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Single Breath Assessing Airway Inflammation with FeNO
1 Applying Science With a Single Breath Assessing Airway Inflammation with FeNO NIOX VERO® and NIOX® are registered trademarks of Circassia AB. CIRCASSIA is a registered trademark of Circassia Limited. © 2016 Circassia Pharmaceuticals, Inc.. All rights reserved. October XXXXXX-XX
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IMPORTANT INFORMATION REGARDING NIOX VERO®
NIOX VERO is a portable system for the non-invasive, quantitative, simple and safe measurement of Nitric Oxide (NO) in human breath. Nitric Oxide is frequently increased in some inflammatory processes such as asthma. FeNO measurements provide the physician with means of evaluating an asthma patient’s response to anti-inflammatory therapy, as an adjunct to the established clinical and laboratory assessments in asthma. The NIOX VERO is intended for prescription use and should only be used as directed in the NIOX VERO User Manual by trained healthcare professionals. NIOX VERO is suitable for children, approximately 7–17 years, and adults 18 years and older. NIOX VERO cannot be used with infants or by children approximately under the age of 7, as measurement requires patient cooperation. NIOX VERO should not be used in critical care, emergency care or in anesthesiology. Circassia Pharmaceuticals, Inc. © All rights reserved.
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Objectives This presentation is intended to show:
FeNO is a diagnostic marker of allergic (Th2) airway inflammation FeNO is a predictor of inhaled corticosteroid (ICS) response FeNO is helpful in determining adherence to therapy FeNO helps to optimize ICS dose and reduces exacerbations by up to 50% FeNO, fractional exhaled nitric oxide Circassia Pharmaceuticals, Inc. © All rights reserved.
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Pakhale et al. BMC Pulm Med. 2011;11:27.
Asthma Is A Complex Condition That Is Both Over- and Under-diagnosed Asthma is a clinical diagnosis Symptoms can be variable and misleading Objective information should be, but is rarely, used in initial or ongoing assessment of asthma Approximately 1/3 of patients with asthma do not have asthma when objectively assessed 71% $$$ Pakhale et al. BMC Pulm Med. 2011;11:27. of misdiagnosed patients are on therapy Pharmaceuticals represent the single largest expenditure in asthma care Circassia Pharmaceuticals, Inc. © All rights reserved.
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Asthma Is A Condition That Can Be Difficult And Costly To Manage
Two ‘types’ of asthma exist: “Typical” asthma Relatively easy to diagnose and manage Responsive to therapy Relatively low cost “Difficult” asthma Difficult to diagnose and manage Poorly responsive to traditional therapy (due to resistance, non-adherence, etc.) Very costly Under- and over-diagnosis can result in significant cost, morbidity, and mortality FeNO Can Assist in the Diagnosis and Management of Typical and Difficult Asthma Circassia Pharmaceuticals, Inc. © All rights reserved.
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Asthma Heterogeneity Leads to Difficulty In Diagnosis And Management
Complex genetic disorder with heterogeneous phenotype1 Largely attributed to interactions among many genes and between these genes and the environment Increasingly recognized as syndrome rather than specific disease2,3 Variability in underlying inflammation, clinical symptoms, natural history, and response to treatment2,3 Variability contributes to suboptimal therapeutic control 1. Hakonarson et al. Am J Pharmacogenomics. 2002;2(3): Lötvall et al. J Allergy Clin Immunol. 2011;127(2): Dolovich et al. Thorax ;36(9): Circassia Pharmaceuticals, Inc. © All rights reserved.
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Phenotypes In Asthma “A cluster of characteristics that define a disease and its subsets”1 Three ways to classify asthma phenotypes1 Trigger induced (eg., allergic vs. non allergic; exercise induced; viral induced) Clinical presentation (eg., exacerbation-prone asthma; adult vs. childhood onset, steroid resistant) Inflammatory markers / pattern of inflammation (eg., biomarkers, genotypes) Phenotypes based on biomarkers (eg., FeNO, periostin, eosinophils) Phenotypes based on genotypes (eg., possible genes associated aspirin-exacerbated respiratory disease; genes associated with FeNO)2,3 Traditional measures do not allow phenotyping by pattern of inflammation 1. Lockey RF, Haley JA. Asthma Phenotypes Taskforce. Available from: Accessed 2 June Ledford DK, et al. J Allergy Clin Immunol Pract 2014;2: Modena BD, et al. Am J Respir Crit Care Med 2014;190: Circassia Pharmaceuticals, Inc. © All rights reserved.
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Problems With The Current Approach to Evaluate / Manage Asthma
Available tools: Symptom / History Assessment Inconsistent reporting by patients Correlates more with bronchial hyper-responsiveness than with inflammation Pulmonary Function Testing Identifies obstruction which is not necessarily correlated with inflammation Heavily dependent upon patient effort Medications Only patients with T2 inflammation seem to respond to most anti-inflammatory therapies available Dependent upon adherence which is difficult to assess FeNO is an adjunct tool that can help to fill gaps left by other measures Circassia Pharmaceuticals, Inc. © All rights reserved.
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Cluster Phenotyping By Degree Of Th2 Inflammation
Two distinct molecular phenotypes: Therapy targeting Th2 cytokines only benefits Th2-driven phenotypes Non-Th2-driven asthma does not respond well to current therapies including ICS Woodruff PG, et al. Am J Respir Crit Care Med. 2009;180(5): Circassia Pharmaceuticals, Inc. © All rights reserved.
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Asthma Phenotypes: Not All Asthma Is Th2 Inflammation
Wenzel SE. Nat Med. 2012;18(5): Circassia Pharmaceuticals, Inc. © All rights reserved.
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Tools To Assess Inflammation
BAL, bronchoalveolar lavage; NO, nitric oxide. Circassia Pharmaceuticals, Inc. © All rights reserved.
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Nitric Oxide (NO) Production1,2 – Exhaled NO Is A Direct Signal Of Th2 / Allergic Airway Inflammation NO — endogenous regulatory molecule Synthesis regulated by family of enzymes — NO synthases (NOS) Inducible NOS-derived NO is predominantly produced in bronchial wall epithelial cells Exhaled NO levels increase during Th-2 (allergic) inflammation—often correlate with eosinophilic inflammation AP, activator protein; iNOS, inducible nitric oxide synthase; IL, interleukin; IFN-, interferon-gamma; STAT, signal transducer and activator of transcription. 1. Yates. Immunol Cell Biol. 2001;79(2): Alving and Malinovschi. Eur Respir Mon. 2010;49:1-31. Circassia Pharmaceuticals, Inc. © All rights reserved.
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A Framework For Utilizing FeNO In Asthma
“Typical” Asthma Identifies Th2 phenotype and likelihood of response to ICS therapy Identifies adherence / non-adherence Identifies ongoing allergen exposure Can be used to monitor and titrate dose of ICS to reduce exacerbations and optimize therapy Differentiates symptoms (cough, wheeze, short of breath) related to Th2 inflammation from symptoms related to other causes (GERD, VCD, AR/Sinusitis, etc.) Severe / Difficult-to-manage Asthma Identifies persistence (or absence) of Th2 inflammation despite therapy Identifies non-adherence as possible cause of difficulty with asthma control May help to predict / identify patients in whom therapy with biologics should be considered Omalizumab Mepolizumab Dupilumab Hankin CS et al. J Allergy Clin Immunol 2013; 131s: AB126. Circassia Pharmaceuticals, Inc. © All rights reserved.
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FEV1 bronchodilator response
Significantly Better Than FEV1 – FeNO Measurement Predicts ICS Responsiveness 1.00 In patients with nonspecific symptoms, a FeNO value of > 47 ppb is highy indicative of corticosteriod responsiveness FeNO measurement was significantly better than FEV1, bronchodilator for predicting response to inhaled fluticasone propionate (P < 0.01) 0.75 Sensitivity 0.50 0.25 FeNO 52 patients referred by their family practitioners to the hospital with persistent, previously undiagnosed respiratory symptoms FEV1 bronchodilator response 1-Specificity 1.00 1. Smith et al. Am J Respir Crit Care Med. 2005;172(4): Circassia Pharmaceuticals, Inc. © All rights reserved.
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Exhaled NO Identifies Steroid Responsiveness
Unlikely to respond to inhaled steroids (negative predictive value – NPV) Likely to respond to inhaled steroids (positive predictive value – PPV) 47 ppb Nonspecific respiratory symptoms 91% NPV 82% PPV 91% NPV 25 ppb 35 ppb Cough 88% PPV 91% NPV 30 ppb Patients with “difficult asthma” already on ICS 88% PPV FeNO measurements provide the physician with means of evaluating asthma patients’ response to anti-inflammatory therapy, as an adjunct to the established clinical and laboratory assessments in asthma. Not all patients with asthma will have an elevated FeNO level. FeNO levels should be interpreted in the clinical context 1. Smith et al. Am J Respir Crit Care Med. 2005;172(4): Circassia Pharmaceuticals, Inc. © All rights reserved.
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Study Design of FeNO Guided Therapy
Asthma Control Questionnaire (ACQ), SABA, ICS use recorded at every visit Total subjects 181 (93 FeNO, 88 Control) recruited from 17 primary care sites in Sweden, mild-to-moderate asthma Average age: 40.9 FeNO, 41.1 Control Baseline FEV1 (% predicted): 84.3 ± FeNO, 83.7 ±12.5; Baseline ICS dose μG/D Syk et al. J Allergy Clin Immunol Pract. 2013;1(6): Circassia Pharmaceuticals, Inc. © All rights reserved.
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FeNO-directed Therapy Reduces Exacerbations
No significant difference between groups concerning lung function mean daily use of SABA mean daily use of ICS Syk et al. J Allergy Clin Immunol Pract. 2013;1(6): Circassia Pharmaceuticals, Inc. © All rights reserved.
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Cochrane: FeNO-based Management Reduces Exacerbation Rates
Population Meta-Analysis Design Odds Ratio for Reducing Exacerbations Using FeNO vs. Symptoms-based Approach Adult1 7 Studies, 1700 Randomized Subjects, 1546 Completed Study OR 0.60 (95% CI ); NNTB in one year = 12 (95% CI 8-32) Pediatric2 9 Studies , 1426 Randomized Subjects, 1370 Completed Study OR 0.63 (95% CI ) Conclusions: Tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreases the frequency of asthma exacerbations 1. Petsky HL et al. Cochrane Database of Systematic Reviews 2016; Petsky HL et al. Cochrane Database of Systematic Reviews 2016; abstract submitted for publication Circassia Pharmaceuticals, Inc. © All rights reserved.
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FeNO Facilitates Early Detection of ICS Non-adherence
Good adherence (n=21) Moderate adherence (n=9) 200 180 160 140 120 100 80 60 40 20 Poor adherence (n=11) No steroids (n=12) Mean value ± SD FEV , % predicted FeNO, ppb Mean FeNO levels were significantly reduced in patients with good ICS adherence* FEV1 levels were not substantially different among adherence groups SD, standard deviation. *Adherence determined by calculating number of doses taken per day/doses prescribed x 100. Good, moderate, and poor adherence defined as >75% adherence, 50% to 75% adherence, or <50% adherence to prescribed medication, respectively. Delgado-Corcoran et al. Pediatr Crit Care Med. 2004;5(1):48-52 Circassia Pharmaceuticals, Inc. © All rights reserved.
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Identifying Inflammation Without FeNO
Observational study of 50 previously diagnosed asthma patients (age 7-60) in a large allergy practice CONSENT Patient evaluation Exam Asthma Control test Spirometry FeNO (not revealed) HCP assessment of airway inflammation: High Intermediate Low Treatment recommendation FeNO score revealed TREATMENT MODIFICATION, IF NEEDED Laforce et al. Ann Allergy Asthma Immunol. 2014;113(6): Circassia Pharmaceuticals, Inc. © All rights reserved.
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Predicting Airway Inflammation Is a Coin Toss
FeNoO and Clinical evaluation inconsistent, n=25 FeNO and clinical evaluation agree, n=25 Standard clinical assessment of airway inflammation (history, symptom evaluation, spirometry) was inconsistent with underlying inflammation revealed by FeNO in 50% of patients (1/3 overestimate of inflammation, 2/3 underestimate of inflammation) Laforce et al. Ann Allergy Asthma Immunol. 2014;113(6): Circassia Pharmaceuticals, Inc. © All rights reserved.
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A Framework For Utilizing FeNO In Asthma
“Typical” Asthma Identifies Th2 phenotype and likelihood of response to ICS therapy Identifies adherence / non-adherence Identifies ongoing allergen exposure Can be used to monitor and titrate dose of ICS to reduce exacerbations and optimize therapy Differentiates symptoms (cough, wheeze, short of breath) related to Th2 inflammation from symptoms related to other causes (GERD, VCD, AR/Sinusitis, etc.) Severe / Difficult-to-Manage Asthma Identifies persistence (or absence) of Th2 inflammation despite therapy Identifies non-adherence as possible cause of difficulty with asthma control May help to predict / identify patients in whom therapy with biologics should be considered Omalizumab Anti-IL-5 (mepolizumab, reslizumab) Dupilumab (?) Hankin CS et al. J Allergy Clin Immunol 2013; 131s: AB126. Circassia Pharmaceuticals, Inc. © All rights reserved.
