Omalizumab

Omalizumab, a monoclonal antibody that targets circulating IgE, is approved as add-on therapy for adult and adolescent patients with severe allergic asthma in the EU and moderate to severe allergic asthma in the US. Several randomized, double-blind trials have demonstrated the therapeutic efficacy of subcutaneously administered omalizumab as add-on therapy in patients with allergic asthma. The INNOVATE study included only patients with severe persistent disease, and omalizumab was associated with a statistically significant relative reduction of 26% in the rate of clinically significant asthma exacerbations (primary endpoint) compared with placebo (after adjustment for an imbalance in the exacerbation history at baseline). Results for a number of secondary outcomes also significantly favored omalizumab over placebo. Two large studies in patients with moderate to severe allergic asthma showed that, compared with placebo, omalizumab was associated with statistically significant relative reductions of 41–58% in the mean number of asthma exacerbations (primary endpoint) during the trial. Omalizumab also significantly reduced asthma symptom scores and the use of inhaled corticosteroids and rescue medication. Moreover, all of these trials showed that omalizumab was associated with clinically and statistically significant improvements from baseline in overall asthma-related quality of life.

In general, omalizumab was well tolerated in clinical trials. Most adverse events were mild or moderate in severity and occurred at a similar frequency among omalizumab and placebo recipients. Injection-site reactions were the most commonly reported adverse events in clinical trials with omalizumab. Although rare, anaphylactic reactions have occurred following administration of omalizumab, and appropriate precautions should be taken.

Results of several large randomized trials, therefore, have established omalizumab as an effective and well tolerated agent for use as add-on therapy in patients with severe persistent allergic asthma (EU labeling) or those with moderate to severe disease (US labeling). In addition, international treatment guidelines acknowledge the importance of omalizumab as a treatment option in these difficult-to-treat patient populations.

Omalizumab is a humanized IgG monoclonal antibody that improves the control of allergic asthma by binding to the Cε3 domain of free IgE, thereby inhibiting the binding of IgE to the surface of mast cells and basophils, reducing the release of inflammatory mediators. In patients with moderate to severe allergic asthma, treatment with omalizumab for ≈6 months decreased serum free IgE levels by 89–99% from baseline.

Subcutaneously administered omalizumab has a mean absolute bioavailability of 62%. Absorption into the systemic circulation is slow, with peak serum concentrations achieved after a mean of 7–8 days. Omalizumab exhibits linear pharmacokinetics at approved dosage regimens. IgG clearance processes, as well as specific binding and complex formation with IgE, are involved in omalizumab clearance. The mean elimination half-life of omalizumab is 26 days.

The clinical efficacy of subcutaneously administered omalizumab as add-on therapy in patients with allergic asthma has been demonstrated in several well designed trials. The 28-week, randomized, double-blind INNOVATE study in patients with severe persistent disease showed a statistically significant relative reduction of 26% in the rate of clinically significant asthma exacerbations (primary endpoint) with omalizumab compared with placebo (after adjustment for an imbalance in exacerbation history at baseline). Results for a number of secondary outcomes, including reduction in the rate of severe exacerbations and improvement in Asthma Quality of Life Questionnaire (AQLQ) scores, also significantly favored omalizumab over placebo.

In two large randomized, double-blind trials in patients with moderate to severe allergic asthma, omalizumab was associated with statistically significant relative reductions of 41–58% compared with placebo in the mean number of asthma exacerbations (primary endpoint) during the 16-week stable-corticosteroid phase and the 12-week corticosteroid-reduction phase of the trials. Both studies also showed that omalizumab significantly reduced asthma symptom scores, inhaled corticosteroid dosage, and rescue medication use compared with placebo. Mean improvement from baseline in overall AQLQ scores was also significantly greater among omalizumab than placebo recipients.

These data are supported by results of a smaller randomized, double-blind trial and a randomized, open-label (naturalistic) study in patients with moderate to severe asthma. In addition, results of the SOLAR trial in patients with concomitant moderate to severe allergic asthma and persistent allergic rhinitis showed significant improvement in the co-primary endpoint of asthma exacerbation rate and asthma- and rhinitis-related quality of life among omalizumab-treated patients compared with those who received placebo.

Omalizumab was generally well tolerated in clinical trials, with most adverse events being mild or moderate in severity and reported with a similar frequency to those in placebo or control groups. The most frequently reported adverse events with omalizumab in clinical trials were injection-site reactions (45%), viral infection (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). Anaphylactic reactions have occurred with omalizumab, usually (but not always) within 2 hours after administration of the first or subsequent doses. Although the incidence of anaphylaxis is low (≈0.1–0.2%), a boxed warning regarding anaphylaxis appears in US prescribing information, and appropriate precautions should be taken.