit.

A simplified dose strategy was desired for large‑scale use.  The individualized dose scheme (mg/kg/[IU/mL]) was modified to group individuals into tiers in which each patient received at least the proposed minimum effective dose.  The dose assigned to each cell in the dosing table (see Tables 5 and 6) was determined by a combination of body weight (kg) and baseline IgE (IU/mL) and the minimum effective SC dose (0.008 mg/kg/IU/mL every 2 weeks or 0.016 mg/kg/IU/mL every 4 weeks) for that interval.

 

 

 

 

 

3.5       Phase III PHARMACOKINETIC/PHARMACODYNAMIC Results

Consistent free IgE suppression was achieved for all dose groups in the Phase III trials using the proposed dosing regimens as shown in Figure 3.  Combined data from Studies 008, 009, 010, and 011 demonstrated that >60% of patients achieved serum free IgE levels £25 ng/mL and >93% achieved serum free IgE levels of £50 ng/mL.  In addition, serum free IgE concentrations on treatment were consistent for high‑dose, high baseline IgE patients as well as low-dose, low baseline IgE patients.  For patients with AA, reduction of free IgE to £50 ng/mL was related to improved clinical outcomes.  There was little indication that suppressing free IgE concentrations lower than 12 ng/mL would result in substantially improved clinical effectiveness.

 

Figure 3

Free IgE Reductions in Patients with AA (Phase III) Using AA Dosing Table
(Studies 008, 009, 010, 011)

Error bars indicate 5th and 95th percentiles of serum free IgE
Numbers above error bars indicate number of patients per dose group.

 

The consistent free IgE suppression was also associated with clinical benefit across dose, age, and indication population subgroups, which are summarized in Section 5.

 

4.         Summary of Clinical Trials

Early evaluation of the safety, efficacy, and dose response of omalizumab was conducted in 10 Phase I/II clinical studies.  Subsequently, extensive data on the safety and efficacy of omalizumab in AA was obtained from the two pivotal Phase III studies (008 and 009).  These were conducted in adolescents and adults with moderate to severe AA requiring ICSs and as-needed rescue medications.  Five supportive studies (Q0694g, 010C, 011C, IA04, and Q2143g) in patients with AA provided additional efficacy and safety data.  Since the original Biologics License Application (BLA), the proposed indication has been focused on adults and adolescents with AA.  However, studies performed in patients with allergic rhinitis and atopic dermatitis are included in the safety database.  Tables 7–9 summarize the completed and ongoing clinical studies for Phases I, II, and III.  In addition, a single‑dose pharmacokinetic study (2203, not listed in tables) enrolled 87 patients and is included in the safety database.

 

 

 

 

 

 

 

 

 

5.         Clinical efficacy

5.1       PIVOTAL STUDIES

The primary objective of the clinical development program for AA was to document the efficacy and safety of omalizumab treatment in adolescents and adults (12–75 years old) with moderate to severe disease.  The study design for the pivotal trials was tailored to this objective.  The patient populations studied were those with moderate to severe AA who had ongoing symptoms and exacerbations despite levels of therapy that would be expected to control most patients.  It was not appropriate in this population to perform the standard design in which patients are “washed out” from all therapy and then randomized to study drug or control.  Rather, the effects of the addition of omalizumab to a daily regimen of ICSs and as-needed b‑₂ agonist were chosen, with asthma exacerbations requiring steroid bursts as the primary efficacy variable. 

In the two pivotal trials (008 and 009), treatment with omalizumab demonstrated a significant reduction in the number of exacerbations per patient, a reduction in the requirement for ICSs and rescue medication, and a reduction in asthma symptoms.  These key pivotal studies document the efficacy of omalizumab in the treatment of AA in adolescents and adults.

 

5.1.1   Design and Patient Population

a.   Study Design

Studies 008 and 009 were identical in design.  Study 008 was conducted in the United States, and Study 009 was conducted in Europe, Africa, Australia, and the United States.  These were Phase III, 7‑month, randomized, double‑blind, placebo‑controlled, parallel, multicenter studies with a 5‑month blinded extension conducted in adolescents and adults (12–75 years old).  Patients had moderate to severe AA that was not well controlled despite daily treatment with ICSs (BDP 420–1008 µg/day) and b‑agonist rescue medication.

 

Figure 4

Study Design of Pivotal Studies 008 and 009

BDP=beclomethasone dipropionate; b₂=rescue albuterol.

 

In both studies, there were the following five sequential periods (see Figure 4): 

1)     A 1‑week screening period

2)     A 4‑ to 6‑week BDP conversion period (including a 2-week baseline period)

3)     A 7‑month, double‑blind core study period

The 7‑month core portion of the study was designed to assess the efficacy as well as the safety of omalizumab compared with placebo.  It was divided into two periods: 

·        A 4‑month stabilization period during which patients received randomly assigned omalizumab or placebo treatment and a stable dose of BDP, and

·        A 3‑month steroid dose‑reduction period during which the patient continued the study treatment and the BDP dose was reduced by 25% of the baseline dose every 2 weeks until total elimination of inhaled steroids or development of uncontrolled asthma during the first 8 weeks, and then maintenance of the stable lowest‑tolerated BDP dose for 4 weeks. 

During these core double‑blind treatment periods, patients were not allowed to take any other asthma medication except for the fixed dose of BDP, rescue b‑2 agonists, and treatment for asthma exacerbations.

4)     A 5‑month extension period

The 5‑month extension was primarily designed to assess the long‑term safety of omalizumab; however, secondary assessments included the effects of omalizumab on asthma exacerbations, CS usage, and QOL.  Patients continued receiving the double‑blind treatment as in the 7‑month core study.  During the extension period, patients were allowed to be treated with other asthma medications (e.g., LABA, ICSs other than BDP) if necessary for asthma control at the investigator’s discretion. 

5)     A 12‑week follow‑up visit

This was a single visit that took place 12 weeks after the final visit for posttreatment clinical evaluation and a blood draw to evaluate serum total and free IgE and anti‑omalizumab antibody levels.

b.   Study Treatment

Based on the patient’s body weight and total serum IgE level at the screening visit, patients were treated with omalizumab 150–375 mg every 2 or 4 weeks (see Tables 5 and 6).

c.   Study Population

Studies 008 and 009 were conducted in patients 12–75 years old with moderate to severe AA who had FEV₁ £80% of predicted and were symptomatic (mean total asthma symptom score ³3 of 9 [maximum] during the 14 days prior to randomization) despite receiving maintenance BDP
(420–840 µg/day in Study 008; 420–1008 µg/day in Study 009) and as‑needed or regular b₂‑agonists (albuterol; maximum 8 puffs/day) therapy.

d.   Efficacy Outcome Measures

Measures for efficacy were assessed during the 7‑month, double‑blind core period of the pivotal studies.  The effect of omalizumab on the incidence of asthma exacerbations was chosen as a clinically relevant measure of efficacy.  Unlike measurements of pulmonary function, asthma exacerbations represent clinically significant events indicative of inadequate asthma control.  Secondary variables included the ability of omalizumab to reduce the dose of ICSs, as well as total asthma symptom score, rescue medication use, morning peak expiratory flow rate (PEFR), forced expiratory volume in 1 second (FEV₁), and QOL.

