Benefits Shown for Omalizumab in Uncontrolled Asthma

Caroline Helwick

May 20, 2010

May 20, 2010 (New Orleans, Louisiana) — As add-on therapy to standard treatment, the monoclonal antibody omalizumab significantly reduced exacerbations in patients with moderate to severe allergic asthma. Omalizumab also improved asthma-related quality of life, according to a phase 3b randomized controlled trial presented here at the American Thoracic Society 2010 International Conference.

"The addition of omalizumab to patients at steps 5 and 6 of asthma care reduced risks and improved asthma-related quality of life," reported William W. Busse, MD, from the University of Wisconsin, Madison, in a late-breaking presentation.

In other studies reported at the meeting, omalizumab was effective over 7 years of use, and was associated with a reduction in healthcare use.

Efficacy Validated in Phase 3b Study

The phase 3b study consisted of 850 patients with moderate to severe asthma, defined as the occurrence of at least 1 asthma exacerbation in the previous year, despite treatment with high-dose inhaled corticosteroids (HDIC) and a long-acting beta-agonist. Nearly two thirds of patients also used a third controller medication, including chronic oral corticosteroids.

Patients on stable HDIC and a long-acting beta-agonist (and additional controllers if necessary) were randomized to receive omalizumab for 48 weeks or placebo, and were then assessed monthly. Omalizumab 150 to 375 mg was given subcutaneously every 2 to 4 weeks; dosage and frequency were determined by baseline serum total immunoglobulin E and body weight.

The primary outcome was rate of asthma exacerbations during the 48 weeks of omalizumab treatment requiring systemic corticosteroids for at least 3 days or at least a 20-mg increase in oral corticosteroids over baseline for at least 3 days. Secondary outcomes were asthma symptom scores, number of puffs of rescue medication, and asthma-related quality of life.

The groups were similar with regard to demographics. Mean age was approximately 45 years, mean duration of asthma was 24 years, mean percent predicted forced expiratory volume in 1 second was 65%, the mean number of exacerbations in the previous year was 2, and about 10% had been hospitalized for asthma in the previous year. About one third were receiving only HDIC and a long-acting beta-agonist, nearly half needed another controller (excluding oral corticosteroids), and 17% required at least 4 oral corticosteroid courses in 12 months.

At the end of 48 weeks, approximately 80% of the placebo group and approximately 85% of the omalizumab group remained in the study.

Exacerbations Reduced by 25% With Omalizumab

At 48 weeks, the omalizumab group demonstrated a 25% reduction in exacerbations, compared with placebo. The protocol-defined exacerbation rates were 0.66% and 0.88%, respectively (P = .0058), Dr. Busse reported.

Time to first asthma exacerbation was also significantly delayed with omalizumab (P < .05). Treatment benefit was seen in all patients except those requiring oral corticosteroids (P = .79).

Patients receiving omalizumab also experienced a statistically significant improvement in Asthma Quality of Life Questionnaire scores, with significantly greater changes observed over baseline at all time points (P < .01). Mean change overall was 1.0 for placebo and 1.2 for omalizumab (P = .0047), he reported.

A reduction in the need for rescue medication was observed in both groups, but was significantly greater in patients receiving omalizumab (P = .0904). Change in total asthma symptoms score was also significantly greater with omalizumab (= .0379).

In an exploratory analysis, the addition of omalizumab was associated with significant reductions in the fractional concentration of exhaled nitric oxide, a marker of inflammation in asthma, Dr. Busse added.

Adverse events occurred in 79.5% of the placebo group and 80.4% of the omalizumab group, with serious adverse events reported in 10% and 9.3%, respectively. There was no difference in the occurrence of acute-phase reactions or thrombocytopenia.

The current standard of care for moderate to severe asthma that is inadequately controlled by inhaled corticosteroids is the addition of a long-acting beta-agonist and/or another controller medication. In this study, when patients remained refractory, they were allowed to receive chronic oral corticosteroids "as a last resort," Dr. Busse told the media.

Use of omalizumab (and US Food and Drug Administration approval) has been restricted to severe disease, primarily because of cost concerns, he explained. "As a consequence, it has been studied in patients with the most exacerbations, hospitalizations, and so forth — the group at greatest risk." He estimated that at least 20% of asthma patients fall into this category.

The findings "validate the current treatment recommendations" of the National Heart, Lung and Blood Institute Expert Panel Report 3 (NHLBI EPR-3), he said, which are that patients at steps 5 and 6 of asthma care who remain symptomatic might benefit from omalizumab add-on therapy.

Long-Term Benefit, Reduction in Healthcare Use

At a poster discussion session, Swiss investigators reported that long-term use of omalizumab was safe and effective, according to a study of 7 severe corticosteroid-dependent asthmatics who received the drug for 7 years. Omalizumab reduced asthma exacerbations and the use of antibiotics, aerosol therapy, and oral corticosteroids, with the effects most evident after 4 years of use. Once patients discontinued the drug, however, the beneficial immunomodulatory effects disappeared, according to investigators from the Dutch Asthma Centre in Davos, Switzerland.

Investigators from Poland conducted a randomized open-label study of 404 patients and found a 67% reduction in the rate of hospitalizations for exacerbations (P = .037), a 60% reduction in visits to the emergency department (P < .001), and shorter hospitalizations (P = .007).

Paul O'Byrne, MD, from McMaster University in Hamilton, Ontario, who is chair of the Global Initiative for Asthma, commented on these findings for Medscape Pulmonary Medicine. "We are now getting long-term efficacy and safety data for omalizumab, which is showing it to be very effective and safe," he said, "but we learned today that the immune effects are not permanently altered, as we had hoped they would be. When you stop the drug, they come back."

"Because of its expense, in most countries, [the use of] omalizumab has been very clearly limited to the severe end of the spectrum, that is, patients whose disease carries a large healthcare cost," he continued. "In this population, there is evidence of clear benefit and, at the most extreme end, the cost-benefit studies show justification for its use."

Dr. Busse’s trial was supported by Genentech, Inc. The Polish study was supported by Novartis. Dr. Busse reports receiving grant support and consulting fees from Novartis. Dr. O'Byrne has disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2010 International Conference: Abstract A5405. Presented May 19, 2010.

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