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Xolair

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Xolair

Xolair

CLINICAL PHARMACOLOGY

Mechanism Of Action

Allergic Asthma

Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcsRI) on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcsRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcsRI receptors on basophils in atopic patients.

Chronic Idiopathic Urticaria

Omalizumab binds to IgE and lowers free IgE levels. Subsequently, IgE receptors (FcsRI) on cells down-regulate. The mechanism by which these effects of omalizumab result in an improvement of CIU symptoms is unknown.

Pharmacodynamics

Allergic Asthma

In clinical studies, serum free IgE levels were reduced in a dose dependent manner within 1 hour following the first dose and maintained between doses. Mean serum free IgE decrease was greater than 96% using recommended doses. Serum total IgE levels (i.e., bound and unbound) increased after the first dose due to the formation of omalizumab:IgE complexes, which have a slower elimination rate compared with free IgE. At 16 weeks after the first dose, average serum total IgE levels were five-fold higher compared with pre-treatment when using standard assays. After discontinuation of Xolair dosing, the Xolair-induced increase in total IgE and decrease in free IgE were reversible, with no observed rebound in IgE levels after drug washout. Total IgE levels did not return to pre-treatment levels for up to one year after discontinuation of Xolair.

Chronic Idiopathic Urticaria

In clinical studies in CIU patients, Xolair treatment led to a dose-dependent reduction of serum free IgE and an increase of serum total IgE levels, similar to the observations in allergic asthma patients. Maximum suppression of free IgE was observed 3 days following the first subcutaneous dose. After repeat dosing once every 4 weeks, predose serum free IgE levels remained stable between 12 and 24 weeks of treatment. Total IgE levels in serum increased after the first dose due to the formation of omalizumab-IgE complexes which have a slower elimination rate compared with free IgE. After repeat dosing once every 4 weeks at 75 mg up to 300 mg, average predose serum total IgE levels at Week 12 were two-to three-fold higher compared with pre-treatment levels, and remained stable between 12 and 24 weeks of treatment. After discontinuation of Xolair dosing, free IgE levels increased and total IgE levels decreased towards pre-treatment levels over a 16-week follow-up period.

Pharmacokinetics

After SC administration, omalizumab was absorbed with an average absolute bioavailability of 62%. Following a single SC dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7-8 days. In patients with CIU, the peak serum concentration was reached at a similar time after a single SC dose. The pharmacokinetics of omalizumab was linear at doses greater than 0.5 mg/kg. In patients with asthma, following multiple doses of Xolair, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after the first dose. In patients with CIU, omalizumab exhibited linear pharmacokinetics across the dose range of 75 mg to 600 mg given as single subcutaneous dose. Following repeat dosing from 75 to 300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose levels.

In vitro, omalizumab formed complexes of limited size with IgE. Precipitating complexes and complexes larger than 1 million daltons in molecular weight were not observed in vitro or in vivo. Tissue distribution studies in Cynomolgus monkeys showed no specific uptake of 125I-omalizumab by any organ or tissue. The apparent volume of distribution of omalizumab in patients with asthma following SC administration was 78 ± 32 mL/kg. In patients with CIU, based on population pharmacokinetics, distribution of omalizumab was similar to that in patients with asthma.

Clearance of omalizumab involved IgG clearance processes as well as clearance via specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG included degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also excreted in bile. In studies with mice and monkeys, omalizumab:IgE complexes were eliminated by interactions with Fcy receptors within the RES at rates that were generally faster than IgG clearance. In asthma patients omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging 2.4 ± 1.1 mL/kg/day. Doubling body weight approximately doubled apparent clearance. In CIU patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days and apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient).

Special Populations

Allergic Asthma

The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics in patients with allergic asthma. Analyses of these data suggested that no dose adjustments are necessary for age (12-76 years), race, ethnicity, or gender.

Chronic Idiopathic Urticaria

The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics and other factors on omalizumab exposure in patients with CIU. Covariate effects were evaluated by analyzing the relationship between omalizumab concentrations and clinical responses. These analyses demonstrate that no dose adjustments are necessary for age (12 to 75 years), race/ethnicity, gender, body weight, body mass index or baseline IgE level.

Clinical Studies

Allergic Asthma

Adult and Adolescent Patients 12 Years of Age and Older

The safety and efficacy of Xolair were evaluated in three randomized, double-blind, placebo-controlled, multicenter trials.

The trials enrolled patients 12 to 76 years old, with moderate to severe persistent (NHLBI criteria) asthma for at least one year, and a positive skin test reaction to a perennial aeroallergen. In all trials, Xolair dosing was based on body weight and baseline serum total IgE concentration. All patients were required to have a baseline IgE between 30 and 700 IU/mL and body weight not more than 150 kg. Patients were treated according to a dosing table to administer at least 0.016 mg/kg/IU (IgE/mL) of Xolair or a matching volume of placebo over each 4-week period. The maximum Xolair dose per 4 weeks was 750 mg.

