Rationale: For many patients with asthma, allergic airway inflammation is primarily a Th2-weighted process; however, heterogeneity in patterns of inflammation suggests phenotypic distinctions exist that influence disease presentation and treatment effects.

Objectives: To assess the potential of fractional exhaled nitric oxide (Fe_NO), peripheral blood eosinophil count, and serum periostin as biomarkers of Th2 inflammation and predictors of treatment effects of omalizumab.

Methods: The EXTRA omalizumab study enrolled patients (aged 12–75 yr) with uncontrolled severe persistent allergic asthma. Analyses were performed evaluating treatment effects in relation to Fe_NO, blood eosinophils, and serum periostin at baseline. Patients were divided into low- and high-biomarker subgroups. Treatment effects were evaluated as number of protocol-defined asthma exacerbations during the 48-week treatment period (primary endpoint).

Measurements and Main Results: A total of 850 patients were enrolled. Data were available from 394 (46.4%), 797 (93.8%), and 534 (62.8%) patients for Fe_NO, blood eosinophils, and serum periostin, respectively. After 48 weeks of omalizumab, reductions in protocol-defined exacerbations were greater in high versus low subgroups for all three biomarkers: Fe_NO, 53% (95% confidence interval [CI], 37–70; P = 0.001) versus 16% (95% CI, −32 to 46; P = 0.45); eosinophils, 32% (95% CI, 11–48; P = 0.005) versus 9% (95% CI, −24 to 34; P = 0.54); and periostin, 30% (95% CI, −2 to 51; P = 0.07) versus 3% (95% CI, −43 to 32; P = 0.94).

Conclusions: The difference in exacerbation frequency between omalizumab and placebo was greatest in the three high-biomarker subgroups, probably associated with the greater risk for exacerbations in high subgroups. Additional studies are required to explore the value of these biomarkers in clinical practice.

Clinical trial registered with www.clinicaltrials.gov (NCT00314574).