Throughout the double‑blind treatment period, patients were closely monitored for signs of worsening asthma and instructed to contact the investigator if one or more of the following criteria of worsening asthma developed:

·        Worsening of asthma at any time requiring an urgent (unscheduled) visit for medical care

·        PEFR <50% of patient’s personal best

·        Decrease in morning PEFR of ³20% on ³2 of 3 successive days compared with the last week prior to randomization (the lowest morning PEFR in the week prior to Visit 3 provided the baseline value for this determination)

·        >50% increase in 24‑hour rescue medication use on ³2 of 3 successive days compared with the last week prior to randomization (had to exceed 8 puffs)

·        ³2 of 3 successive nights with awakenings because of asthma symptoms that required rescue medication

Patients who developed any of the above criteria and/or who experienced a decrease in FEV₁ of ³20% compared with Visit 3 (baseline; when measured and obtained in similar relationship to time of the day and b‑agonist use) were evaluated by the investigator.  Investigators used National Heart, Lung, and Blood Institute (NHLBI 1997) Guidelines for the Diagnosis and Management of Asthma to manage patients who experienced asthma exacerbations.

The investigator’s clinical judgment for additional treatment over and above the maintenance BDP dose and as‑needed b‑2 agonist rescue medication was defined as an investigator’s assessment of asthma exacerbations.  To strengthen its clinical relevance/significance, only those asthma exacerbations that, in the investigator’s clinical judgement, necessitated the use of systemic steroid (oral/parenteral steroid) or required a doubling of the patient’s baseline maintenance BDP dose for at least 3 days were included in the primary efficacy analyses (referred to as protocol‑defined asthma exacerbations).

e.   Demographic and Baseline Characteristics

Table 10 summarizes key demographic and baseline variables for the placebo‑controlled pivotal studies.

 

 

At baseline, the active and placebo groups were comparable in both studies.  An analysis of all randomized patients revealed no significant difference between the omalizumab and placebo groups with respect to the above variables.

Table 11 summarizes patient disposition for the placebo-controlled, pivotal studies.  More patients in the placebo groups of both studies discontinued from the study prematurely.

 

 

 

5.1.2   Efficacy

a.   Asthma Exacerbations

Tables 12 and 13 present the summary of asthma exacerbations during the stabilization and steroid‑reduction phases, respectively, in the pivotal studies.

 

 

 

 

In Studies 008 and 009 and in the pooled results of these studies, omalizumab was significantly superior to placebo with respect to the number of asthma exacerbations per patient during the treatment‑stabilization and steroid‑reduction periods.  Compared with placebo, the mean number of asthma exacerbations per patient in the omalizumab group was 48%–58% lower during the stabilization phase and 41%–52% lower during the steroid‑reduction period.  In both studies, a significantly lower percentage of omalizumab‑treated patients experienced asthma exacerbations requiring ICS treatment than placebo‑treated patients.  Kaplan-Meier plots of time to first asthma exacerbation are presented in Figures 5 and 6.

 

Figure 5

Time to First Asthma Exacerbation in Pivotal Study 008

p = 0.0067 ^a; hazard ratio estimate = 0.63.
^a  Log-rank test.

 

 

Figure 6

Time to First Asthma Exacerbation in Pivotal Study 009

p = 0.0001 ^a; hazard ratio estimate = 0.51.
^a  Log-rank test.

 

b.   Steroid‑Dose Reduction

In both pivotal studies, omalizumab was significantly superior to placebo with respect to percent reduction in the dose of BDP and the proportion of patients with steroid‑dose reduction (see Table 14).

 

 

 

c.   Total Asthma Symptom Score, Rescue Medication Use, Morning PEFR, and FEV₁

Total asthma symptoms score, rescue medication use, morning PEFR, and FEV₁ were analyzed during the stabilization period.  Omalizumab was significantly superior to placebo (p<0.05) with respect to total asthma symptom score (Weeks 5–16 in Study 008, p£0.047; Weeks 0–16 in Study 009, p£0.01), number of puffs of rescue medication used (Weeks 12–16 in Study 008, p=0.029; Weeks 0–16 in Study 009, p£0.001), morning PEFR (Weeks 5–16 in Study 008, p£0.026; Weeks 0–16 in Study 009, p<0.001), and FEV₁ (Weeks 0–16 in Study 008, p£0.021; Weeks 0–12 in Study 009, p£0.025).  Table 15 summarizes the results of selected secondary and exploratory variables at the end of the stabilization phase for Studies 008 and 009.

 

 

 

d.   QOL and Pharmacoeconomic Evaluations in the Pivotal Studies

QOL was measured in Studies 008 and 009 using the self‑administered Juniper’s pediatric (£17 years old) and adult (>17 years old) asthma QOL questionnaire (AQLQ).

The QOL variables were as follows:

·        Change from baseline in AQLQ was assessed at the end of the stabilization and steroid‑reduction phases for the following domains:  activity limitations, symptoms, emotional function, environmental exposure, and overall.  A positive change meant improvement in QOL.

·        Number of patients achieving clinically important changes (³0.5) in AQLQ scores at the end of the stabilization and steroid‑reduction phases

The results of the AQLQ scores for Studies 008 and 009 are summarized in Table 16.

 

 

Following study drug administration in Studies 008 and 009, AQLQ scores improved in both the omalizumab and placebo groups; the improvement was significantly greater in the omalizumab group than in the placebo group.  The proportion of patients achieving clinically important changes (³0.5) in AQLQ scores with respect to each domain and overall score was greater in the omalizumab group than in the placebo group during the stabilization and steroid‑reduction phases in both studies (see Table 17).

 

 

 

e.   Extension Periods

Study 008.  A total of 460 patients were enrolled and continued with the treatment that was assigned during the core study (245 omalizumab, 215 placebo), and 440 patients completed the extension study (233 omalizumab, 207 placebo).  The mean number of asthma exacerbations per patient during the extension period was 0.80 for omalizumab-treated patients versus 1.31 for placebo‑treated patients (p<0.01).  The difference in inhaled steroid use between the two treatment groups remained stable throughout the extension period.  No BDP medication was used by 27% of omalizumab‑treated patients versus 10% of placebo‑treated patients during the extension period (p<0.01).  The mean improvement in QOL scores at Week 52 over baseline was 1.2 for the omalizumab-treated patients versus 0.9 for the placebo‑treated patients.  These results demonstrated that the efficacy benefit observed in the core period of the study was present for at least 12 months.

Study 009.  A total of 483 patients were enrolled and continued with the treatment that was assigned during the core study (254 omalizumab, 229 placebo), and 447 patients completed the extension study (244 omalizumab, 203 placebo).  The mean number of asthma exacerbations per patient during the extension period for omalizumab-treated patients was 0.65 versus 1.51 (p<0.01) for placebo-treated patients.  The ICS dose at Week 52 demonstrated a difference in treatment means very similar to the difference in ICS dose at the end of the steroid-reduction phase.  No BDP medication was used by 33% of omalizumab‑treated patients versus 15% of placebo‑treated patients during the extension period (p<0.01).  The mean improvement in QOL scores at Week 52 compared with baseline was 0.98 for the omalizumab‑treated patients versus 0.8 for the placebo‑treated patients.  These results also demonstrated that the efficacy benefit observed in the core period was present for at least 12 months.

 

5.1.3   Robustness of Primary Endpoint Results

Additional analyses were performed to evaluate the robustness of results for the co-primary endpoints of Studies 008 and 009 (number of protocol-defined asthma exacerbations per patient) to alternative imputation methods for patients who discontinued prematurely.  In both Studies 008 and 009, roughly twice as many placebo-treated than omalizumab-treated patients discontinued prematurely and more placebo-treated patients reported “unsatisfactory therapeutic effect” as the primary reason for discontinuation, suggesting possible informative missingness.

The number of protocol-defined asthma exacerbations per subject was analyzed using the protocol-specified generalized Cochran-Mantel-Haenszel (Van Elteren) test stratified by dosing schedule.

 

The following imputation methods were implemented:

·        Protocol‑Defined Method:  Within the period that a patient discontinued, the patient was assigned their observed number of exacerbations for that phase plus one additional exacerbation for each 14 days of lost follow‑up (i.e., observed number in study phase + round [days lost in the study phase/14]).  Patients that discontinued in the stabilization phase were assigned for the steroid reduction phase one more than the maximum number of exacerbations observed in the steroid reduction phase over all patients in both treatment groups in that study (i.e., maximum observed in steroid reduction [over both treatment groups] + 1). 

·        Observed‑Exacerbation Method:  Within the phase that a patient discontinued, the patient was assigned the number of exacerbations observed for that individual in the phase prior to discontinuation.  Patients that discontinued in the stabilization phase were assigned zero (overall median) exacerbations for the steroid reduction phase.

·        Average Rate Method:  The average exacerbation rate (observed events per patient-weeks) was computed within each phase and treatment group.  Patients discontinuing prematurely were assigned their observed number of exacerbations for that phase plus the expected number of exacerbations over the missed observation period (treatment- and phase-specific exacerbation rate ´ missed observation time).

In both Studies 008 and 009, the observed exacerbation rate was substantially less than the protocol-defined imputation rate, hence the protocol-defined imputation method overestimates the mean number of exacerbations per patient in each group.  Because there were more discontinuations among placebo-treated than omalizumab-treated patients, the magnitude of this bias is greater in the placebo group and the observed treatment effect overestimates the true effect.  Assigning no additional exacerbations to patients who discontinued prematurely (i.e., analyzing the observed exacerbations only) underestimates the mean number of exacerbations per patient in each group and the corresponding treatment effect.  The Average Exacerbation Rate imputation method gives unbiased estimates of the mean number of exacerbations per patient in each group and the treatment effect when the underlying missingness process is non-informative.  When the missingness process is informative such that patients who discontinue prematurely are at greater exacerbation risk, then this method underestimates the treatment effect, but less conservatively than the Observed Exacerbation method.

Results of robustness analyses for the stable steroid phases of Studies 008 and 009 are shown in Table 18.  Because all three analyses resulted in p<0.05, we conclude that the results for Study 008’s stable steroid phase are robust and that our best estimate of the treatment effect, based on the Average Rate method, is a relative reduction of 42% in mean number of exacerbations per patient over placebo.  Similarly, for Study 009’s Stable Steroid phase, all three analyses gave p<0.05, so we conclude that the primary analysis results are robust with a best estimate of 63% relative reduction in mean exacerbations per patient over placebo. 

 

 

 

 

Results of the robustness analyses for the steroid reduction phases of Studies 008 and 009 are shown in Table 19.  In Study 008, the protocol-defined and Average Rate imputation methods both resulted in p<0.05, but the Observed Exacerbation method gave p=0.124.  Since the Observed Exacerbation method is overly conservative, we still conclude that the Study 008 reduction phase results are robust and that our best estimate of treatment effect, based on the average rate imputation method, is 35% relative reduction in mean exacerbations per patient over placebo.  For Study 009’s Steroid Reduction phase, all three analyses again gave p<0.05.  Hence, we conclude that the primary analysis results are robust with a best treatment effect estimate of 41% relative reduction in mean number of exacerbations per patient over placebo.

 

 

These analyses demonstrate that the co-primary endpoint results for Studies 008 and 009 are robust to alternative imputation methods that are more consistent with the observed exacerbation rates.  Furthermore, they suggest that treatment with omalizumab reduces the mean number of exacerbations per patient by 35%–63%, relative to placebo.

 

5.2       SUPPORTIVE STUDIES PROVIDING ADDITIONAL EFFICACY DATA

Three placebo-controlled supportive studies (Q0694g, 010C/Ext, and 011C) provided further efficacy data in patients with AA.  Efficacy data from two additional open‑label studies (IA04 and Q2143 [ALTO]) were also summarized.  However, because these latter studies were not placebo‑controlled, and because Studies 010C/Ext, 011, and Q0694g were not designed to detect reductions in asthma exacerbations, the results must be interpreted with caution.  Specifically, Studies IA04 and Q2143g (ALTO) were neither blinded nor placebo‑controlled trials and therefore were subject to potential observation and reporting biases.  Study 011C was placebo‑controlled but designed primarily to evaluate the effects of omalizumab on steroid reduction and was not statistically powered to show reductions in asthma exacerbations.  Because of the design differences in the studies, patient populations and efficacy endpoints differed among the five studies.  The results are presented separately by study.

 

5.2.1   Study Q0694g

This was an adequate and well-controlled study conducted in patients with AA to evaluate the efficacy and dose response of IV omalizumab.

a.   Design

Study Q0694g was a multicenter, randomized, double-blind, placebo‑controlled Phase II study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of omalizumab in patients with moderate to severe AA requiring daily use of inhaled and/or oral CSs.  The study duration was 35 weeks and consisted of a 4‑week run-in and 1-week baseline phase, a 12-week randomized and placebo-controlled treatment phase, an 8-week CS-tapering phase, and a 10‑week follow-up phase.  During the run-in phase, CS treatment was switched to inhaled triamcinolone (³600 mg/day), oral prednisone (£20 mg/day or £40 mg every other day), or oral methylprednisolone (£16 mg/day), as appropriate, to control symptoms.  A b‑agonist, albuterol, served as rescue medication throughout the study.

The study included patients 12–45 years old who were male or female nonsmokers with moderate to severe AA, a total serum IgE of £1750 IU/mL, and positive skin test reactivity.

Patients who met the eligibility criteria at the end of the run-in/baseline phase were randomized in a 1:1:2:2 ratio to four treatment groups administered every 2 weeks for 20 weeks:  low-dose placebo, high-dose placebo, low-dose IV omalizumab (0.006 mg/kg/IgE [IU/mL]), or high-dose IV omalizumab (0.014 mg/kg/IgE [IU/mL]).  During the CS‑tapering phase, patients continued double-blind omalizumab or placebo use while tapering ICSs from high to low dose or withdrawing oral CSs.

b.   Outcome Measures

The primary measure of efficacy was the change in overall asthma symptom scores.  Secondary efficacy measures included change in inhaled or oral daily doses of CSs, change in daily PEFR, change in total daily rescue medication (MDI albuterol) use, incidence of asthma exacerbations (not prospectively defined as an endpoint in the protocol), and change in QOL using the AQLQ.

Results.  A total of 317 patients were enrolled and randomized to treatment (106 high‑dose omalizumab, 106 low‑dose omalizumab, 105 placebo) and 283 patients (95 high‑dose omalizumab, 99 high‑dose omalizumab, 89 placebo) completed the study.  Efficacy results are summarized in Table 20.

 

Conclusions.  This study demonstrated the efficacy of omalizumab at doses of 0.006 mg/kg/IgE [IU/mL] and 0.014 mg/kg/IgE [IU/mL] IV every 2 weeks for 20 weeks in a population of moderate to severe allergic asthmatics requiring regular inhaled and/or oral CSs and as‑needed bronchodilator use.  Omalizumab added to standard therapy significantly improved asthma symptoms, PEFR, and QOL.  Omalizumab decreased asthma exacerbations and produced meaningful reductions in CS use while decreasing reliance on bronchodilator rescue drugs.  Study Q0694g also supported the omalizumab dosing regimen selected for the Phase III studies.