In all three trials an exacerbation was defined as a worsening of asthma that required treatment with systemic corticosteroids or a doubling of the baseline ICS dose. Most exacerbations were managed in the out-patient setting and the majority were treated with systemic steroids. Hospitalization rates were not significantly different between Xolair and placebo-treated patients; however, the overall hospitalization rate was small. Among those patients who experienced an exacerbation, the distribution of exacerbation severity was similar between treatment groups.

Asthma Studies 1 and 2

At screening, patients in Asthma Studies 1 and 2 had a forced expiratory volume in one second (FEV1) between 40% and 80% predicted. All patients had a FEV1 improvement of at least 12% following beta2-agonist administration. All patients were symptomatic and were being treated with inhaled corticosteroids (ICS) and short acting beta2-agonists. Patients receiving other concomitant controller medications were excluded, and initiation of additional controller medications while on study was prohibited. Patients currently smoking were excluded.

Each study was comprised of a run-in period to achieve a stable conversion to a common ICS (beclomethasone dipropionate), followed by randomization to Xolair or placebo. Patients received Xolair for 16 weeks with an unchanged corticosteroid dose unless an acute exacerbation necessitated an increase. Patients then entered an ICS reduction phase of 12 weeks during which ICS dose reduction was attempted in a step-wise manner.

The distribution of the number of asthma exacerbations per patient in each group during a study was analyzed separately for the stable steroid and steroid-reduction periods.

In both Asthma Studies 1 and 2 the number of exacerbations per patient was reduced in patients treated with Xolair compared with placebo (Table 6).

Measures of airflow (FEV1) and asthma symptoms were also evaluated in these studies. The clinical relevance of the treatment-associated differences is unknown. Results from the stable steroid phase Asthma Study 1 are shown in Table 7. Results from the stable steroid phase of Asthma Study 2 and the steroid reduction phases of both Asthma Studies 1 and 2 were similar to those presented in Table 7.

Table 6 : Frequency of Asthma Exacerbations per Patient by Phase in Studies 1 and 2

Stable Steroid Phase (16 wks)
Exacerbations per patient Asthma Study 1 Asthma Study 2
Xolair
N = 268 (%)
Placebo
N = 257 (%)
Xolair
N = 274 (%)
Placebo
N=272 (%)
0 85.8 76.7 87.6 69.9
1 11.9 16.7 11.3 25
≥ 2 2.2 6.6 1.1 5.1
p-Value 0.005 < 0.001
Mean number exacerbations/patient 0.2 0.3 0.1 0.4
Steroid Reduction Phase (12 wks)
Exacerbations per patient Xolair
N = 268 (%)
Placebo
N = 257 (%)
Xolair
N = 274 (%)
Placebo
N=272 (%)
0 78.7 67.7 83.9 70.2
1 19 28.4 14.2 26.1
≥ 2 2.2 3.9 1.8 3.7
p-Value 0.004 < 0.001
Mean number exacerbations/patient 0.2 0.4 0.2 0.3

Table 7: Asthma Symptoms and Pulmonary Function During Stable Steroid Phase of Study 1

Endpoint Xolair
N=268a
Placebo
N = 257a
Mean Baseline Median Change (Baseline to Wk 16) Mean Baseline Median Change (Baseline to Wk 16)
Total asthma symptom score 4.3 -1.5b 4.2 -1.1b
  Nocturnal asthma score 1.2 -0.4b 1.1 -0.2b
  Daytime asthma score 2.3 -0.9b 2.3 -0.6b
FEV1 % predicted 68 3b 68 0b
Asthma symptom scale: total score from 0 (least) to 9 (most); nocturnal and daytime scores from 0 (least) to 4 (most symptoms).
a Number of patients available for analysis ranges 255-258 in the Xolair group and 238-239 in the placebo group.
b Comparison of Xolair versus placebo (p < 0.05).

Asthma Study 3

In Asthma Study 3, there was no restriction on screening FEV1, and unlike Asthma Studies 1 and 2, long-acting beta2-agonists were allowed. Patients were receiving at least 1000 Mg/day fluticasone propionate and a subset was also receiving oral corticosteroids. Patients receiving other concomitant controller medications were excluded, and initiation of additional controller medications while on study was prohibited. Patients currently smoking were excluded.

The study was comprised of a run-in period to achieve a stable conversion to a common ICS (fluticasone propionate), followed by randomization to Xolair or placebo. Patients were stratified by use of ICS-only or ICS with concomitant use of oral steroids. Patients received Xolair for 16 weeks with an unchanged corticosteroid dose unless an acute exacerbation necessitated an increase. Patients then entered an ICS reduction phase of 16 weeks during which ICS or oral steroid dose reduction was attempted in a step-wise manner.

The number of exacerbations in patients treated with Xolair was similar to that in placebotreated patients (Table 8). The absence of an observed treatment effect may be related to differences in the patient population compared with Asthma Studies 1 and 2, study sample size, or other factors.

