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Figure 8 Reduction in asthma exacerbations with omalizumab treatment: pivotal phase III studies (60-62). Patients received either omalizumab (0.016mg/kg/IU/ mL) or placebo for 16 weeks. Exacerbation was defined as worsening of asthma requiring treatment with oral or I.V. corticosteroids or doubling of baseline beclo-methasone dipropionate dose.

Busse W, et al. Soler M, et al. Milgrom H, et al. 200160 200161 200162

Figure 8 Reduction in asthma exacerbations with omalizumab treatment: pivotal phase III studies (60-62). Patients received either omalizumab (0.016mg/kg/IU/ mL) or placebo for 16 weeks. Exacerbation was defined as worsening of asthma requiring treatment with oral or I.V. corticosteroids or doubling of baseline beclo-methasone dipropionate dose.

Busse W, et al. Soler M, et al. Milgrom H, et al 200160 200161 200182

Busse W, et al. Soler M, et al. Milgrom H, et al 200160 200161 200182

Figure 9 Median (%) change in inhaled corticosteroid dose with omalizumab: pivotal phase III studies (60-62). Patients received either omalizumab (0.016 mg/kg/IU/mL) or placebo for 16 weeks.

Figure 9 Median (%) change in inhaled corticosteroid dose with omalizumab: pivotal phase III studies (60-62). Patients received either omalizumab (0.016 mg/kg/IU/mL) or placebo for 16 weeks.

using ICS (33.5% vs. 13.5%, p < 0.001) and remained exacerbation-free (76% vs. 59.4%, p < 0.001), and omalizumab recipients maintained a lower dose of ICS than placebo recipients throughout (p < 0.001).

Asthma-related quality of life (QoL) in the three pivotal studies by Busse (60), Soler (61), and Milgrom (62) was assessed by Finn et al. (65), Buhl et al. (66), and Lemanske et al. (67), respectively. The effect of omalizumab therapy was assessed using the Juniper Asthma Quality of Life Questionnaire (AQLQ) (68) over 52 weeks in adults, and the pediatric AQLQ (PAQLQ) over 28 weeks in children. In adults with moderate to severe asthma (66), progressive improvements throughout the 52 weeks were observed across all four domains of the AQLQ (activities, emotions, symptoms, and exposure) and overall AQLQ, which were significant at the end of each treatment phase versus placebo (all p < 0.05). Juniper et al. have determined that improvements in the AQLQ score of >0.5, 1.0, and 1.5 represented the minimal clinically important difference, a moderate change, and alarge change in QoL, respectively (69). The proportion ofpatients achieving large improvements in AQLQ (increase in overall score >1.5 points from baseline) was significantly higher in omalizumab recipients than placebo recipients in all domains, except exposure, and overall at the end of the steroid-reduction phase. Results in the Finn assessment (65) were similar, with omalizumab recipients showing significant improvements in AQLQ domain and overall scores at the end of each phase compared to placebo (p < 0.05

for all changes, apart from the emotions domain at the end of the extension phase). In addition to the statistical analysis, more omalizumab recipients showed clinically relevant improvements [defined as an increase in AQLQ >0.5 points from baseline (69)] than placebo recipients in all domains at the end of the steroid-stable and extension phases (p < 0.05). In pediatric patients with allergic asthma well controlled by daily ICS (67), at the end of both the 16-week steroid-stable phase and the 12-week steroid-reduction phase, PAQLQ scores improved across all domains, except emotions, and overall in the omalizumab recipients versus placebo recipients at the end of the steroid-reduction phase (p < 0.05). Again, the proportion of patients achieving clinically relevant [>0.5 points (69)] or large [>1.5 points (69)] improvements was greater in the omalizumab group than in the placebo group, and significantly so in the activities domain and overall at the end of steroid reduction. These studies have shown that the reduction in asthma exacerbations seen with omalizumab treatment correlates with improvements in QoL.

Asthma exacerbations are potentially life-threatening episodes of acute airways inflammation, and hospitalization resulting from exacerbations constitutes the greatest cost to the health care system for asthma. In patients with allergic asthma, exacerbation reduction is one of the most important goals of management (70), particularly for patients with severe asthma. To determine the effect of long-term omalizumab therapy on the rate of serious exacerbations, data from the three phase-III pivotal studies (60-62) were pooled and analyzed (71). The rates of unscheduled, asthma-related outpatient visits (rate ratio 0.60, p < 0.01) and emergency room visits (rate ratio 0.47, p < 0.05) were lower for omalizumab-treated patients versus patients receiving placebo, and hospitalizations were markedly reduced from 3.42 events per 100 patient years on placebo treatment to 0.26 on omalizumab treatment (rate ratio 0.08, p < 0.01).

Following the three pivotal studies in moderate to severe asthma, a study focusing on patients with severe asthma evaluated the efficacy of omalizumab as add-on therapy (72). This multicenter, randomized, double-blind, and placebo-controlled study included 146 patients (aged 12 to 75 years) who required >1000 mg/day fluticasone to maintain control of their asthma. During a 6- to 10-week run-in, ICS therapies were standardized by switching patients to fluticasone. This was followed by a 32-week double-blind treatment period in which patients received omalizumab [at least 0.016 mg/kg/ IgE (IU/mL) every four weeks; n = 126] or placebo (n = 120) as add-on therapy, including a 16-week fluticasone-stable period, a 12-week fluticasone-reduction period, and a four-week maintenance period in which patients were maintained on the minimum fluticasone dose for adequate symptom management. Patients receiving omalizumab had a greater reduction in fluticasone dose during the 32-week treatment period than patients receiving placebo (median 60.0% vs. 50.0%, p = 0.003), and more patients receiving omalizumab reduced their fluticasone dose by >50% than patients on placebo (73.8% vs. 50.8%, p = 0.001). Despite the reduction in fluticasone dose, there was no loss of control of asthma symptoms with omalizumab. Indeed, patients in the omalizumab group showed improvements in asthma symptom scores (0.9 vs. 1.4) and reduced rescue-medication use (-0.75 vs. 0.1) over placebo at the end of the 32-week steroid-stable period, which were significant at most time points throughout the steroid-stable and steroid-reduction periods (p < 0.05). Likewise, more omalizumab than placebo recipients showed improvements in asthma-related QoL [AQLQ (68)] scores throughout the 32-week treatment period that were clinically relevant (>0.5 points; overall score 57.5% vs. 38.6%, p < 0.001) and large (>1.5 points; overall score 16.0% vs. 5.9%, p < 0.05). The results showed that add-on therapy with omalizumab in patients with severe allergic asthma not only reduced the requirement for ICS, but also improved disease control. This suggests that omalizumab therapy is particularly beneficial for this very severe patient population.

VI. Selecting Patients for Anti-IgE Therapy with Omalizumab

Omalizumab is currently licensed in the United States for the treatment of moderate to severe persistent allergic asthma in patients of 12 years of age or more. Patients are required to have a positive skin test or in vitro IgE reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids. To help identify the place of oma-lizumab in therapy, additional analyses of clinical data from asthma studies have been performed to determine which patients are most likely to benefit from omalizumab therapy.

One such analysis investigated whether patients at high risk of exacerbations and hospitalizations would be likely to benefit. This meta-analysis (73) evaluated three randomized, double-blind, placebo-controlled studies (60,61,72), including a total of 1412 adults and adolescents with moderate to severe asthma requiring daily treatment with ICS. A subgroup of 254 patients [69/525 patients from Busse 2001 (60), 73/546 patients from Soler 2001 (61), and 112/341 patients from Holgate 2001 (72)] was identified as being at high risk of serious asthma-related morbidity or mortality on the basis of baseline asthma history: Patients were identified as high risk if they had ever been intubated before screening, or if they had visited an emergency room, experienced overnight hospitalization, or undergone treatment in an intensive care unit during the year prior to screening. Of the 254 high-risk patients, 135 were treated with omalizumab and 119 received placebo. The primary outcome measure was the annualized rate of significant asthma exacerbation episodes in the 16-week steroid-stable phase. Significant asthma exacerbation episodes were defined as exacerbations that required a doubling of baseline ICS dose (60,61) or use of systemic corticosteroids (in all three studies).

The significant asthma exacerbation rate in the steroid-stable phase was more than halved in the omalizumab group to 0.69 per patient year compared with 1.56 in the placebo group (p = 0.007). This translated into prevention of 87 significant asthma exacerbations for every 100 patients treated with omalizumab for one year. In addition, the proportion of patients with at least one significant asthma exacerbation during this phase was reduced to 18% with omalizumab compared with 35% with placebo. Although most patients experiencing significant asthma exacerbations experienced only a single significant asthma exacerbation, fewer patients receiving omalizumab experienced multiple significant asthma exacerbations. Likewise, over the whole 32-week study period, the significant asthma exacerbation rate decreased to 0.92 from 2.04 (omalizumab vs. placebo, p < 0.001) and the proportion of patients with at least one significant asthma exacerbation decreased to 44% from 66% (omalizumab vs. placebo). On the basis of these results, it was estimated that omalizumab would prevent significant asthma exacerbations in 17 patients of every 100 treated during stable ICS treatment, and in 22 of every 100 treated in the entire 32-week study. This corresponds to a number needed to treat (NNT) of 5.7 or 4.6 patients to maintain one patient free of significant asthma exacerbations (steroid-stable phase or whole study period, respectively).

Another analysis was used to determine which patient characteristics are associated with a response to omalizumab. This was a pooled exploratory analysis (74) of the two adult pivotal studies (60,61). Among the participants in these two studies were 1070 poorly controlled patients, who were symptomatic despite therapy with moderate to high doses of ICS (mean dose 725 mg/day BDP) or who had a history of emergency asthma treatment in the last year. Of these, 542 received omalizumab and 528 received placebo over a 16-week period. The factor most predictive of best response on treatment with omalizumab was a history of emergency asthma treatment in the preceding year: The response rate in patients with this history was 67% with omalizumab and 42% with placebo, versus 63% and 54%, respectively, in patients without (p = 0.015). High dose of ICS (>800mg/ day) was also predictive: Response rates were 65% with omalizumab and 40% with placebo in patients receiving high-dose ICS versus 63% and 55%, respectively, in patients receiving lower-dose ICS (p = 0.037). Low FEV1 (<65% predicted) was suggestive of a response: Response rates were 60% with omalizumab and 40% with placebo in patients with low FEV1 versus 67% and 53%, respectively, in patients with high FEV1 (p = 0.072). Patients with at least one of these factors showed odds of responding that were 2.25 times higher than placebo (95% CI; 1.68-3.01). These results suggest that omalizumab treatment is most likely to benefit patients with severe, poorly controlled asthma.

The same analysis (74) also evaluated the time taken for patients to respond to omalizumab therapy and how this related to the eventual response at study end (16 weeks). Of the patients who responded at 16 weeks, 61% had responded as early as four weeks after initiation of therapy, while the figure increased to 87% at 12 weeks. These findings support a minimum duration of treatment of 12 weeks as add-on therapy with omalizumab before deciding whether to continue therapy.