 

5.2.2   Study 010

Study 010 was an adequate and well-controlled study conducted in children
6–12 years old with AA and was submitted as a pivotal study in the original BLA.  However, Study 010 was not powered to detect a reduction in asthma exacerbations, and approval is not being pursued in this age group at this time.  Study 010 is now presented as a supportive study.  

a.   Design

Study 010 was a Phase III, 7‑month, double-blind, randomized, parallel-group, placebo‑controlled, multicenter trial with a 5‑month, open-label extension period.  The 7‑month, double-blind core study included a 16‑week stable treatment period followed by a 12‑week steroid dose-reduction period.  Patients received SC omalizumab at a dose of at least 0.008 mg/kg/IgE [IU/mL] every 2 weeks or 0.016 mg/kg/IgE [IU/mL] every 4 weeks or placebo given every 2 or 4 weeks.

During the 5-month, open-label extension period, all patients received omalizumab at a dose of at least 0.008 mg/kg/IgE [IU/mL] every 2 weeks or 0.016 mg/kg/IgE [IU/mL] every 4 weeks.

Patients were male or premenarchal female, 6–12 years old, with moderate to severe AA whose asthma was well controlled with daily ICSs and as-needed or regular use of bronchodilator therapy.  All patients who completed the 7‑month core study were eligible for the 5-month extension.

b.   Outcome Measures

The primary outcome measure was the safety and tolerability of SC omalizumab.  Secondary outcome measures included the 7‑month effects of omalizumab treatment compared with placebo on ICS dose reduction and QOL; the pharmacokinetics and pharmacodynamic effects of omalizumab, including the pharmacoeconomic resource utilization in omalizumab‑treated patients; and asthma exacerbations per patient. 

c.   Results

A total of 334 patients were enrolled and randomized to treatment (225 omalizumab, 109 placebo), and 306 patients (209 omalizumab, 97 placebo) completed the core study and continued on the 5-month open‑label extension.  An additional 3 patients who enrolled in the core study but discontinued prematurely were enrolled in the extension.  Efficacy results from Study 010 are presented in Table 21.

 

Table 21 Efficacy Results (Supportive Study 010)
	Omalizumab	Placebo	p‑value
Median % reduction in ICS dose at end of treatment compared with baseline	100	66.7	0.001
Steroid-stable phase
Mean asthma exacerbations per patient	0.30	0.40	0.093 a
Percent of patients with no asthma exacerbations	84.4	77.1	0.095
Steroid-reduction phase
Mean asthma exacerbations per patient	0.42	0.72	<0.001 a
Percent of patients with no asthma exacerbations	81.8	61.5	<0.001
ICS=inhaled corticosteroid. a   Generalized Cochran‑Mantel‑Haenszel test.

 

In the 7-month double-blind core study, omalizumab was also significantly superior to placebo in both patient and investigator global evaluation of treatment effectiveness (p<0.001).  Omalizumab‑treated patients consistently used less rescue medication than placebo‑treated patients.  Safety results are presented in Section 6.

d.   Conclusions

In children (6–12 years old) with AA, omalizumab had a steroid‑sparing effect, reduced asthma exacerbations during the steroid‑reduction phase, and improved asthma control. 

 

5.2.3   Study 011

Study 011 was conducted in adolescents and adults 12–75 years old with severe AA requiring daily treatment with high‑dose ICSs with or without oral CSs.

a.   Design

Study 011 was a Phase III, 32‑week, randomized, double-blind, parallel‑group, placebo‑controlled, multicenter, pilot trial to assess CS reduction, efficacy, safety, tolerability, steady‑state omalizumab concentration, and pharmacodynamics of SC omalizumab in adolescents and adults with severe AA requiring daily treatment with high‑dose ICSs with or without oral CSs.  During a 6 to 10 week run‑in phase, oral therapy was switched to prednisolone and ICS therapy was switched to fluticasone and adjusted to establish the minimum stable dose.  Patients were then randomized to placebo or omalizumab at a minimum dose of 0.008 mg/kg/IgE [IU/mL] every 2 weeks or 0.016 mg/kg/IgE [IU/mL] every 4 weeks.  The 32‑week, double‑blind treatment phase consisted of a 16‑week stabilization phase followed by a 16‑week steroid‑reduction phase.  Inhaled or oral CS dose was reduced during the 16‑week steroid-reduction phase.

Patients were 12–75 years old, had ³1 year history of chronic severe asthma, and required high‑dose ICSs for at least 1 year.

b.   Outcome Measures

The primary outcome measure was the amount of ICS use in patients receiving high‑dose ICS therapy compared across the two arms at Week 32.  The secondary outcome measures included oral and overall CS use, number of asthma exacerbations, rescue medication use, lung function, asthma-related QOL, and pharmacoeconomic effects.

c.   Results

A total of 341 patients were randomized.  A total of 176 patients were randomized to omalizumab (126 ICS subpopulation, 50 oral CS subpopulation), and 165 patients were randomized to placebo (120 ICS subpopulation, 45 oral CS subpopulation).  A total of 311 patients completed the study; 160 were omalizumab‑treated patients (115 ICS population, 45 oral CS subpopulation), and 151 were placebo‑treated patients (109 ICS subpopulation, 42 oral CS subpopulation).

Percent reduction in fluticasone dose was greater in omalizumab‑treated than placebo‑treated patients receiving ICSs only (median 60% vs. 50%, p=0.003).  Absolute reduction in fluticasone dose was significantly greater in omalizumab‑treated patients receiving ICSs only than in placebo‑treated patients (750 mg/day vs. 500 mg/day, p=0.003). 

There was no statistical difference between the treatment groups in the number of asthma exacerbations.  Omalizumab protected against asthma exacerbations during the steroid reduction period.  Asthma exacerbations increased in placebo-treated patients during the steroid reduction period compared with the steroid-stabilization period (0.34 vs. 0.23 asthma exacerbations per patient, respectively).  Asthma exacerbations remained more constant across the stabilization and steroid reduction periods in the omalizumab-treated patients than in the placebo‑treated patients (0.15 vs. 0.19 asthma exacerbations per patient, respectively).

For patients who received both oral and inhaled CSs, it is important to note that baseline disease was more severe in patients who were randomized to receive omalizumab than in patients who were randomized to receive placebo.  This was evidenced by significant baseline differences in several measures of disease severity, including night time awakenings, rescue medication use, and asthma symptom scores.  In this subgroup, percent and absolute reduction in oral prednisolone dose at the end of treatment did not differ between omalizumab‑treated and placebo‑treated patients.  However, mean asthma exacerbations increased markedly in placebo‑treated patients during the steroid reduction phase compared with the stabilization phase (0.73 vs. 0.31 asthma exacerbations per patient, respectively).  The asthma exacerbations remained constant in the omalizumab‑treated patients between the steroid reduction and stabilization phases (0.42 vs. 0.49 asthma exacerbations per patient, respectively). 

Despite slightly higher CS usage at baseline, omalizumab‑treated patients used fewer puffs of rescue medication from Week 4 onwards, reaching statistical significance compared with placebo between Weeks 26 and 28 (p=0.032) and between Weeks 28 and 30 (p=0.028).

Both the placebo and omalizumab groups showed an improvement in morning PEF in the stabilization phase; this was greater in omalizumab‑treated patients.  This improvement was sustained during the reduction phase in the omalizumab group, but there was a decline in PEF over time in the placebo group.  Significant differences in change in morning PEF, in favor of omalizumab‑treated patients, were seen at Weeks 20 and 30 (p-values of 0.048, 0.032, respectively).

