Update on Biologicals for ABPA and AsthmaDiagnosis of ABPA modified for CF 1. Acute or subacute...
34
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
Transcript of Update on Biologicals for ABPA and AsthmaDiagnosis of ABPA modified for CF 1. Acute or subacute...
Update on Biologicals for ABPA
and Asthma
5th Advances Against Aspergillosis Istanbul
27 Jan 2012
Richard B. Moss MD Professor of Pediatrics
Stanford University Palo Alto CA USA
Presenter
Presentation Notes
25 min total 12:15-12:40
What is Asthma? • Disease of chronic airway
inflammation • Characterized by
– 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
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
Spectrum of Pulmonary Disease Caused by Aspergillus
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
Th17
Pathogenesis of ABPA
Courtesy D Hartl
Presenter
Presentation Notes
Strongest evidence for TLR2/Dectin-1 Dectin-1: especially for alveolar macrophages proinflammatory responses: elicited by A. fumigatus conidia Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states fumigatus is a saprophytic fungus ubiquitous in the environment (1). Human exposure most commonly occurs following inhalation of airborne resting conidia (RC),1 which are an ideal size for alveolar deposition. Bronchoalveolar macrophages can phagocytose and kill RC and thus are thought to constitute the first line of defense against the fungus. Should this initial defense fail, the RC become metabolically active and grow into swollen conidia (SC) and eventually hyphae (H), the invasive form of the fungus. DCs Defective airway surface liquid (ASL) => Impaired airway clearance => Increased sampling frequency by the lung dendritic cells (DCs). The DCs form an immune sensory mesh surrounding the airway, rapidly taking up and processing antigens from the environment; they do this by extending processes through intercellular spaces in the epithelium and sampling the airway milieu, a mechanism described as “snorkeling” [28, 29]. The increased exposure and activation of DCs could explain the increased prevalence of adaptive T-cell responses such as allergic bronchopulmonary aspergillosis (ABPA) in CF patients [30].
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
Presenter
Presentation Notes
2011 Danish study – Af in 51% CF, 22% chronic, 4.5% azole resistance. Mortensen KL et al, JCMicro 2011 Jun;49(6):2243-51
Overview of the Allergic Inflammatory Cascade
8
IgE Binds to Mast Cells at the High Affinity Receptor (FcεRI)
IgE molecule bound to mast cell
Mast cell
FcεRI receptor
IgE molecule FcεRI binding site
Presenter
Presentation Notes
This illustration demonstrates the binding of IgE to a mast cell which takes place at the constant region of the IgE molecule. Molecular bridging of FcRI receptors, which occurs when an allergen interacts with receptor-bound IgE molecules, causes activation of the cell and the release of preformed and newly generated mediators.
IgE-dependent Release of Inflammatory Mediators
IgE Allergens
FcεRI
Over Minutes Lipid mediators: Prostaglandins Leukotrienes
Wheezing Bronchoconstriction
Over Hours Cytokine production: Specifically IL-4, IL-13
Mucus production Eosinophil recruitment
Immediate Release Granule contents: Histamine, TNF-α, Proteases, Heparin
Sneezing Nasal congestion Itchy, runny nose Watery eyes
Presenter
Presentation Notes
IgE binds to high- and low-affinity receptors (FcRI or FcRII) on effector cells. The inflammatory cascade is initiated when IgE bound to effector cells is cross-linked by allergen. This results in the degranulation of effector cells and the release of a comprehensive array of mediators that are linked to the pathophysiology of asthma.
Omalizumab Blocks IgE Binding to Mast Cells
Mast cell
IgE molecule
FcεRI receptor
Omalizumab
Omalizumab binds to CH3 on IgE at FcεRI interaction site
Presenter
Presentation Notes
This slide illustrates Omalizumab binding to an IgE molecule, which also takes place at the constant region of the IgE molecule. Note that IgE binds either to the FcRI receptor on the mast Cell OR to Omalizumab, but it cannot bind to both at the same time. Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor FcRI on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcRI-bearing cells limits the degree of release of mediators of the allergic response.