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Severe Asthma: Increased Cost, Morbidity and Mortality
5 - 10% of 26 million Americans suffering from asthma experience severe disease About 1/2 of patients with severe asthma have uncontrolled severe asthma Approximately 1/2 of direct asthma costs related to care of patients with severe disease ($56 billion total, $28 billion for severe asthma) Patients with uncontrolled severe asthma incur up to 3x cost compared to controlled severe asthma ($21 billion) 2.5% - 5% (650,000 – 1.3 million) with severe uncontrolled disease account for 37.5% of asthma-related direct costs Estimated per-patient direct asthma costs between $16,154 - $32,308 per year Pharmaceuticals represent the single largest expenditure for asthma care Hankin CS et al. J Allergy Clin Immunol 2013; 131s: AB126. Circassia Pharmaceuticals, Inc. © All rights reserved.
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FeNO Measurement May Help Guide Treatment Response To Other Therapies
FeNO measurements may be of value in predicting likelihood of response to treatments other than ICS: Anti-IgE1, Omalizumab4 Drugs inhibiting the IL-4 and IL-13 pathway2,3 Anti-TSLP therapy5 Mepolizumab6 Oral Steroids7 FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; IL, interleukin. 1. Hanania et al. Am J Respir Crit Care Med. 2013;187: Corren et al. N Engl J Med. 2011;365: Wenzel et al. N Engl J Med ;368: Hanania et al. Ann Intern Med. 2011;154: Gauvreau et al. N Engl J Med. 2014;370: Pavord ID et al. Lancet 2012;380: Kupczyk M, et al. Respiratory Medicine 2013;107:1521–1530. Circassia Pharmaceuticals, Inc. © All rights reserved.
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FeNO Measurement Identifies Oral Steroid Responsiveness In Severe Asthma
“Sputum eosinophils and FeNO represented the most promising options for predicting favorable outcome to oral steroid treatment” Factor Odds Ratio 95% CI RR eNO > 50 ppb 6.94 1.13, 42.38 4.82 1.06, 21.78* Blood eosinophils > 0.44 x 109/L 3.72 1.09, 12.68 2.891 1.08, 7.58** *p=0.03; **p=0.029. eNO/FeNO, exhaled nitric oxide. 1. Kupczyk M, et al. Respiratory Medicine 2013;107:1521–1530. Circassia Pharmaceuticals, Inc. © All rights reserved.
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Diagnostic Accuracy of FeNO, Blood Eosinophils, Total IgE And Their Combinations To Identify Sputum Eosinophils ROC Characteristics for FeNO, Blood Eosinophils, IgE and combinations Westerhof et al. Eur Respir J. 2015;46(3): Circassia Pharmaceuticals, Inc. © All rights reserved.
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FeNO May Predict Response To Omalizumab
FeNO identifies patients likely (and unlikely) to respond to Xolair® (omalizumab) – $10,000 - $30,000 per year treatment for moderate-to-severe allergic asthma CI = confidence interval. Mean percent reduction (95% CI) in protocol-defined asthma exacerbation rate in the low- and high-biomarker subgroups (baseline fractional exhaled nitric oxide [FeNO], peripheral blood eosinophils, and serum periostin). *Exacerbation reduction P values; omalizumab versus placebo in each biomarker subgroup. Hanania et al. Am J Respir Crit Care Med. 2013;187: Circassia Pharmaceuticals, Inc. © All rights reserved.
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FeNO Measures Response To A New α-IL4 Monoclonal Antibody
Note that FeNO changes also correlate well with lung function changes in this trial! Wenzel et al. N Engl J Med. 2013;368: Circassia Pharmaceuticals, Inc. © All rights reserved.
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Eosinophils And FeNO Predict Response To Mepolizumab
FeNO > 50 and blood eosinophil ≥300 predicted response to mepolizumab Mepolizumab reduced sputum eosinophils in patients with eosinophilic asthma Eosinophils were a better predictor than FeNO, but both identified patients likely to respond Pavord ID et al. Lancet 2012;380: Circassia Pharmaceuticals, Inc. © All rights reserved.
