Update on Biologicals for ABPA and Asthma 5 th Advances Against Aspergillosis Istanbul 27 Jan 2012 Richard B. Moss MD Professor of Pediatrics Stanford University Palo Alto CA USA
Disease of chronic airway inflammation Characterized by What is Asthma? Episodic reversible airflow obstruction Airway hyper-responsiveness Episodic/Chronic Symptoms Cookson W. Nature 1999; 402S: B5-11
Asthma Phenotypes Wenzel S. Lancet 2006;368:804-13
Asthma Phenotype and Endotype Phenotype = Observable characteristics and response to treatment Endotype = Subtype by distinct pathophysiologic mechansim Lotvall J et al JACI 2011;127:355-60
Lotvall J et al. JACI 2011;127:355-60
Spectrum of Pulmonary Disease Caused by Aspergillus Saprophytic: structurally damaged host (bronchiectasis, cavities, necrotic tissue) Aspergilloma (mcyetoma) Chronic necrotizing aspergillosis Allergic: immunocompetent host Asthma/Severe Asthma with Fungal Sensitization (SAFS) Allergic bronchopulmonary aspergillosis (ABPA) Hypersensitivity pneumonitis (allergic alveolitis) Bronchocentric granulomatosis Eosinophilic pneumonia Invasive: immunosuppressed host Angioinvasive aspergillosis Acute bronchopneumonia Pseudomembranous necrotizing tracheobronchitis Invasive pleural disease
Potential Targets for New Asthma Drugs Thomson NC et al. BMC Medicine 2011;9:102
Diagnostic Criteria for ABPA Five or more of: Asthma Central bronchiectasis on HRCT Immediate skin test reactivity to A. fumigatus Total serum IgE >1000 ng/ml (~417 U/mL) Elevated IgG and/or IgE antibodies to A. fumigatus Pulmonary infiltrates on CXR Serum precipitins to A. fumigatus Eosinophilia
Diagnosis of ABPA modified for CF 1. Acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise induced asthma, change in pulmonary function, increased sputum) not attributable to another etiology. 2. Total serum IgE >500 IU/mL. 3. Immediate skin test reactivity, or in vitro demonstration of IgE antibody, to A. fumigatus. 4. One or both of the following: a. Serum precipitins, or IgG antibody, to A. fumigatus. b. New or recent abnormalities on the chest radiograph (infiltrates, mucus plugging) or chest CT (bronchiectasis) that have not cleared with antibiotics and standard physiotherapy. Stevens et al. Clin Infect Dis 2003;37:S225-64
Pathogenesis of ABPA Th 17 Courtesy D Hartl
Therapeutic Approaches for ABPA Systemic glucocorticosteroids Toxicity Azoles Validated by DBPC RCTs Frequent toxicities (Vori>Itra). Absorption, metabolism, drug interactions mandate drug level monitoring. Resistance. Inhaled amphotericin B Multiple formulations, doses, delivery systems. Pulse IV methylprednisolone Potential for reduced steroid toxicity. Omalizumab
Overview of the Allergic Inflammatory Cascade 8
IgE Binds to Mast Cells at the High Affinity Receptor (FcεRI) FcεRI binding site IgE molecule FcεRI receptor IgE molecule bound to mast cell Mast cell
IgE-dependent Release of Inflammatory Mediators IgE Allergens FcεRI Immediate Release Granule contents: Histamine, TNF-α, Proteases, Heparin Sneezing Nasal congestion Itchy, runny nose Watery eyes Over Minutes Lipid mediators: Prostaglandins Leukotrienes Wheezing Bronchoconstriction Over Hours Cytokine production: Specifically IL-4, IL-13 Mucus production Eosinophil recruitment
Omalizumab Blocks IgE Binding to Mast Cells IgE molecule Omalizumab FcεRI receptor Omalizumab binds to CH3 on IgE at FcεRI interaction site Mast cell
Omalizumab Prevents the Triggering of Allergic Inflammation
Removal of IgE and Down-Regulation of FcεRI by Omalizumab IgE must be reduced >99% for FcεRI to become unoccupied and down-regulated
Doses Are Determined by IgE Level and Body Weight Fixed target range for free-ige suppression requires doses determined by individual s pretreatment IgE High pre-rx IgE Low pre-rx IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE IgE + Omalizumab + Omalizumab IgE IgE IgE IgE Target IgE <10 IU/mL Graphical representation assumes patients of equal body weight.
Omalizumab Mechanism in IgE-mediated Asthma Reduces mediator release ε-switch Release of IgE B lymphocyte Allergic mediators Plasma cell Allergic Inflammation: eosinophils and lymphocytes Allergens Exacerbation Binds free IgE, reducing cellbound IgE Reduces high-affinity IgE receptors Reduces exacerbations
Omalizumab Reduces Exacerbations in Adults with Severe Allergic Asthma Annual exacerbation rate treatment difference Percent reduction p-value INNOVATE study 1 0.37 26.2% 0.042 ETOPA study 2 1.49 60.4% <0.001 SOLAR study 3 0.29 37.5% 0.027 Busse study 4 0.40 40.3% <0.001 Solèr study 5 0.70 57.6% <0.001 Holgate study 6 0.42 26.5% 0.165 ALTO study 0.18 15.3% 0.077 (n=2511 O, 1797 P) Pooled 7 0.56 38.3% <0.0001 1. Humbert M, et al. Allergy 2005; 2. Ayres JG, et al. Allergy 2004; 3. Vignola AM, et al. Allergy 2004 4. Busse W, et al. J Allergy Clin Immunol 2001; 5. Solèr M, et al. Eur Respir J 2001 6. Holgate ST, et al. Clin Exp Allergy 2004; 7. Bousquet J, et al. Allergy 2005
Omalizumab Reduces Health Utilization for Severe Asthma Rate per year Omalizumab Control p-value for rate ratio Percent reduction Total emergency visits 0.332 0.623 <0.0001 47% Hospital admissions 0.030 0.062 0.041 51% Emergency room visits 0.026 0.066 0.013 60% Unscheduled doctor visit 0.252 0.443 0.0003 43% Bousquet J et al. Allergy 2005;60:302-8
Effect of Omalizumab on Symptoms, Exacerbations, and Dose of Inhaled Steroids in Young Urban Asthmatics Reduction 0.48 days/ 2 weeks P<0.001 60 week DBPC RCT in 419 asthmatics 6-20 years old Reduction of 18.5% P<0.001 Reduction 109 µg/d P<0.001 Busse WW et al. NEJM 2011;364:1005-15
Omalizumab Reduced Exacerbations in Inadequately Controlled Asthma Patients on Optimal ICS-LABA Therapy n=850 48 wks 12-75 yr P=0.008, RR 25% Hanania N A et al. Ann Intern Med 2011;154:573-82
Modifying Omalizumab Dosing for ABPA
Omalizumab in ABPA Spanish Series 2 of 18 patients in this series had CF Treatment 16 weeks. Follow-up median 36 wks (IQR 28-42) Dose ~600 mg/week Perez-de-Llano LA et al. Thorax 2011; 66:539-40
Omalizumab in ABPA French Series 16 adults, no CF Tillie-Lebond I et al. Allergy 2011;66:1254-6
Long-term Response to Omalizumab 2.00 1.80 Omalizumab started Omalizumab Gap FEV1 1.60 1.40 1.20 Annualized FEV1% change: 2 yr prior to omalizumab 9 5 yr on omalizumab +6 1.00 Nov-12 May-12 Nov-11 May-11 Nov-10 May-10 Nov-09 May-09 Nov-08 Jun-08 Dec-07 Jun-07 Dec-06 Jun-06 Dec-05 Jun-05 Dec-04 Jun-04 Dec-03 FEV1 Prednisone Tx 6 per. Mov. Avg. (FEV1)
Inflammatory Pathways in Asthma Kraft M. NEJM 2011;365:1141-4
Anti-IL5 (Mepolizumab) Effect on Severe Exacerbations in Refractory Eosinophilic Asthma DBPC RCT 29 active 32 placebo Monthly x 1 year RR = 0.57 95% CI = 0.3-0.9 p = 0.02 Haldar P et al. NEJM 2009;360:973-84
Anti-IL5 (Mepolizumab) Effect on Severe Exacerbations in Refractory Eosinophilic Asthma DBPC RCT 9 active 11 placebo Monthly x 26 wks Nair P et al. NEJM 2009;360:985-93
Effect of Reslizumab (Anti-IL5) on Asthma Control and Lung Function in Poorly Controlled Eosinophilic Asthma DBPC RCT Adults 53 active 53 placebo Monthly x 4 Castro M et al. AJRCCM 2011;184:1125-32
Effect of Lebrikizumab (Anti-IL13) on Lung Function in Adults with Uncontrolled Asthma * *Periostin: an epithelial IL13- induced matricellular protein, marker of T H 2- high endotype Corren J et al. NEJM 2011;365:1088-98
Eosinophilic T H 2 Asthma RNA Targets - Using Antisense Oligonucleotides AS-ODN ASA4 AS-ODN 143 Inhaled combo TMP ASM8 reduced sputum eos 50% & early asthmatic response Wegmann M.AJRCMB 2011;45:667-74 Gauvreau GM et al. AJRCCM 2008;177:952-8
Conclusions Asthma is heterogeneous fungal asthma, SAFS and ABPA are forms of allergic/t H 2 endotypic asthma along a severity spectrum Omalizumab (anti-ige) is an effective biological approach to allergic asthma, including ABPA Other biologicals targeting the T H 2 pathway (IL4/13, IL5, eosinophils, others) show promise for selected severe T H 2 endotype asthma/abpa patients Controlled trials of biologics are needed in fungal asthma, SAFS and ABPA