Omalizumab generally improved asthma QOL compared with placebo, particularly in the steroid reduction phase.  The mean change from baseline in the QOL score during the steroid-stabilization period was 0.52 in omalizumab‑treated patients versus 0.28 in placebo patients (p=0.043).  The mean change from baseline in the QOL score during the steroid-reduction period was 0.68 in omalizumab‑treated patients versus 0.26 in placebo‑treated patients (p=0.003).  

d.   Conclusions

In asthmatic patients dependent on high-dose ICSs, treatment with omalizumab allowed a significantly greater reduction of high‑dose ICSs compared with placebo.

 

5.2.4   Study IA04

This was an open‑label study to evaluate the efficacy and tolerability of SC omalizumab in patients with poorly‑controlled moderate to severe AA in a naturalistic setting.

a.   Design

Study IA04 was a Phase IIIb, open‑label, randomized, controlled, multicenter study to evaluate the efficacy and tolerability of omalizumab in addition to current asthma treatment (CAT) according to best medical practice.  After a 4‑week screening period, patients were randomized 2:1 to receive CAT plus omalizumab or to receive CAT alone for 52 weeks.  Patients received omalizumab at a dose of at least 0.008 mg/kg/IgE [IU/mL] every 2 weeks or 0.016 mg/kg/IgE [IU/mL] every 4 weeks.  Patients were evaluated at 3‑month intervals during treatment and 4 weeks after the end of treatment for efficacy and safety variables.

Patients were 12–75 years old, had moderate to severe persistent AA (NIH 1997) for at least 2 years, and had required hospitalizations or ER visits and oral CSs in the previous year.

b.   Outcome Measures

The primary outcome measure was the annualized number of asthma‑related deterioration incidents (ARDIs), defined as at least one of the following:  a 2‑day course of antibiotics, a course of oral or systemic CSs, missing work or school days because of asthma, having had a hospital stay because of asthma, or having had an unscheduled physician visit or ER visit because of asthma.

The secondary outcome measures were as follows:

·        Annualized number of clinically significant asthma exacerbations (defined as episodes of worsening of asthma symptoms reported as adverse events that required treatment with systemic CSs)

·        Number of days of systemic CS use, absenteeism from school/work, unscheduled physician visits, ER visits, or hospitalization days because of asthma

·        Number of daily puffs of short-acting b‑agonist for the 2 weeks preceding each visit

·        Morning FEV₁ at scheduled physician visits

·        Wasserfallen (1997) clinical asthma symptom scale, obtained at scheduled physician visits

·        Change in QOL score from baseline to endpoint

c.   Results

A total of 312 patients were randomized (206 omalizumab, 106 CAT), and 175 patients (85%) in the omalizumab group and 77 patients (73%) in the CAT‑treated group received study treatment for at least 48 weeks.  Baseline patient demographics and disease characteristics were similar for the two treatment groups.

Primary analysis of ARDI data and clinically significant asthma exacerbation data was based on the ITT population with imputation.  Results are presented in Table 22.

 

Table 22 Efficacy Results (Supportive Study IA04)
	Omalizumab	CAT	p‑value
Annualized mean number of ADRIs	4.92	9.76	<0.001
Percent of patients with no ADRIs	36.1	20.2	0.002
Annualized mean number of clinically significant asthma exacerbations	1.12	2.86	<0.001
Percent with no clinically significant asthma exacerbations	49.5	26.4	0.001
Change in mean (SD) BDP equivalent Dose of ICS between visits 2 and 6	–342 (878)	68 (913)	<0.001
Mean (range) days taking systemic CS	29.0 (1–368)	32.5 (1–370)	0.037
Percent of patients with unscheduled physician visits	33.5	50.6	0.007
Percent of patients with emergency room visits	12.6	19.1	NS
Percent of patients with hospital stays	8.4	9.0	NS
Median (range) days of absenteeism, working group	7.5 (1–140)	10.0 (1–124)	0.01
ADRI=asthma‑related deterioration incidents; BDP=beclomethasone dipropionate; CS=corticosteroid; ICS=inhaled corticosteroids; NS=not significant; SD=standard deviation.

 

In addition, treatment with omalizumab plus CAT compared with treatment with CAT alone resulted in the following:

·        Significant and clinically meaningful improvement in morning FEV₁

·        Significant improvement in the total asthma clinical symptom scores at all visits

·        Reduction in the intake of short‑acting b‑agonist therapy

·        Improvement in the total mini asthma QOL score throughout treatment that was sustained at follow‑up

d.   Conclusions

In patients 12–75 years old with poorly controlled moderate to severe persistent AA, omalizumab significantly reduced the number of ARDIs and the number of clinically significant asthma exacerbations, improved daily asthma symptom control (as shown by improvements in clinical symptom scores), improved QOL (as measured by the mini‑asthma QOL instrument), reduced bronchodilator use, and improved FEV₁.

 

5.2.5   Study Q2143g (ALTO)

This was an open‑label safety trial in patients 6–75 years old with moderate to severe persistent AA.

a.   Design

Study Q2143g was a Phase III, 24‑week, open‑label, multicenter, randomized, controlled safety trial.  Patients were randomized 2:1 to receive their usual therapy with or without SC omalizumab 0.008 mg/kg/IgE [IU/mL] every 2 weeks or 0.016 mg/kg/IgE [IU/mL] every 4 weeks.

Patients were 6–75 years old, had a diagnosis of moderate to severe persistent AA, and received moderate doses of ICSs and/or oral CSs and at least one of the following:  long‑acting b‑adrenergic agent, LTRA, xanthine derivatives, or sodium cromoglycate.

b.   Outcome Measures

The primary outcome measure was the incidence of all serious adverse events.  The secondary outcome measures were the incidence of all adverse events, protocol-defined asthma exacerbations, and nocturnal symptoms as measured by the Modified Inner City Asthma Study Morbidity Assessment.  Asthma exacerbations were defined as a worsening of asthma requiring an unscheduled medical visit, ER visit or hospitalization, and one or more of the following:  doubling of inhaled steroid dose and/or an increase in the dose of oral steroids or inception of oral, IV, or SC steroids.

c.   Results

A total of 1899 patients were enrolled and randomized to treatment (1262 omalizumab, 637 control), and 1638 patients completed the study.  There were no differences in baseline demographics or disease characteristics between the two study groups.

A separate analysis was conducted for each of the following four endpoints of asthma exacerbation:

·        Any protocol-defined asthma exacerbation

·        Protocol-defined asthma exacerbation that resulted in hospitalization

·        Protocol-defined asthma exacerbation that resulted in an ER visit

·        Protocol-defined asthma exacerbation that resulted in an unscheduled or urgent visit for medical care

Table 23 summarizes the rate ratios for the four endpoints for each treatment group.

 

Although not designed as an efficacy study, patients treated with omalizumab experienced a 20% reduction in protocol‑defined asthma exacerbations (p<0.05). 

Asthma nocturnal symptom scores were recorded at baseline and Weeks 4, 12, and 24.  The score refers to the number of nights in the previous 14 days subjects were awakened because of wheezing, coughing, or tightness in the chest.  Changes from baseline were compared between treatment groups (active and control) using the Wilcoxon rank‑sum test.

Subjects in the active treatment group experienced a greater reduction in the nocturnal symptom score at each of Visits 3, 4, and 5 (Weeks 4, 12, and 24; p<0.001). 