The efficacy of add-on therapy with omalizumab in a poorly controlled subpopulation of patients has since been confirmed in a "real-life" clinical setting by Ayres et al. (75). Patients enrolled in this randomized, open-label, multicenter, parallel-group study had moderate to severe asthma that was poorly controlled by current asthma therapies, prescribed according to best standard care (BSC). BSC included ICS and long-acting p2-agonists (LABAs). The study included adults and adolescents receiving high-dose ICS (BDP or equivalent >800 mg/day adults, >400 mg/day adolescents). Poor control was defined as >1 emergency room visit or hospitalization and >1 additional course of oral corticosteroids for asthma in the year preceding the study. The primary efficacy variable was the annualized mean number of asthma-deterioration-related incidents (ADRIs) recorded in patient daily diaries and defined as at least one of the following events due to asthma: course of systemic corticosteroids or antibiotics for >2 days, >2 missed school or work days, unscheduled physician visit, hospitalization or emergency room visit. Of 312 patients enrolled, 38.8% were receiving a daily dose of 2000 mg BDP, 30.1% a daily dose of 1000 mg BDP, and 16.0% a daily dose of 4000 mg BDP at baseline. In addition, 77.9% of patients were receiving concomitant LABAs, and 21.2% were receiving systemic corticosteroids at baseline. The 206 patients randomized to receive BSC with omalizumab experienced a reduced ADRI rate compared with the 106 patients receiving BSC alone (4.92 vs. 9.76 per patient year, p < 0.001). The asthma exacerbation rate decreased with omalizumab (2.86 placebo vs. 1.12 omalizumab per patient year, p < 0.001); the significant reduction in asthma exacerbations with omalizumab therapy was not affected by concomitant medication with LABAs or anti-leukotrienes (Fig. 10). Compared with BSC alone, add-on therapy with omalizumab also increased the proportion of patients requiring less than one day per week of rescue medication (20.7% vs. 41.4%, p < 0.001), improved FEV1 (2.28 vs. 2.48 L, p = 0.02), and reduced symptom scores (-0.7 vs. -6.5, p < 0.001). In addition, omalizumab decreased the mean asthma exacerbation rate irrespective of the concomitant asthma medications used (such as LABAs).

Current guidelines recommend the use of LABAs in addition to ICS therapy for the long-term preventive management of step 3 (moderate persistent) and 4 (severe persistent) asthma in adults and children over five years old (70). Given this widespread LABA use, it is important to evaluate the added benefits of omalizumab alongside concomitant LABA medication.

Figure 10 The effect of concomitant asthma medications on relative asthma exacerbation rates in patients with poorly controlled moderate to severe asthma receiving omalizumab therapy. Source: From Ref. 75.

In the Ayres study, above (75), a similar proportion (78%) of patients in the omalizumab and BSC groups were receiving LABAs. The reduction in exacerbation rate with omalizumab was similar whether patients were also receiving LABAs or not: Rate ratios with LABAs versus without LABAs were 0.41 versus 0.35. Similarly, leukotriene-modifying agents and oral steroids did not affect the efficacy of omalizumab. These results suggest that the benefits of omalizumab are independent of concomitant medication use.

Taken together, the results from these studies indicate that patients benefiting most from omalizumab add-on therapy are those high-risk patients with more severe disease whose asthma is poorly controlled despite the best available therapies. This corresponds to a considerable burden, as the overall rate of asthma-related hospitalizations is considerable [19.5 per 10,000 population in the United States in 1995 with an average stay length of 3.7 days (76)]. In these patients, omalizumab has the potential to substantially improve disease control and symptoms.

To confirm this, a multicenter, randomized, double-blind, and placebo-controlled, parallel-group trial is currently in progress to evaluate the efficacy of add-on therapy with omalizumab in adults and adolescents with poorly controlled severe persistent allergic asthma. A total of420 patients with serious symptoms of allergic asthma (frequent asthma exacerbations) who were inadequately controlled by GINA step 4 treatment [high-dose ICS (BDP > 1000 mg/day), long-acting |b2-agonists, and other concomitant asthma therapy, including oral corticosteroids] were randomized. Exacerbation rates, asthma symptoms, QoL, and lung function will be studied over the 28-week double-blind treatment period to provide information regarding the efficacy of omalizumab in this most severe asthma population that, despite all available therapies, continues to be poorly controlled and experience frequent asthma exacerbations.

VII. Studies in Other IgE-Mediated Allergies

Although allergic asthma is an extremely prevalent condition, globally affecting 100 to 150 million people (77), other IgE-mediated reactions are also major public health concerns. These include intermittent allergic rhinitis, which can be seasonal (SAR), persistent allergic rhinitis (PAR), latex allergy, and peanut- and tree-nut-induced anaphylaxis. These diseases often coexist (78) and have many pathophysiological features in common. Indeed, concomitant rhinitis is linked with more severe asthma, and in a retrospective study in 4944 patients with allergic asthma, patients treated for allergic rhinitis had approximately half the risk of subsequent asthma-related hospitalizations or emergency room visits (p = 0.001) (79). It seems likely, therefore, that appropriate treatment of one disease may confer improvements in the other.

In the United States alone, approximately 40 million people have SAR (80), while PAR affects 20 to 40 million people (81). SAR and PAR are characterized by ocular and nasal symptoms that can have a considerable detrimental effect on patients' QoL (82). Omalizumab has been shown to be effective in the treatment of both conditions. In an eight-week randomized, double-blind, and placebo-controlled trial in 251 adult patients with a history of SAR, average daily nasal symptom severity scores were unchanged throughout treatment during the pollen season in patients receiving omalizumab (0.71 at baseline vs. 0.70 overall), while they increased in placebo recipients (0.78 at baseline vs. 0.98 overall) (p < 0.001) (83). Average daily ocular symptom severity scores decreased from baseline (0.47 vs. 0.43), in contrast to an increase in placebo recipients (0.43 vs. 0.54) (p = 0.031). The average number of tablets of rescue antihistamine taken per day (0.59 vs. 1.37) and the proportion of days on which rescue medication was taken (49% vs. 28%) was lower in the omalizumab group versus placebo (both p < 0.001). QoL was improved in the omalizumab group versus placebo for all domains of the rhinitis quality of life questionnaire (RQLQ) (84), as well as the total score, and clinically relevant improvements [>0.05 units (85)] were observed in total score and the four domains of activities, nasal symptoms, non-nose-eye symptoms, and practical problems. Patients' assessments of treatment effectiveness favored omalizumab over placebo (p = 0.001).

A 12-week multicenter, randomized, double-blind, and dose-ranging, placebo-controlled trial was conducted in 536 patients aged 12 to 75 years with a history of moderate to severe ragweed-induced SAR (86). Patients received 50, 150, or 300 mg omalizumab or placebo subcutaneously every three to four weeks, depending on baseline IgE levels. Nasal symptoms were less severe in patients receiving the 300 mg dose of omalizumab than in the placebo group (p = 0.002). The reduction in nasal symptoms correlated with reductions in IgE [<50ng/mL, 20.8 IU/mL (59)] and rescue antihistamine use (all p < 0.05), and rescue antihistamine use was reduced in the 300 mg dose group compared with placebo (p = 0.005). In addition, RQLQ scores were consistently improved across the domains in patients receiving the 300 mg dose of omalizumab compared with placebo (p < 0.05 for activities, sleep, non-nasal and emotions domains, and overall).

A 16-week, randomized, double-blind, placebo-controlled trial of omalizumab in 289 adults and adolescents (aged 12 to 70 years) demonstrated its efficacy in moderate to severe symptomatic PAR (87). A dose of at least 0.016 mg/kg/IgE (IU/mL) per four weeks reduced average daily nasal severity scores throughout treatment versus placebo (p < 0.001). Again, average rescue-antihistamine use and proportion of days on which it was taken were both lower in the omalizumab group (both p < 0.005). Patients randomized to omalizumab experienced greater improvements in rhinoconjunctivitis-specific quality of life (RQoL) scores, and patients' global evaluation of treatment efficacy favored omalizumab versus placebo (p < 0.001).

