David F. Choy, BS, Guiquan Jia, MD, Alexander R. Abbas, PhD, Katrina B

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Peripheral blood gene expression predicts clinical benefit from anti–IL-13 in asthma David F. Choy, BS, Guiquan Jia, MD, Alexander R. Abbas, PhD, Katrina B. Morshead, PhD, Nicholas Lewin-Koh, PhD, Rajiv Dua, PhD, Pauline Rivera, MS, Priscilla Moonsamy, BS, Marcel Fontecha, BS, Aarthi Balasubramanyam, MS, Chris Santini, BS, Ekaterina Bassett, PhD, Jill M. Ray, PhD, Christopher R. Cabanski, PhD, Mary S. Bradley, PhD, Romeo Maciuca, PhD, Sofia Mosesova, PhD, Heleen Scheerens, PhD, Joseph R. Arron, MD, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 4, Pages 1230-1233.e8 (October 2016) DOI: 10.1016/j.jaci.2016.06.008 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Discovery of an ERGS. A, Multiple regression of contemporaneously assessed absolute blood eosinophil count (#/μL), adjusted by subject age, with blood gene expression (PAXgene microarrays) was conducted for 298 subjects with moderate-to-severe asthma from the EXTRA study at baseline and is represented by volcano plot; coefficient estimate of blood eosinophil count (β) from multiple regression and −log10 P values are plotted on X and Y axes, respectively. Genes selected for ERGS evaluation are annotated. B, Predictive performance of ERGS genes for eosinophilic airway inflammation (≥3% sputum eosinophils or ≥22 tissue eosinophils/mm2) was assessed by receiver-operating characteristic analysis and compared with serum periostin, and blood eosinophils. Only subjects with complete biomarker data are included in this analysis (n = 50). AUC measures are tabulated in the legend. AUC, Area under the curve. Journal of Allergy and Clinical Immunology 2016 138, 1230-1233.e8DOI: (10.1016/j.jaci.2016.06.008) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Predictive performance of ERGS genes in MILLY and LUTE/VERSE studies of anti–IL-13. Measures of ERGS predictive performance were assessed in MILLY and LUTE/VERSE studies. A, Positive correlations (Spearman ρ) of continuous values of ERGS expression and blood eosinophil count were observed. B, Predictive performance of baseline ERGS expression for enriched clinical benefit from lebrikizumab was assessed. Treatment effect difference (ΔΔFEV1%) as week 12 between dichotomous diagnostic classification of baseline ERGS expression was estimated and compared with reference biomarkers blood eosinophil count and serum periostin. Journal of Allergy and Clinical Immunology 2016 138, 1230-1233.e8DOI: (10.1016/j.jaci.2016.06.008) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Boxplots of blood biomarkers in pediatric and adult patients with asthma in the EXTRA study. A, Serum periostin. B, Blood eosinophil count. Difference in medians (95% CI, Hodges-Lehmann estimator) between less than 18-year-old versus more than 18-year-old subjects is annotated in the plots. Journal of Allergy and Clinical Immunology 2016 138, 1230-1233.e8DOI: (10.1016/j.jaci.2016.06.008) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Scatterplots of ERGS gene expression with blood eosinophils and age from the EXTRA study. ERGS gene expression (Y axes) from PAXgene is plotted versus blood eosinophils count (#/μL), X-axes) and age (years) from the EXTRA study for CANCG6 (A), CCL23 (B), GPR44 (C), HSD3B7 (D), IDO1 (E), and SIGLEC8 (F). Linear regression lines are plotted in blue. Journal of Allergy and Clinical Immunology 2016 138, 1230-1233.e8DOI: (10.1016/j.jaci.2016.06.008) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Relative change in FEV1 (ΔFEV1) by biomarker subgroups in the MILLY study. Mean ± standard error of ΔFEV1% are plotted by dichotomous diagnostic classification of blood eosinophils (A), serum periostin (B), and ERGS genes (C-H) for placebo and lebrikizumab treatment arms. Diagnostic population is divided at the respective study median (closed left) for all biomarkers except for serum periostin (50 ng/mL). Journal of Allergy and Clinical Immunology 2016 138, 1230-1233.e8DOI: (10.1016/j.jaci.2016.06.008) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Relative change in FEV1 (ΔFEV1) by biomarker subgroups in LUTE/VERSE studies. Mean ± standard error of ΔFEV1% are plotted by dichotomous diagnostic classification of blood eosinophils (A), serum periostin (B), and ERGS genes (C-H) for placebo and lebrikizumab treatment arms. Diagnostic population is divided at the respective study median (closed left) for all biomarkers except for serum periostin (50 ng/mL). Journal of Allergy and Clinical Immunology 2016 138, 1230-1233.e8DOI: (10.1016/j.jaci.2016.06.008) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions