Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses

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Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses Gail M. Gauvreau, PhD, Jonathan P. Arm, MD, Louis-Philippe Boulet, MD, Richard Leigh, MBChB, Donald W. Cockcroft, MD, Beth E. Davis, PhD, Irvin Mayers, MD, J. Mark FitzGerald, MB, Barbro Dahlen, MD, Kieran J. Killian, MB, Michel Laviolette, MD, Christopher Carlsten, MD, Nikolaos Lazarinis, MD, Richard M. Watson, BSc, Joanne Milot, BSc, Veronica Swystun, PhD, Miranda Bowen, MSc, Linda Hui, MSc, Ann-Sofie Lantz, MSc, Karin Meiser, PhD, Suzanne Maahs, PharmD, Philip J. Lowe, PhD, Andrej Skerjanec, PhD, Anton Drollmann, MD, Paul M. O'Byrne, MB Journal of Allergy and Clinical Immunology Volume 138, Issue 4, Pages 1051-1059 (October 2016) DOI: 10.1016/j.jaci.2016.02.027 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Study design. Journal of Allergy and Clinical Immunology 2016 138, 1051-1059DOI: (10.1016/j.jaci.2016.02.027) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Effect of different doses of QGE031 and omalizumab on allergen PC15 in the airways. A, Individual subject time-course data grouped by cohorts for placebo, the 3 dose levels of QGE031, and omalizumab. Data are presented as the fold change from baseline. A 10- or 100-fold decrease in sensitivity indicates that a 10- or 100-fold higher dose of allergen was required to elicit the same 15% change in FEV1. Red-colored data represent subjects with baseline IgE levels of greater than 700 IU/mL. B and C, Statistical analyses of the week 12 geometric mean ratios of required allergen concentrations versus omalizumab (Fig 2, B) and placebo (Fig 2, C). Error bars represent 95% CIs. Journal of Allergy and Clinical Immunology 2016 138, 1051-1059DOI: (10.1016/j.jaci.2016.02.027) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effect of different doses of QGE031 and omalizumab on the area under the curve (AUC) of the wheal response to allergen skin prick titration with allergen. A, Individual subject time-course data grouped by cohorts for placebo, the 3 dose levels of QGE031, and omalizumab. Data are presented as the percentage change in dilution curve AUC from individual patient baseline. Red-colored data represent subjects with baseline IgE levels of greater than 700 IU/mL. B and C, Statistical analyses of the week 12 geometric mean ratios of AUC of wheal size across all dilutions versus omalizumab (Fig 3, B) and placebo (Fig 3, C). Error bars represent 95% CIs. Lower ratios indicate lower sensitivity to allergen and therefore greater inhibition by the drug. Journal of Allergy and Clinical Immunology 2016 138, 1051-1059DOI: (10.1016/j.jaci.2016.02.027) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of different doses of QGE031 and omalizumab on IgE and IgE receptor expression. Shown are the individual subject time course of circulating total IgE (A), basophil surface IgE levels (B), and basophil expression of FcεRI (C) grouped by cohorts for placebo, the 3 dose levels of QGE031, and omalizumab. Red-colored data represent subjects with baseline IgE levels of greater than 700 IU/mL. Units for the basophil FACS assay were molecules of equivalent soluble fluorophore (MESF) divided by 1000. Journal of Allergy and Clinical Immunology 2016 138, 1051-1059DOI: (10.1016/j.jaci.2016.02.027) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Simulation of steady-state (week 24) dose responses to QGE031 for a patient population split by the median baseline IgE level (>250 IU/mL or ≤250 IU/mL). Simulated doses on the x-axis are those for QGE031 administered every 4 weeks. Omalizumab error bars refer to simulated doses administered according to the US dosing table. Wheal measurements are for the area under the complete dilution curve. PC15 values represent the concentration of allergen required to elicit a 15% decrease in FEV1 on the log2 scale. On the original scale, log2(6) would be a concentration (inverse of dilution) of 64, whereas log2(12) is 4096. Journal of Allergy and Clinical Immunology 2016 138, 1051-1059DOI: (10.1016/j.jaci.2016.02.027) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions