Effects of omalizumab on RV infections, illnesses, and exacerbations of asthma. James Gern, MD Ann Esquivel, MD University of Wisconsin, Madison

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1 Effects of omalizumab on RV infections, illnesses, and exacerbations of asthma James Gern, MD Ann Esquivel, MD University of Wisconsin, Madison

2 Background: Omalizumab Mechanism of Action Primary Mechanism of Action binds to free IgE Secondary Mechanism of Action downregulation of Fc ε RI on basophils and mast cells 1 J Asthma Allergy, 2011

3 Background: How IgE affects interferon responses Normal Airway Rhinovirus Allergic Airway Inflammation pdc Allergen pdc FcεRI IgE IFN α Viral Replication Mild Illness Omalizumab: Reduces IgE receptors Reduces IgE May restore IFN responses IFN α Viral Replication Wheezing Illness Asthma Exacerbation

4 PROSE = PReseasonal Treatment with either Omalizumab or an inhaled corticosteroid boost to prevent fall [Seasonal] asthma Exacerbations 2 Comparison of OMZ vs ICS boost (2x) vs placebo (guidelines care) started 4 6 weeks before school and continued through fall season 4 9 month run in and 4 month intervention 478 inner city allergic asthmatic children ages 6 17, randomized 3:3:1 OMZ:ICS boost:placebo Also examined effects of OMZ on IFN α responses to rhinovirus 2 Teach S, et al. JACI 2015

5 PROSE study results 2 Exacerbations significantly lower in OMZ vs placebo arms (11.3% vs 21.0%, OR 0.48, 95% CI ) OMZ improved IFN α responses to rhinovirus, and in OMZ group, greater IFN α associated with fewer exacerbations 2, 3 Our study was a planned mechanistic study of effects of omalizumab (OMZ) on viral infection and illness 2 Teach S, et al. JACI Gill M, et al. J Immunol 2010

6 Research Questions 1) Does OMZ decrease the number or duration of viral infections? 2) Does OMZ decrease the frequency of viral colds? Does OMZ have an anti viral effect?

7 We think OMZ boosts IFN IFN doesn t PREVENT infection, it LIMITS infection Hypotheses 1) Treatment with omalizumab or boosted ICS (compared to standard treatment) will have no effect on the number of rhinovirus infections. 2) Treatment with omalizumab (which restores IFN) will reduce the number of viral illnesses.

8 Study Population (n=478)

9 Run in period (4 9 months) EVERYONE on guidelines based care Methods Weekly nasal samples and respiratory illness assessments of school aged (6 17y) allergic asthmatics starting at randomization for 16 weeks during Fall 2012 or 2013 August/September November (3:3:1) omalizumab 2x ICS boost placebo OR OR Virology: 6,117 viral samples from 478 participants PCR on all nasal samples RV+ samples sequenced to determine species (A, B or C) and type

10 Respiratory Illness Assessment

11 Definitions Term Definition # of cases/16 week monitoring period Acute asthma exacerbation Systemic steroids required Viral exacerbation Viral detection +/ 7 days of acute exacerbation N=171 N=114 Infection Detection of virus N=1683 Illness Symptoms N=601 Viral cold Viral detection with symptoms of illness N=113

12 Data

13 Omalizumab treatment decreased the rate of viral detection OR=0.7, 95% CI P= Boosted ICS no effect RV adjusted prevalence (%) Esquivel, et al. AAAAI 2015

14 Interpretation Omalizumab: lower rate of RV detection Possible explanations Did omalizumab reduce the number of infections? OR Did omalizumab shorten the duration of infection?

15 Omalizumab decreased duration of RV detection Infection Length in Days Xolair OMZ Placebo p-value Any HRV 11.3 (568) 12.0 (189) 0.05 Single HRV-A 10.7 (177) 11.2 (56) 0.53 Single HRV-B 13.0 (169) 13.9 (62) 0.43 Single HRV-C 9.9 (160) 11.7 (54) 0.08 Multiple HRV 9.2 (62) 10.6 (17) 0.47 EV 9.7 (9) 9.8 (13) 0.97 Other 7.9 (9) 10.5 (4) 0.51 Any Virus (HRV/EV/Other) 11.0 (918) 12.1 (331) 0.04 * Values are mean length (# of infections) There was no difference in infection frequency between treatment arms (Data not shown)

16 OMZ decreased cold Prevalence 0.15 Treatment Steps 2 to (0.61, 0.9) 0.12 Rate of Colds Rate of Colds Placebo Omalizumab Decrease of ~26% for rate of colds in OMZ group as compared to placebo.

17 OMZ decreased viral cold prevalence Rate of Colds placebo omalizumab Significant reduction in rate of viral colds for those treated with OMZ.

18 Conclusions Treatment with omalizumab decreased the rate of RV detection. This was due to a shorter duration of RV infection. Omalizumab significantly decreases rate of colds, including viral colds These conclusions support the idea that omalizumab does have an anti viral effect.

19 Acknowledgements University of Wisconsin James Gern Ann Esquivel William Busse Kristine Grindle Rho statistics Agustin Calatroni Jeremy Wildfire Patricia LeBeau Melissa Yaeger NIAID funding Peter Gergen Clinical Sites and Investigators University of Texas Southwest Rebecca Gruchalla Columbia University M Kattan Cincinnati Children s G Khurana Hershey Henry Ford H Kim National Jewish Andrew Liu University of Colorado Stan Szefler Children s National Stephen Teach Boston University B West Lurie Children s Hospital of Chicago Jacqueline Pongracic

20 References 1) Pelaia G, et al. Update on optimal use of omalizumab in management of asthma. J Asthma and Allergy, ) Teach ST, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol, Oct ) Gill MA, Bajwa G, George TA, Dong CC, Dougherty II, Jiang N, Gan VN, Gruchalla RS. Counterregulation between the Fc epsilon RI pathway and antiviral responses in human plasmacytoid dendritic cells. J Immunol 2010; 184:

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