Concomitant asthma and rhinitis is common and correlates with more severe asthma (79). The efficacy of omalizumab in a comorbid population of patients with asthma and rhinitis was investigated in a 28-week, multicenter, randomized, double-blind, and parallel group, placebo-controlled trial (88). A total of 405 adults and adolescents with concomitant moderate to severe allergic asthma (history of at least one year) and moderate to severe persistent PAR (history of at least two years) receiving moderate- to high-dose ICS (BDP > 400mg/day) were randomized. The coprimary efficacy variables were the incidence of asthma exacerbations during the 28-week treatment period and the proportion of patients who responded to treatment with a >1.0 point improvement in both asthma and rhinitis QoL scores. Omalizumab was given to 209 patients as add-on therapy to existing treatment regimens and placebo to 196. Omalizumab reduced the incidence of asthma exacerbations compared with placebo (20.6% patients vs. 30.1%, respectively, p = 0.02), and resulted in more responders (>1.0 point improvement in both AQLQ and RQLQ scores) than placebo (57.7% vs. 40.6%, p < 0.001). Omalizumab treatment also improved total Wasserfallen symptom scores for asthma (treatment difference -1.8, p = 0.023), and rhinitis (-3.53, p < 0.001) compared with placebo. Exacerbation rates were similar in patients receiving and not receiving LABAs. These results show that, in patients with concomitant asthma and rhinitis, omalizumab is effective in reducing symptoms of both diseases when added to standard asthma and rhinitis therapies. These results are consistent with previous suggestions that coordinated management of asthma and rhinitis achieves optimal disease control. As both diseases share the common mechanism of IgE-mediated immune pathology, anti-IgE therapy is of particular benefit in comorbid patients.

In addition to treating rhinitis, omalizumab has demonstrated potential efficacy in the treatment of other IgE-mediated allergic diseases. Latex allergy primarily affects health care workers because they are frequently exposed to latex gloves and other latex-containing medical supplies. Their exposure to latex is ongoing and product avoidance is difficult. Symptoms may be local and/or systemic and include debilitating conjunctivitis, rhinitis, urticaria, and bronchospasm in addition to anaphylaxis. Prevalence among health care workers as high as 17% has been reported (89), but more representative figures today would be 5% to 10%. A 16-week, randomized, placebo-controlled trial evaluated the efficacy of omalizumab in 18 health care workers with latex allergy (90). The primary efficacy variable was the conjunctival challenge test score and all participants had a positive test score at baseline. Participants receiving omalizumab (150-750 mg/mo according to body weight and total serum IgE) showed improvements in conjunctival test scores at the end of the study compared with placebo (p = 0.019). Placebo recipients subsequently treated with open-label omalizumab also had improved scores. Anti-IgE is a promising strategy for latex allergy and further studies are required.

Peanut- and tree-nut-induced anaphylaxis is potentially life threatening. It is estimated to affect 1.5 million people in Britain (91) and about three million Americans (92). The prevalence in developed countries is estimated as 0.6% to 1.0% (93). Peanut avoidance can be impracticable in the current era of convenience foods and supermarket food shopping. As peanut-induced anaphylaxis is mediated by IgE, prophylactic treatment with an anti-IgE antibody could protect sufferers from anaphylaxis. A 20-week, randomized, double-blind, placebo-controlled, dose-ranging study of a humanized anti-IgE IgG1 monoclonal antibody (very similar to omalizumab) was conducted in 84 patients with a history of immediate hypersensitivity to peanut (94). Patients received placebo, 150, 300, or 450 mg of the antibody subcutaneously every four weeks, and underwent a final oral food challenge four weeks after the last dose and a final evaluation at week 20. In patients receiving 450 mg doses, the mean threshold of sensitivity to peanut at the final oral food challenge increased from a baseline of 178 mg (equivalent to approximately half a peanut) in a dose-responsive manner to a maximum of 2805 mg (equivalent to approximately nine peanuts) (p < 0.001). These results suggest that anti-IgE therapy could be a beneficial new treatment option for patients with this life-threatening condition.

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