Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic Omalizumab in Severe Asthma in Adults: Results of the SoMOSA Study

Abstract

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting β-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-β-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.

Figure 1.

Consolidated Standards of Reporting Trials diagram. OCS = oral corticosteroid.

Figure 2.

Urine eicosanoids, 2,3-dinor-11-β-PGF_2α, and LTE₄ (leukotriene E₄). (A) Baseline concentrations of 2,3-dinor-11β-PGF2α (primary outcome) and LTE₄ (pg/ml) in patients defined as responders or nonresponders based on Global Evaluation of Therapeutic Effectiveness score. (B) Changes in concentrations of 2,3-dinor-11-β-PGF_2α and LTE₄ in the entire cohort (responders and nonresponders) from baseline to 16 weeks analyzed by Mann-Whitney U test. (C) Receiver operating characteristic area under the curve for 2,3-dinor-11β-PGF2α in respect to the prediction of early (Global Evaluation of Therapeutic Effectiveness–based) and late (acute exacerbation–based) response to omalizumab. AUC = area under the curve; GETE = Global Evaluation of Therapeutic Effectiveness; OCS = oral corticosteroid.

Figure 3.

Volcano plots of baseline concentrations of all biomarker variables in responders and nonresponders. Responses shown include early response judged by GETE response (A) and late response defined by ⩾50% reduction in exacerbations (B). The red and blue biomarkers (all P < 0.05) are labeled by numbers (see Table E4 for identities). Green and red dots represent greater than onefold different biomarkers. The data are shown as the means of concentrations in the responders from which the means of the concentrations in the nonresponders have been subtracted (i.e., responder minus nonresponder). They are shown as log2-transformed data. The P values were obtained by Mann-Whitney U test. GETE = Global Evaluation of Therapeutic Effectiveness.

Figure 4.

Breath volatile organic compounds (VOCs) and plasma lipids that predict early or late clinical responses. (A) The biomarker identities of the VOCs were derived from the variables detected by gas chromatography–mass spectrometry, whereas the identities of the plasma lipids were derived from the variables detected by ultra–high-performance supercritical fluid chromatography–ion mobility–tandem mass spectrometry. Receiver operating characteristic area under the curve figures show predictions by VOCs (B) and lipids (C) of early clinical responses judged by GETE score and late responses by reduction in asthma exacerbations. See Table E3 for the receiver operating characteristic area under the curve values for the other omics platforms (sputum lipids, sputum proteins, urine proteins, and eicosanoids). AUC = area under the curve; GETE = Global Evaluation of Therapeutic Effectiveness