Table 8: Percentage of Patients with Asthma Exacerbations by Subgroup and Phase in Study 3

Stable Steroid Phase (16 wks)
Inhaled Only Oral + Inhaled
Xolair
N = 126
Placebo
N = 120
Xolair
N = 50
Placebo
N=45
% Patients with ≥ 1 exacerbations 15.9 15 32 22.2
Difference (95% CI) 0.9 (-9.7, 13.7) 9.8 (-10.5, 31.4)
Steroid Reduction Phase (16 wks)
Xolair
N = 126
Placebo
N = 120
Xolair
N = 50
Placebo
N=45
% Patients with ≥ 1 exacerbations 22.2 26.7 42 42.2
Difference(95% CI) -4.4 (-17.6, 7.4) -0.2 (-22.4, 20.1)

In all three of the studies, a reduction of asthma exacerbations was not observed in the Xolair-treated patients who had FEV1 > 80% at the time of randomization. Reductions in exacerbations were not seen in patients who required oral steroids as maintenance therapy.

Pediatric Patients 6 to < 12 Years of Age

Clinical studies with Xolair in pediatric patients 6 to 11 years of age have been conducted [see Use in Specific Populations]

Pediatric Patients < 6 Years of Age

Clinical studies with Xolair in pediatric patients less than 6 years of age have not been conducted [see Use In Specific Populations]

Chronic Idiopathic Urticaria

Adult and Adolescent Patients 12 Years of Age and Older

The safety and efficacy of Xolair for the treatment of CIU was assessed in two placebocontrolled, multiple-dose clinical studies of 24 weeks' duration (CIU Study 1; n= 319) and 12 weeks' duration (CIU Study 2; n=322). Patients received Xolair 75, 150, or 300 mg or placebo by SC injection every 4 weeks in addition to their baseline level of H1 antihistamine therapy for 24 or 12 weeks, followed by a 16-week washout observation period. A total of 640 patients (165 males, 475 females) were included for the efficacy analyses. Most patients were white (84%) and the median age was 42 years (range 12-72).

Disease severity was measured by a weekly urticaria activity score (UAS7, range 0-42), which is a composite of the weekly itch severity score (range 0-21) and the weekly hive count score (range 0-21). All patients were required to have a UAS7 of ≥ 16, and a weekly itch severity score of ≥ 8 for the 7 days prior to randomization, despite having used an H1 antihistamine for at least 2 weeks.

The mean weekly itch severity scores at baseline were fairly balanced across treatment groups and ranged between 13.7 and 14.5 despite use of an H1 antihistamine at an approved dose. The reported median durations of CIU at enrollment across treatment groups were between 2.5 and 3.9 years (with an overall subject-level range of 0.5 to 66.4 years).

In both CIU Studies 1 and 2, patients who received Xolair 150 mg or 300 mg had greater decreases from baseline in weekly itch severity scores and weekly hive count scores than placebo at Week 12. Representative results from CIU Study 1 are shown (Table 9); similar results were observed in CIU Study 2. The 75-mg dose did not demonstrate consistent evidence of efficacy and is not approved for use.

Table 9: Change from Baseline to Week 12 in Weekly Itch Severity Score and Weekly Hive Count Score in CIU Study 1a

  Xolair 150mg Xolair 300mg
Xolair 75mg Placebo
n 77 80 81 80
Weekly Itch Severity Score
Mean Baseline Score (SD) 14.5 (3.6) 14.1 (3.8) 14.2 (3.3) 14.4 (3.5)
  Mean Change Week 12(SD) -6.46 (6.14) -6.66 (6.28) -9.40 (5.73) -3.63 (5.22)
Difference in LS means vs.placebo -2.96 -2.95 -5.8
  95% CI for difference -4.71, -1.21 -4.72, -1.18 -7.49, -4.10 -
Weekly Hive Count Score b
Mean Baseline Score (SD) 17.2 (4.2) 16.2 (4.6) 17.1 (3.8) 16.7 (4.4)
  Mean Change Week 12(SD) -7.36 (7.52) -7.78 (7.08) -11.35 (7.25) -4.37 (6.60)
Difference in LS means vs.placebo -2.75 -3.44 -6.93
  95% CI for difference -4.95, -0.54 -5.57, -1.32 -9.10, -4.76 -
a Modified intent-to-treat (mITT) population: all patients who were randomized and received at least one dose of study medication.
b Score measured on a range of 0-21

The mean weekly itch severity score at each study week by treatment groups is shown in Figure 1. Representative results from CIU Study 1 are shown; similar results were observed in CIU Study 2. The appropriate duration of therapy for CIU with Xolair has not been determined.

Figure 1 : Mean Weekly Itch Severity Score by Treatment Group Modified Intent to Treat Patients

Mean Weekly Itch Severity Score - Illustration

In CIU Study 1, a larger proportion of patients treated with Xolair 300 mg (36%) reported no itch and no hives (UAS7=0) at Week 12 compared to patients treated with Xolair 150 mg (15%), Xolair 75 mg (12%), and placebo group (9%). Similar results were observed in CIU Study 2.

Last reviewed on RxList: 4/10/2014
This monograph has been modified to include the generic and brand name in many instances.

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