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Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy  Pamela A. Frischmeyer-Guerrerio, MD,

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Presentation on theme: "Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy  Pamela A. Frischmeyer-Guerrerio, MD,"— Presentation transcript:

1 Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy  Pamela A. Frischmeyer-Guerrerio, MD, PhD, Madhan Masilamani, PhD, Wenjuan Gu, MS, Erica Brittain, PhD, Robert Wood, MD, Jennifer Kim, MD, Kari Nadeau, MD, PhD, Kirsi M. Jarvinen, MD, PhD, Alexander Grishin, PhD, Robert Lindblad, MD, Hugh A. Sampson, MD  Journal of Allergy and Clinical Immunology  Volume 140, Issue 4, Pages e8 (October 2017) DOI: /j.jaci Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Whole blood basophil CD63 percentage expression in omalizumab-treated (blue) and placebo-treated (red) subjects after stimulation with milk (0.001, 0.01, 0.1, 1, or 10 μg/mL) or anti-IgE at baseline (BL) and visits at months (M) 4, 16, 22, 28, 30 and 32. Statistically significant P values are indicated in the text. These data were previously presented in Chinthrajah et al.5 Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Percentage HR from washed basophil-enriched suspensions from omalizumab-treated (blue) and placebo-treated (red) subjects stimulated with the 5 concentrations of milk (0.001, 0.01, 0.1, 1, and 10 μg/mL), anti-IgE, or medium alone (Spont Med) at baseline (BL) and visits at months (M) 4, 16, 22, 28, 30, and 32. Statistically significant P values are indicated in the text. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Percentage of MOIT doses given during the escalation or maintenance phases of MOIT or over the course of the entire study that led to moderate-to-severe (Mod/Severe) symptoms, gastrointestinal (GI) symptoms, or any symptom excluding oropharyngeal symptoms (Symptoms excl. oral) in subjects who achieved SU, were desensitized only (D), or failed the month 28 desensitization OFC (F). P values for a difference in ordinal outcomes (SU/D/F; ord. pval) are presented. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Relationship between percentage of MOIT doses that led to moderate-to-severe (Mod/Severe) symptoms, gastrointestinal (GI) symptoms, or any symptom excluding oropharyngeal symptoms (Symptoms excl. oral) over the course of MOIT and basophil CD63 percentage expression at a milk stimulant concentration of 10 μg/mL (%CD63+: Milk 10) measured at baseline (BL) or the month 4 visit. Statistically significant P values are discussed in the text. The gray vertical line at CD63 percentage expression at baseline illustrates the proposed threshold for greatest treatment difference. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Percentage of MOIT doses that led to moderate-to-severe (Mod/Severe) symptoms, gastrointestinal (GI) symptoms, or any symptom excluding oropharyngeal (Symptoms excl. oral) over the course of MOIT in subjects whose baseline basophil CD63 percentage expression at a milk stimulant concentration of 10 μg/mL was less than or greater than 40% (%CD63 Milk 10 > 40 or %CD63 Milk < 40, respectively). P values are indicated in the graphs. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Ratio of basophil CD63 percentage expression at a milk stimulant concentration of 10 μg/mL over anti-IgE percentage CD63 (%CD63: Milk10/anti-IgE) or ratio of milk IgE over total IgE level (IgE Ratio: Milk/Total) in placebo-treated (red) and omalizumab-treated (blue) subjects who achieved SU, were desensitized only (D), or failed (F). Statistically significant P values are discussed in the text. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 A, Baseline values of the ratio of CD63 percentage to a milk stimulant concentration of 10 μg/mL over CD63 percentage to anti-IgE (%CD63: Milk10/anti-IgE) were evaluated in relation to the baseline milk IgE/total IgE ratio (IgE Ratio: Milk/Total) in a logistic interaction model. The shaded area indicates a region of numerically positive treatment estimate in terms of likelihood of achieving SU. Subjects who achieved SU are shown in open points; those who were desensitized only or failed are depicted in filled points (Not SU). B, Number of omalizumab- or placebo-treated subjects whose baseline biomarker values were greater than (%CD63 Milk10/anti-IgE > x IgE Ratio: Milk/Total) or less than (%CD63 Milk10/anti-IgE < x IgE Ratio: Milk/Total) the line of positive effect described in Fig 7, A, who achieved SU, were desensitized only (D), or failed (F). P values for a difference in SU (SU. p) and for a difference in ordinal outcomes (SU/D/F; ord. p) are presented. C, Percentage of MOIT doses that led to moderate-to-severe (Mod/Severe) symptoms, gastrointestinal (GI) symptoms, or any symptom excluding oropharyngeal symptoms (Symptoms excl. oral) over the course of MOIT in the 2 subsets of subjects described in Fig 7, B. P values are indicated in the graphs. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E1 Percentage of Foxp3hiCD4+ T cells (Treg cells) of total proliferating CD4+ T cells after casein stimulation in omalizumab-treated (blue) or placebo-treated (red) subjects at baseline (BL) and month (M) 4, 28, or 32. Neither group demonstrated a significant increase in Treg cell counts at any time point studied. Although data on all subjects are represented, statistical analysis was limited to matched pairs between baseline and each of the time points studied (n = 6, 10, and 10 in the omalizumab arm at months 4, 28, and 32, respectively; n = 7, 8, and 6 in the placebo arm at months 4, 28, and 32, respectively). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E2 Relationship between the percentage of MOIT doses that led to symptoms, including moderate-to-severe (Mod/Severe) symptoms, gastrointestinal (GI) symptoms, or any symptom excluding oropharyngeal symptoms (Symptoms excl. oral), over the course of MOIT and after biomarkers: basophil CD63 percentage expression at a milk stimulant concentration of 1 μg/mL (%CD63+: Milk1; A) AUC (%CD63+: AUC; B), and ratio of CD63 percentage expression at milk concentrations of 1 μg/mL (%CD63 Milk1/anti-IgE; C) and 10 μg/mL (%CD63 Milk10/anti-IgE; D) or AUC (%CD63 AUC/anti-IgE; E) over CD63 percentage to anti-IgE, all measured at the baseline (BL) or month (M) 4 visits. Additional biomarkers included age at study entry (F), milk IgE level (in kilounits of antigen per liter), and milk-specific IgE/total IgE ratio (IgE Ratio: Milk/Total; G), as well as log casein IgG4/casein IgE ratio (log Casein: IgG4/IgE) and log β-lactoglobulin IgG4/β-lactoglobulin IgE ratio (log Beta-lactoglobulin: IgG4/IgE; H), all measured at the baseline visit. Each point represents an individual subject; omalizumab is shown in blue, and placebo is shown in red. Overall, all markers of basophil activation (individually or as a ratio of greater than CD63 percentage to anti-IgE) had a significant positive association with the occurrence of symptoms (P < .001 at month 4). Additionally, several parameters were significantly associated with symptoms in the placebo group at baseline, including CD63 percentage at a milk concentration of 1 μg/mL/CD63 percentage to anti-IgE with moderate-to-severe symptoms and any symptom other than oropharyngeal (P = .035 and P = .003, respectively), CD63 percentage at a milk concentration of 10 μg/mL/CD63 percentage to anti-IgE with any symptom other than oropharyngeal (P = .007), and AUC/CD63 percentage to anti-IgE with any symptom other than oropharyngeal (P = .034). Although not significant in the overall population, the log casein IgG4/IgE ratio was negatively associated with any symptoms other than oropharyngeal (P = .032) and gastrointestinal (P = .034) symptoms in the omalizumab group at baseline. Additional significant P values are indicated in the text. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E2 Relationship between the percentage of MOIT doses that led to symptoms, including moderate-to-severe (Mod/Severe) symptoms, gastrointestinal (GI) symptoms, or any symptom excluding oropharyngeal symptoms (Symptoms excl. oral), over the course of MOIT and after biomarkers: basophil CD63 percentage expression at a milk stimulant concentration of 1 μg/mL (%CD63+: Milk1; A) AUC (%CD63+: AUC; B), and ratio of CD63 percentage expression at milk concentrations of 1 μg/mL (%CD63 Milk1/anti-IgE; C) and 10 μg/mL (%CD63 Milk10/anti-IgE; D) or AUC (%CD63 AUC/anti-IgE; E) over CD63 percentage to anti-IgE, all measured at the baseline (BL) or month (M) 4 visits. Additional biomarkers included age at study entry (F), milk IgE level (in kilounits of antigen per liter), and milk-specific IgE/total IgE ratio (IgE Ratio: Milk/Total; G), as well as log casein IgG4/casein IgE ratio (log Casein: IgG4/IgE) and log β-lactoglobulin IgG4/β-lactoglobulin IgE ratio (log Beta-lactoglobulin: IgG4/IgE; H), all measured at the baseline visit. Each point represents an individual subject; omalizumab is shown in blue, and placebo is shown in red. Overall, all markers of basophil activation (individually or as a ratio of greater than CD63 percentage to anti-IgE) had a significant positive association with the occurrence of symptoms (P < .001 at month 4). Additionally, several parameters were significantly associated with symptoms in the placebo group at baseline, including CD63 percentage at a milk concentration of 1 μg/mL/CD63 percentage to anti-IgE with moderate-to-severe symptoms and any symptom other than oropharyngeal (P = .035 and P = .003, respectively), CD63 percentage at a milk concentration of 10 μg/mL/CD63 percentage to anti-IgE with any symptom other than oropharyngeal (P = .007), and AUC/CD63 percentage to anti-IgE with any symptom other than oropharyngeal (P = .034). Although not significant in the overall population, the log casein IgG4/IgE ratio was negatively associated with any symptoms other than oropharyngeal (P = .032) and gastrointestinal (P = .034) symptoms in the omalizumab group at baseline. Additional significant P values are indicated in the text. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E3 Number of omalizumab- or placebo-treated subjects whose baseline basophil CD63 percentage expression at a milk stimulant concentration of 10 μg/mL was greater than or less than 40% (%CD63 Milk10 > 40 or %CD63 Milk10 < 40, respectively) and who achieved SU were desensitized only (D), or failed (F). P values for a difference in SU (SU. p) and for a difference in ordinal outcomes (SU/D/F; ord. p) are presented. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Fig E4 Basophil CD63 percentage expression at a milk stimulant concentration of 1 μg/mL (%CD63+: Milk 1; A), AUC (%CD63+: AUC; B), ratio of CD63 percentage expression at a milk concentration of 1 μg/mL (%CD63 Milk1/anti-IgE; C), AUC (%CD63 AUC/anti-IgE; D) over CD63 percentage to anti-IgE and milk IgE (in kilounits of antigen per liter; E), log ratio casein IgG4 over casein IgE (log Casein: IgG4/IgE; F), log ratio of β-lactoglobulin IgG4/β-lactoglobulin IgE (log Beta-lactoglobulin: IgG4/IgE; G), and subject age in years (H) all measured at the baseline (BL) visit in omalizumab-treated (blue) or placebo-treated (red) subjects who achieved SU, were desensitized only (D), or failed the month 28 desensitization OFC (F). Statistically significant P values are discussed in the text. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

14 Fig E5 Basophil CD63 percentage expression at a milk stimulant concentration of 1 μg/mL (%CD63+: Milk1; A) or 10 μg/mL (%CD63+: Milk10; B), AUC (%CD63+: AUC; C), ratio of CD63 percentage expression at a milk concentration of 1 μg/mL (%CD63 Milk1/anti-IgE; D) or 10 μg/mL (%CD63 Milk10/anti-IgE μg/mL; E) or AUC (%CD63 AUC/anti-IgE; F) over CD63 percentage to anti-IgE, casein IgG4/casein IgE ratio (log Casein: igG4/IgE; G), and β-lactoglobulin IgG4/β-lactoglobulin IgE ratio (log Beta-lactoglobulin: IgG4/IgE; H) measured at the indicated visit (month 28 or 32) in omalizumab-treated (blue) or placebo-treated (red) subjects who achieved SU, were desensitized only (D), or failed the month 28 desensitization OFC (F). Statistically significant P values are discussed in the text. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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