Safety results are presented in Section 6.

d.   Conclusions

Omalizumab was safe and effective in the treatment of moderate to severe persistent AA in patients receiving other asthma medications.

 

5.3       Analysis of Asthma-Related Clinical Outcomes among All Controlled Studies

Analyses were conducted describing the effects of treatment with SC omalizumab on the frequency of asthma‑related outpatient medical visits, ER visits, and hospitalizations across all completed, controlled, Phase III studies in patients with AA.  Included were the placebo‑controlled, pivotal Studies 008 and 009 and their extensions; Study 010; Study 011C, a placebo‑controlled study in patients with severe asthma; and the open‑label, naturalistic Studies IA04 and Q2143g (ALTO).  The effects of omalizumab treatment on the reduction of the rate of these events (asthma‑related outpatient medical visits, ER visits, and hospitalizations) in patients with moderate to severe asthma are summarized in Table 24.

 

 

With data pooled from all six studies (008C/Ext, 009C/Ext, 010C/Ext, 011C, IA04, and Q2143g), a trend in rate reduction associated with omalizumab treatment was observed across the three endpoints.  Omalizumab treatment was associated with estimated reductions of 27%, 36%, and 27% in the rates of outpatient medical visits, ER visits, and asthma‑related hospitalizations, respectively.  These reductions were statistically significant for outpatient visits, marginally significant for ER visits, and non-significant for hospitalizations.  For asthma‑related hospitalizations, four of the six studies showed rate reductions for omalizumab‑treated patients compared with placebo‑treated/control patients.  For ER and outpatient visits, each of the six studies showed rate reductions for omalizumab‑treated patients compared with placebo‑treated/control patients, with the latter endpoint reaching statistical significance in four of the six studies.  Analysis of duration of asthma‑related hospitalizations for Studies 008C/Ext, 009C/Ext, 010C, and 011C showed that the mean number of days per hospitalization was similar for omalizumab- and placebo‑treated/control patients. 

 

5.4       analysis of asthma exacerbations among patients using concomitant asthma medications

In pivotal Studies 008 and 009, the efficacy of omalizumab was demonstrated among patients receiving daily ICSs and short-acting b-agonists.  In the open-label studies IA04 and Q2143g (ALTO), a large fraction of patients received long-acting b-agonists (LABAs) and/or LTRAs in addition to corticosteroids.  In this section, the observed effects of omalizumab on protocol-defined asthma exacerbations among patients using these concomitant medications at baseline in Studies IA04 and ALTO are summarized.  As with all subgroup analyses, results must be interpreted with caution due to small numbers in some subgroups and potential treatment group imbalances.

Table 25 summarizes the effects of omalizumab on exacerbation risk and rates among patients utilizing LABAs and LTRAs at baseline in studies IA04 and Q2143g. In Study IA04 roughly half of patients used LABAs at baseline without LTRAs. Within this subgroup there was approximately 39% reduction in risk of exacerbations and 63% reduction in exacerbation rates among omalizumab patients, compared to control. Approximately a quarter of patients used LABAs and LTRAs and within this subgroup there was approximately 10% reduction in risk and 56% reduction in rates of exacerbations among omalizumab patients, compared to control.

In the Q2143g (ALTO) study, roughly half of patients used LABAs at baseline without LTRAs. In this subgroup there was approximately 18% reduction in exacerbation risk and 3% reduction in exacerbation rates among omalizumab patients, compared to control. Approximately half of patients used LABAs and LTRAs in ALTO and within this subgroup there was approximately 33% reduction in exacerbation risk and 32% reduction in exacerbation rates among omalizumab patients, compared to control.

In conclusion, these post-hoc subgroup analyses suggest that omalizumab reduces asthma exacerbation risk and rates among patients receiving LABAs alone or LABAs together with LTRAs in addition to corticosteroids.

 

 

 

5.5       BASELINE ASTHMA SEVERITY IN PLACEBO-CoNTROLLED TRIALS

A post‑hoc analysis was conducted to characterize patients in the placebo‑controlled trials with regard to disease severity; this is discussed in detail in the Amendment to the Integrated Summary of Efficacy.  Patients in Studies 008, 009, 010, and 011 were classified according to baseline asthma symptoms and asthma treatment steps based on the NHLBI guidelines that were in effect when the studies were initiated (NIH 1997). 

Of the patients enrolled in the adult asthma studies (008 and 009), >90% were classified with severe persistent asthma based on clinical symptoms.  In the pediatric study (010), 21% were classified with severe persistent asthma, 44% were classified with moderate persistent disease, and 35% were classified with mild persistent or intermittent disease based on clinical features.  In Study 011, 47% of patients were classified with severe persistent asthma, 34% were classified with moderate persistent disease, and 19% were classified with mild persistent or intermittent disease based on clinical features alone.  When classified by treatment step based on the NHLBI guidelines, 70% of patients in Study 008, 67% of patients in 009, and 49% of patients in 010 were classified as treatment Step 3 (moderate persistent).  These results were consistent with the protocol-specified objectives of Studies 008, 009, 010, and 011. 

Applying the Global Initiative for Asthma (GINA) 2002 asthma severity classification matrix to Studies 008 and 009, >97% of patients would be classified with severe persistent asthma.  For Study 010, 65% of patients would be classified with severe persistent asthma and 35% of patients would be classified with moderate or mild persistent asthma.  For Study 011, 81% of patients would be classified with severe persistent asthma and 19% would be classified with moderate persistent asthma.

 

5.6       clinical efficacy Summary and conclusions

In studies (008 and 009) involving 1071 allergic asthmatic patients (542 omalizumab, 529 placebo) who were symptomatic despite daily treatment with orally inhaled BDP (420–1680 µg/day) and as‑needed or regular rescue albuterol (maximum 8 puff/day), treatment with omalizumab was consistently superior to placebo in reducing asthma exacerbations requiring steroid burst and improving asthma symptoms, respiratory function, and asthma‑related QOL while allowing meaningful reduction of BDP dose.

During the first 16 weeks of study treatment (stabilization phase), the mean number of asthma exacerbations per patients in the omalizumab group (co-primary efficacy variable) was reduced 48%–58% compared with the placebo group.  The proportion of patients experiencing one or more asthma exacerbation was reduced 37%–58% compared with the placebo group.  In addition, there was a significant improvement in daily asthma symptom score along with a decrease in use of albuterol rescue medication, indicating persistent beneficial effects of omalizumab.  These results were both clinically and statistically significant.

The clinical efficacy of omalizumab was also evident in its ability to reduce the CS requirement for control of asthma.  After 12 weeks of treatment, the median percent reduction in the dose of BDP required for asthma control was significantly greater in omalizumab‑treated patients than in placebo‑treated patients (75% vs. 50% in Study 008; 83% vs. 50% in Study 009).  A complete withdrawal (100% reduction) of BDP was achieved in a greater number of omalizumab‑treated patients than placebo‑treated patients (40% vs. 19% in Study 008; 43% vs. 20% in Study 009).  The steroid dose reduction was associated with a clinically and statistically significant decrease in asthma exacerbations for omalizumab compared with placebo.  Despite the reduced dose of ICSs or its discontinuation during the steroid-reduction period, the mean number of asthma exacerbations per patient (co-primary efficacy variable) in the omalizumab group was reduced 41%–52% compared with the placebo group and the proportion of patients in the omalizumab group experiencing one or more asthma exacerbations was reduced 34%–47% compared with the placebo group.  There was also a decrease in albuterol rescue medication use during the steroid‑reduction period.

Lung function assessments revealed a statistically significant difference favoring omalizumab over placebo with respect to FEV₁ and morning PEFR.  Considering the long duration of asthma (mean duration ~20 years), severity of asthma (moderate or severe), and background maintenance therapy with at least moderately high doses of ICSs, these increases in FEV₁ and PEFR, although small, are important evidence of the robust efficacy of omalizumab.

The overall effectiveness of omalizumab was clearly reflected in patients’ self‑assessment of QOL using the validated AQLQ.  While both omalizumab and placebo groups experienced clinically meaningful improvement (change from baseline in AQLQ score ≥0.5), omalizumab was significantly superior to placebo with respect to each of the individual domains (activities, emotions, symptoms, environmental exposure) and overall scores.  Efficacy results from five additional supportive studies were summarized.  These included two adequate and well‑controlled studies (Q0694g, 010C/Ext) and three recently completed omalizumab studies (011C, IA04, and Q2143 [ALTO]) in patients with AA.  However, the latter three studies were either not designed as adequate and well‑controlled efficacy studies or were not designed to detect reductions in asthma exacerbations and should be interpreted accordingly.

Study Q0694g demonstrated that IV omalizumab, when administered to patients with moderate to severe AA who required daily use of ICSs and/or oral CSs, significantly improved asthma symptoms, PEFR, and QOL while decreasing asthma exacerbations, CS usage, and reliance on inhaled bronchodilators.  This study also supported the dosing regimens selected for the Phase III studies.  In Study 010C, omalizumab had a steroid‑sparing effect, reduced asthma exacerbations, and improved asthma control in children 6–12 years old.

Study 011C demonstrated that treatment with omalizumab allowed a statistically significant greater reduction in ICSs compared with placebo without a concomitant increase in asthma exacerbations in patients with asthma dependent on high‑dose ICSs.  Furthermore, omalizumab improved symptom control and maintained symptoms during CS reduction, whereas symptom scores worsened in the placebo group.  Study IA04 showed that treatment with omalizumab in addition to CAT had a significant impact on asthma severity, reduced asthma exacerbations, and improved asthma symptoms and QOL.  Study Q2143g, while primarily a safety study, showed improvements in the rate of asthma exacerbations in individuals who were skin‑test positive and negative to common allergens, as well as improvements in nocturnal asthma symptoms and FEV₁ values.

Analysis of asthma-related clinical outcomes among all controlled studies demonstrated that, with data pooled from six studies, omalizumab treatment was associated with estimated reductions of 27%, 36%, and 27% in the rates of asthma‑related hospitalizations, ER visits, and outpatient medical visits, respectively.  These reductions were statistically significant for outpatient visits marginally significant for ER visits, and non-significant for hospitalizations.  Because exacerbations requiring hospitalization, ER visit, or outpatient visit represent a small subset of the clinically most significant exacerbations, these results should be interpreted in the context of demonstrated reductions in protocol-defined and investigator-assessed exacerbations.

With few exceptions, subgroup analyses of pooled data from Studies 008, 009, and 010 showed consistent reductions in protocol-defined exacerbations of ³30% associated with omalizumab treatment for all subgroups.  The exceptions were geriatric patients in the stabilization period (12% reduction), patients with baseline FEV₁ percent predicted of ³80% in the steroid reduction period (18% reduction), and an observed trend across baseline inhaled steroid dose subgroups in the steroid reduction period (28%, 44%, and 67% reductions for the low, medium, and high steroid dose subgroups, respectively).  These findings were not seen in other studies.  Subgroup analysis of geriatric patients in Study Q2143g (ALTO) revealed rates of reduction in asthma exacerbations similar to those seen in younger patients.  Subgroup analysis of patients with FEV₁ >80% predicted in Study IA04 demonstrated rates of reduction in asthma exacerbations similar to those seen in patients with FEV₁ <80% predicted.

Long‑term studies demonstrated that the beneficial effects of omalizumab in decreasing asthma exacerbations and CS requirements were maintained for over 1 year.  Finally, additional analysis using NHLBI guidelines with respect to asthma severity demonstrated that >90% of patients enrolled in the AA studies (008 and 009), 21% of patients in the pediatric study (010), and 47% of patients in Study 011 were classified with severe persistent asthma.

In these studies, treatment with omalizumab in adolescents and adults with moderate to severe AA requiring daily ICSs demonstrated the following:

·        Reduced asthma exacerbations and improved asthma control

·        Allowed steroid dose reduction while maintaining asthma control

·        Improved asthma symptoms and respiratory function

·        Improved asthma‑related QOL

 

6.         Clinical safety

6.1       Introduction and Overview

The omalizumab safety database included 10 Phase I/II completed studies (see Table 7) and 15 Phase IIb/III studies (see Table 8).  In addition, a single‑dose pharmacokinetic study (2203) in 87atopic individuals with asthma and/or rhinitis has also been completed.  The number of patients enrolled in these studies is summarized by indication in Table 22.  The clinical safety database included a combined total of 6252 patients with complete data; 4265 patients were treated with omalizumab.  As of 18 July 2002, there were nine ongoing Phase III studies with 992 patients, including 536 omalizumab‑treated patients (411 continuing from previous studies and 125 newly exposed) in the open-label extension studies and approximately 228 omalizumab-treated patients (all newly exposed) in the double-blind, placebo-controlled studies (1:1 randomization ratio; see Table 9).

 

 

Overall these studies showed the following:

·        Omalizumab was safe and well tolerated in adolescent/adult patients (≥12 years old) with AA.

·        There was no evidence of an increased risk of drug-related hypersensitivity reactions or infections in patients treated with omalizumab.

·        There was no evidence of an increased risk of gastrointestinal, respiratory, or genitourinary system adverse events that were suggestive of mucosal immunity impairment with omalizumab treatment. 

·        There was no evidence of clinically significant interaction between omalizumab and commonly taken asthma medications or antibiotics with respect to adverse events.

·        There was no evidence of a clinically significant effect on platelets or any other laboratory parameters in patients treated with omalizumab.

·        A small number of malignant neoplasms were observed that showed more neoplasia events among omalizumab-treated patients.  Available data were not sufficient to conclusively assess the effect of omalizumab treatment on the development of malignant neoplasms.  The majority had an onset within 6 months of initiation of treatment, suggesting that these malignancies were unrelated to study drug.

 

6.2       Phase IIb/III studies

This section discusses the following four groups:

·        Phase IIb/III completed, controlled studies

Patients in Studies 006, 007, 008C/Ext, 009C/Ext, 010C, 011C, 012, 013, 014, D01, IA04, and Q2143g

·        Phase IIb/III completed, placebo‑controlled studies

Patients in Studies 006, 007, 008C/Ext, 009C/Ext, 010C, 011C, 012, 013, 014, and D01

·        Phase IIb/III completed, controlled studies in adolescent and adult patients with AA

Patients ³12 years old in Studies 008C/Ext, 009C/Ext, 011C, 012, IA04, and Q2143g

·        Phase IIb/III completed, placebo‑controlled studies in adolescent and adult patients with AA

Patients ³12 years old in Studies 008C/Ext, 009C/Ext, 011C, and 012

Controlled studies refer to those studies with a placebo group and standard therapy control (STC).

Other studies were not included in this section because they involved IV rather than SC omalizumab, single or unusual doses (Phase I/II; see Section 6.3), or were uncontrolled studies.  No significant differences in the safety profile were seen in these studies.