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NIOX VERO® Only available point-of-care device to measure FeNO
Appropriate for patients ≥ 7 years of age Easy-to-follow, on-screen guidance 10 seconds of active patient participation with a moderate exhalation (50 ml/sec) Results available in approximately 1 minute Unlike PFTs, a result cannot be affected by patient effort If the patient exhales outside of range (high / low), no result is delivered, and test can quickly be restarted PFT, pulmonary function test. Circassia Pharmaceuticals, Inc. © All rights reserved.
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Additional Factors Affecting FeNO Levels1-12
Airway infection (viral) Allergic rhinitis Atopy Nitrate-rich diet Effects generally not clinically significant Spirometric maneuvers that cause bronchospasm Smoking Alcohol consumption Exercise 1. Sanders et al. J Allergy Clin Immunol. 2004;113(4): Henriksen et al. Eur Respir J. 1999;13(2): Olin et al. Respir Med ;95(2): Papi et al. Am J Respir Crit Care Med. 2000;162(5): Silkoff et al. Am J Respir Crit Care Med. 1999;159: Terada et al. Am J Respir Crit Care Med. 2001;164: Yates et al. Eur Respir J. 1996;9(6): Piacentini et al. Thorax. 2002;57: Narang et al. Thorax. 2002;57(7): Kaneko et al. Am J Respir Crit Care Med. 1998;158(3): Verleden et al. Chest ;116(1): Silkoff et al. J Allergy Clin Immunol. 2004;114(5): Circassia Pharmaceuticals, Inc. © All rights reserved. 31
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INCREASING FeNO level*
FeNO Interpretation INTERMEDIATE/ INCREASING FeNO level* LOW FeNO level HIGH FeNO level < 25 ppb in adults < 20 ppb in children ppb in adults ppb in children > 50 ppb in adults > 35 ppb in children Eosinophilic inflammation less likely Eosinophilic inflammation likely Symptomatic† patients unlikely to benefit from trial of or additional ICS therapy; consider other possible etiologies‡ Symptomatic patients likely to benefit from trial or or increase in ICS/anti-Th2 therapy; investigate allergen exposure Cautious interpretation; based on clinical judgment, consider initiating trial of or increasing ICS therapy / adherence and monitor change in FeNO levels *Increasing defined as >40% increase from previous stable FeNO level. †Chronic cough and/or wheeze and/or shortness of breath for >6 weeks. ‡For example, rhinosinusitis, bronchiectasis, primary ciliary dyskinesia, anxiety-hyperventilation, cardiac disease, GERD, or vocal cord dysfunction. Dweik et al. Am J Respir Crit Care Med. 2011;184(5): Circassia Pharmaceuticals, Inc. © All rights reserved.
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What Does A ‘Low’ FeNO Suggest?
That there is a low likelihood of Type-2 Inflammation Also known as Th2 or allergic inflammation That there is a low likelihood that the patient will respond to inhaled corticosteroids at the time of measurement Or other anti-inflammatory therapy aimed at Type-2 inflammation, including biologics It is important to note that a low FeNO does not mean a patient does not have asthma or that they may not develop Th2 inflammation at a later time Asthma is a variable disease over time and disease activity can be affected by exposures, allergic sensitivity, and other factors Circassia Pharmaceuticals, Inc. © All rights reserved.
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American Thoracic Society (ATS) Guidelines1 For FeNO Use
In chronic inflammatory airway disease, including asthma, conventional tests such as FEV1 reversibility are only indirectly associated with airway inflammation. FeNO offers advantages for patient care including: Detecting allergic airway inflammation Determining likelihood of inhaled corticosteroid (ICS) responsiveness Monitoring airway inflammation to determine potential need for ICS Unmasking otherwise unsuspected nonadherence to ICS therapy AAAAI and ACAAI have endorsed the ATS Clinical Practice Guideline on FeNO2 1. Dweik et al. Am J Respir Crit Care Med. 2011;184(5): AAAAI and ACAAI. Accessed November 12, 2015. Circassia Pharmaceuticals, Inc. © All rights reserved.
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Reveal if a patient will benefit from ICS treatment
Guide and optimize ICS therapy FeNO Reveal if a patient will benefit from ICS treatment Detect and improve adherence Reduce exacerbations by up to 50% Circassia Pharmaceuticals, Inc. © All rights reserved.
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NIOX VERO® and NIOX® are registered trademarks of Circassia AB
NIOX VERO® and NIOX® are registered trademarks of Circassia AB. CIRCASSIA is a registered trademark of Circassia Limited. © 2016 Circassia Pharmaceuticals Inc.. All rights reserved. October XXXXX-XX
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