Omalizumab Prevents the Triggering of Allergic Inflammation
IgE must be reduced >99% for FcεRI to become unoccupied and down-regulated
Removal of IgE and Down-Regulation of FcεRI by Omalizumab
Doses Are Determined by IgE Level and Body Weight
• Fixed target range for free-IgE suppression requires doses determined by individual’s pretreatment IgE
IgE
IgE
IgE
IgE
+ Omalizumab
+ Omalizumab
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
Graphical representation assumes patients of equal body weight.
Target IgE ↓
<10 IU/mL
Presenter
Presentation Notes
Omalizumab dosing is based on pretreatment IgE level and body weight. Preclinical and clinical studies have shown that circulating free IgE levels below 10 IU/mL are required in order to maximize clinical benefit. This fixed target range was the rationale for development of the Omalizumab dosing strategy. To reach the target range of free-IgE suppression, patients with a high pretreatment IgE level require a higher dose of Omalizumab. Those with lower pretreatment IgE levels require lower doses. Note: 1 IU/mL = 2.4 ng/mL; 1 kU/L = 1 IU/mL Hochhaus G, Brookman L, Fox H, et al. Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma. Curr Med Res Opin. 2003;19:491-498.
Omalizumab Mechanism in IgE-mediated Asthma
Release of IgE
Plasma cell
B lymphocyte
ε-switch
Exacerbation
Allergic Inflammation:
eosinophils and lymphocytes
Allergens
Allergic mediators
Binds free IgE, reducing cell-bound IgE
Reduces high-affinity IgE receptors
Reduces mediator release
Reduces exacerbations
Presenter
Presentation Notes
This slide provides an overview of the series of events that make up the allergic inflammatory cascade in IgE-mediated asthma. In response to antigen stimulation, B lymphocytes differentiate into plasma cells (the epsilon-switch), which produce and release IgE antibodies into the circulation. IgE circulates in the blood, eventually binding to high-affinity IgE receptors (FcRI) on the surface of mast cells in tissue or peripheral-blood basophils. When the subject subsequently re-encounters the offending allergen, binding of the allergen with IgE induces the release of inflammatory mediators, leading to the bronchoconstriction characteristic of an exacerbation.
Omalizumab Reduces Exacerbations in Adults with Severe Allergic Asthma
Annual exacerbation rate treatment
difference Percent
reduction p-value
INNOVATE study1 0.37 26.2% 0.042
ETOPA study2 1.49 60.4% <0.001
SOLAR study3 0.29 37.5% 0.027
Busse study4 0.40 40.3% <0.001
Solèr study5 0.70 57.6% <0.001
Holgate study6 0.42 26.5% 0.165
ALTO study 0.18 15.3% 0.077
Pooled7 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
(n=2511 O, 1797 P)
Presenter
Presentation Notes
In each individual study there were also meaningful differences in the exacerbation rates between patients receiving omalizumab and those receiving control therapy. The differences were comparable in the placebo-controlled studies, ranging between 0.294 and 0.698. The annualized exacerbation rate was significantly lower in studies 1, 2, 3, 4 and 5. Reference Bousquet J, Cabrera P, Berkman N, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy 2005;60:302–8.
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
Presenter
Presentation Notes
Patients with a history of emergency asthma treatment are at the greatest risk of asthma-related morbidity and death and present the greatest concern to physicians. A previous history of life-threatening exacerbations, hospitalization within the previous year, and a history of intubation for asthma are all specific factors associated with an increased risk of asthma mortality. In the pooled analysis, omalizumab significantly reduced each type of emergency visit and the total number of emergency visits as illustrated in the slide. The annualized rates for total emergency visits were 0.332 for those receiving omalizumab compared with 0.623 for the control group; this corresponds to a 47% reduction in total emergency visits. Hospital admissions were reduced by 51%, emergency room visits by 60% and unscheduled visits to a doctor by 43%. Reference Bousquet J, Cabrera P, Berkman N, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy 2005;60:302–8.
Effect of Omalizumab on Symptoms, Exacerbations, and Dose of Inhaled Steroids in Young Urban Asthmatics
Busse WW et al. NEJM 2011;364:1005-15
60 week DBPC RCT in 419 asthmatics 6-20 years old
Reduction 109 µg/d P<0.001
Reduction of 18.5% P<0.001
Reduction 0.48 days/ 2 weeks P<0.001
Presenter
Presentation Notes
Figure 2. Seasonal Variation in Days with Symptoms, Frequency of Exacerbations, and Dose of Inhaled Glucocorticoids. The width of the bands represents the 95% confidence interval.
Omalizumab Reduced Exacerbations in Inadequately Controlled Asthma Patients on Optimal ICS-LABA Therapy
Hanania N A et al. Ann Intern Med 2011;154:573-82
P=0.008, RR 25%
n=850 48 wks 12-75 yr
Presenter
Presentation Notes
Kaplan–Meier estimates of time to first protocol-defined asthma exacerbation.The P value based on a Cox proportional model for the difference of time to exacerbation between the 2 treatment groups was 0.008.
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
Presenter
Presentation Notes
11 Spanish hospitals Dose ~600 mg/wk
Omalizumab in ABPA – French Series
Tillie-Lebond I et al. Allergy 2011;66:1254-6
16 adults, no CF
1.00
1.20
1.40
1.60
1.80
2.00
Dec-03
Jun-04
Dec-04
Jun-05
Dec-05
Jun-06
Dec-06
Jun-07
Dec-07
Jun-08
Nov-08
May-09
Nov-09
May-10
Nov-10
May-11
Nov-11
May-12
Nov-12
FEV
1
Long-term Response to Omalizumab
FEV1 Prednisone Tx 6 per. Mov. Avg. (FEV1)
Omalizumab started Omalizumab Gap
Annualized FEV1% change: 2 yr prior to omalizumab –9 5 yr on omalizumab +6
Inflammatory Pathways in Asthma
Kraft M. NEJM 2011;365:1141-4
Presenter
Presentation Notes
Figure 1. Interleukin-13 and Non–Interleukin-13 Inflammatory Pathways in Asthma. Inhaled allergen activates mast cells, which are maintained by stem-cell factor (SCF) produced by epithelial cells and by dendritic cells, through cross-linking with IgE on their cell surfaces via FcεR1 to release mediators that induce bronchoconstriction, such as histamine, cysteinyl leukotrienes, and prostaglandin D2 (PGD2). Allergens are processed by dendritic cells, which are induced to secrete the CC chemokine ligand (CCL) 17 and CCL22 by thymic stromal lymphopoietin (TSLP). Dendritic cells then attract and activate type 2 helper T-cells (Th2) by the binding of CCL17 and CCL22 with CC chemokine receptor 4 (CCR4) on the Th2 cell surface. Another driver of the allergen sensitization process is interleukin-33 (IL-33), produced by airway epithelial cells, which activates dendritic cells and Th2 through mast-cell–derived tumor necrosis factor alpha (TNF-α). Th2 secrete IL-4 and IL-13, which induce B cells to produce IgE; IL-5, which is necessary for the development and survival of eosinophils; and IL-9, which activates mast cells. T regulatory (Treg) cells inhibit this inflammatory cascade, and there are data that suggest that they may be reduced in asthma, thus promoting ongoing Th2 inflammation. Once IL-13 is produced, it can promote the survival and migration of eosinophils and promotes activation of macrophages to create an M2, or an allergic cell phenotype. Through modulation of the barrier function of airway epithelial cells and subsequent production of transforming growth factor β1 (TGF-β1), the permeability of airway epithelial cells and the production of mucous are increased, and airway fibroblasts transform to myofibroblasts, with subsequent production of monocyte chemoattractant protein 1 (MCP-1), IL-6, and collagen. IL-13 also has direct effects on airway smooth muscle, leading to increased contraction to agonists such as acetylcholine and decreased relaxation with beta-agonists.
Anti-IL5 (Mepolizumab) Effect on Severe Exacerbations in Refractory Eosinophilic Asthma
Haldar P et al. NEJM 2009;360:973-84
RR = 0.57 95% CI = 0.3-0.9 p = 0.02
DBPC RCT 29 active 32 placebo Monthly x 1 year
Presenter
Presentation Notes
Figure 2. Severe Exacerbations during the Course of the Study. Panel A shows the cumulative number of severe exacerbations that occurred in each study group over the course of 50 weeks. Panel B shows the distribution of the number of exacerbations among subjects in each study group during the treatment period of the study. The mean number of exacerbations per subject over the course of the 50-week treatment period was 2.0 in the mepolizumab group, as compared with 3.4 in the placebo group (relative risk, 0.57; 95% confidence interval, 0.32 to 0.92; P=0.02).
Nair P et al. NEJM 2009;360:985-93
DBPC RCT 9 active 11 placebo Monthly x 26 wks
Anti-IL5 (Mepolizumab) Effect on Severe Exacerbations in Refractory Eosinophilic Asthma
Presenter
Presentation Notes
Figure 2. Kaplan–Meier Analysis of the Proportion of Patients without an Asthma Exacerbation during the Study. The median time to exacerbation was 20 weeks in the mepolizumab group and 12 weeks in the placebo group (P=0.003). Two asthma-related events occurred in the mepolizumab group: one patient who was withdrawn from the study because of a protocol violation had an exacerbation associated with sputum neutrophilia, and one patient was withdrawn after an adverse event; there were no exacerbations associated with sputum eosinophilia in this group. In the placebo group, nine patients were withdrawn: eight had exacerbations associated with sputum eosinophilia, and one patient who was withdrawn because of a protocol violation also had an exacerbation associated with sputum eosinophilia.
Castro M et al. AJRCCM 2011;184:1125-32
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
Effect of Lebrikizumab (Anti-IL13) on Lung Function in Adults with Uncontrolled Asthma
Corren J et al. NEJM 2011;365:1088-98
*Periostin: an epithelial IL13- induced matricellular protein, marker of TH2- high endotype
*
Presenter
Presentation Notes
Figure 2. Relative Change in Forced Expiratory Volume in 1 Second (FEV1) in the Intention-to-Treat Population. At week 12, the increase from baseline in FEV1 was higher by 5.5 percentage points (95% CI, 0.8 to 10.2) in the lebrikizumab group than in the placebo group (mean [±SE] change, 9.8±1.9% vs. 4.3±1.5%; P=0.02) (Panel A). In the subgroup of patients with high periostin levels, the relative increase from baseline FEV1 was higher by 8.2 percentage points (95% CI, 1.0 to 15.4) in the lebrikizumab group than in the placebo group (mean change, 14.0±3.1% vs. 5.8±2.1%; P=0.03) (Panel B). Among patients in the low-periostin subgroup, the relative increase from baseline FEV1 was higher by 1.6 percentage points (95% CI, –4.5 to 7.7) in the lebrikizumab group than in the placebo group (mean change, 5.1±2.4% vs. 3.5±2.1%; P=0.61) (Panel C).
Eosinophilic TH2 Asthma RNA Targets - Using Antisense Oligonucleotides
Inhaled combo TMP ASM8 reduced sputum eos 50% & early asthmatic response
Gauvreau GM et al. AJRCCM 2008;177:952-8
AS-ODN 143
AS-ODN ASA4
Wegmann M.AJRCMB 2011;45:667-74
Conclusions • Asthma is heterogeneous – fungal asthma, SAFS and ABPA are forms of allergic/TH2 endotypic asthma along a severity spectrum • Omalizumab (anti-IgE) is an effective biological approach to allergic asthma, including ABPA • Other biologicals targeting the TH2 pathway (IL4/13, IL5, eosinophils, others) show promise for selected severe TH2 endotype asthma/ABPA patients • Controlled trials of biologics are needed in fungal asthma, SAFS and ABPA