 

6.2.1   Demographics and Baseline Characteristics

Patient demographics and baseline characteristics and asthma‑related medical history and baseline characteristics in the Phase IIb/III AA adolescent/adult controlled studies are summarized in Tables 27 and 28, respectively.  Table 29 summarizes key demographic and baseline characteristics in all controlled studies.

 

Table 27 Patient Demographics and Baseline Characteristics in Phase IIb/III AA Adolescent/Adult Controlled Studies (All Safety Analyzable Patients)
	AA Controlled Studies a		AA Placebo-Controlled Studies
Parameter	Omalizumab (n=2076)	Control a (n=1383)	Omalizumab (n=738)	Placebo (n=717)
Sex, n (%)
Male	837 (40.3)	589 (42.6)	313 (42.4)	319 (44.5)
Female	1239 (59.7)	794 (57.4)	425 (57.6)	398 (55.5)
Race, n (%)
Caucasian	1758 (84.7)	1171 (84.7)	655 (88.8)	628 (87.6)
Black	158 (7.6)	99 (7.2)	34 (4.6)	31 (4.3)
Oriental	35 (1.7)	24 (1.7)	7 (0.9)	11 (1.5)
Other race	125 (6.0)	89 (6.4)	62 (5.7)	47 (6.6)
Age, n (%)
12–17 years	151 (7.3)	97 (7.0)	50 (6.8)	47 (6.6)
18–64 years	1791(86.3)	1221 (88.3)	648 (87.8)	644 (89.8)
³65 years	134 (6.5)	65 (4.7)	40 (5.4)	26 (3.6)
Mean (range), years	41.7 (12–76)	40.8 (12–76)	40.0 (12–76)	39.6 (12–74)
Mean total IgE (range), IU/mL	195.0 (20–1118)	196.4 (19–815) b	210.7 (20–1055)	209.7 (19–815)
Note:  Included placebo-controlled Studies 008C/Ext, 009C/Ext, 011C, and 012 and Studies IA04 and Q2143g. a    Placebo plus standard-therapy control. b    Number of patients was 1294.

 

 

 

 

 

A summary of concomitant medications by therapeutic class for selected classes is summarized in Table 30.

 

Table 30 Concomitant Medication Use in Phase IIb/III AA Adolescent/Adult Controlled Studies (All Randomized Patients)
	AA Controlled Studies a		AA Placebo-Controlled Studies
Selected Classes of Concomitant Medications	Omalizumab (n=2076) n (%)	Control a (n=1383) n (%)	Omalizumab (n=738) n (%)	Placebo (n=717) n (%)
Any concomitant medication	1755 (84.5)	1101 (79.6)	433 (58.7)	445 (62.1)
Oral steroids	654 (31.5)	514 (37.2)	194 (26.3)	259 (36.1)
Xanthine derivatives	226 (10.9)	130 (9.4)	6 (0.8)	29 (4.0)
Leukotriene-modifying agents	675 (32.5)	372 (26.9)	22 (3.0)	34 (4.7)
LABAs	1339 (64.5)	785 (56.8)	163 (22.1)	191 (26.6)
Cromolyns	77 (3.7)	43 (3.1)	7 (0.9)	8 (1.1)
Penicillins	338 (16.3)	221 (16.0)	147 (19.9)	131 (18.3)
Fluoroquinolone antibiotics	312 (15.0)	166 (12.0)	85 (11.5)	75 (10.5)
Sulfa antibiotics	42 (2.0)	17 (1.2)	9 (1.2)	4 (0.6)
ACE inhibitors	129 (6.2)	72 (5.2)	28 (3.8)	26 (3.6)
H2-receptor antagonists	129 (6.2)	90 (6.5)	42 (5.7)	41 (5.7)
Calcium-channel antagonists	134 (6.5)	79 (5.7)	30 (4.1)	29 (4.0)
Iodinated radiographic contrast agents	6 (0.3)	1 (0.1)	1 (0.1)	0
LABA=long-acting b-agonist. Note:  Included placebo-controlled Studies 008C/Ext, 009C/Ext, 011C, and 012 and Studies IA04 and Q2143g. a   Placebo plus standard-therapy control.

 

In AA adolescent/adult controlled studies, 85% of the patients were Caucasian, 59% were female, and 87% were 18–64 years old.  In both groups of studies, background characteristics, including severity of asthma, were similar in the omalizumab and control groups (placebo plus STC or placebo alone).  In AA controlled studies, the incidence of patients who used leukotriene-modifying agents and long acting b-agonists was higher in the omalizumab group compared with the control group.  In the AA placebo‑controlled studies, concomitant medication use was similar in the omalizumab and control groups except for oral steroids and xanthine derivatives, which were used more frequently by placebo‑treated patients compared with omalizumab‑treated patients.  In both groups of all completed controlled studies, concomitant medication use was similar in the omalizumab and control groups except for oral CSs and LABAs, which were more frequently used by placebo‑treated patients than omalizumab‑treated patients.

 

6.2.2   Patient Disposition (Phase IIb/III Studies)

Overall, the majority of enrolled patients completed the AA adolescent/adult controlled studies, as well as all controlled studies.  In both groups of studies, premature discontinuations were lower in the omalizumab group compared with the control group.  In all treatment groups, the most frequent reason for discontinuation was withdrawal of consent.  Discontinuations related to adverse events in omalizumab‑treated patients occurred mostly in open‑label studies that used STC.

 

6.2.3   Drug Exposure (Phase IIb/III Studies)

In the Phase IIb/III controlled studies overall, 3224 patients (including 345 children aged 6 to <12 years old) were exposed to omalizumab compared with 2019 in the control group (1311 placebo and 708 STC).  The majority of patients were exposed to study drug for ³24 weeks.  A total of 2060 patients were exposed to omalizumab for ³24 weeks, and 555 patients were exposed for ³52 weeks.  The total patient–year exposure was 49% higher in the omalizumab group than in the control group (1695.2 patient‑years vs. 1136.4 patient‑years).

 

6.2.4   Adverse Events (Phase IIb/III Studies)

a.   All Adverse Events

AA Adolescent/Adult Controlled Studies.  The number of patients with adverse events in the most frequently affected International Medical Nomenclature (IMN) dictionary body systems (³5% in any group) are summarized in Table 31.

 

 

 

In the AA adolescent/adult placebo-controlled studies, the incidence of adverse events was similar in both treatment groups.  In the AA adolescent/adult controlled studies, the incidence of adverse events was also similar in both treatment groups, except for the skin and appendages body system.  Adverse events in this system occurred more frequently in the omalizumab group than the control group.  When the two groups of studies were compared, the overall incidence of adverse events and the incidence of adverse events in each body system was higher in the AA adolescent/adult placebo‑controlled studies than in the AA adolescent/adult controlled studies.

The most common adverse events (³3% in any group) are summarized in Table 32.

 

 

 

 

In both groups of studies and all treatment groups, the most common adverse events were viral infection, upper respiratory infection (URI), sinusitis, and headache.  In both groups of studies, the frequency of various adverse events in the omalizumab group was similar to the control groups with the following exceptions:

·        In all controlled studies, injection‑site reaction occurred more frequently in the omalizumab group.  Sixty-seven of the 69 omalizumab‑treated patients reporting this adverse event were from STC studies. 

Note:  The control group did not receive any study medication and, hence, no similar adverse event was reported by the control patients.

·        In the placebo-controlled studies, dyspepsia occurred more frequently in the placebo group than the omalizumab group.

All Controlled Studies.  The number of patients with adverse events in the most frequently affected IMN body systems (