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Pulmonary integrated care: from bench to bedside in asthma

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1 Pulmonary integrated care: from bench to bedside in asthma
PneumoTrieste 2017 Trieste 3 Aprile 2017 Pulmonary integrated care: from bench to bedside in asthma Leonardo M. Fabbri, MD, FERS, AE Professor of Respiratory and Internal Medicine (-2016) University of Modena and Reggio Emilia

2 THE GOALS OF ASTHMA MANAGEMENT ARE:
Overall Asthma Control achieving reducing Current control Future risk defined by defined by Symptoms Reliever use Instability/ worsening Exacerbations Activity Lung function Loss of lung function Adverse effects of medication

3 Stepwise approach to control asthma symptoms and reduce risk
Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference REVIEW RESPONSE ASSESS ADJUST TREATMENT Symptoms Exacerbations Side-effects Patient satisfaction Lung function Asthma medications Non-pharmacological strategies Treat modifiable risk factors STEP 5 STEP 4 STEP 3 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Refer for add-on treatment e.g. tiotropium,* anti-IgE, anti-IL5* Med/high ICS/LABA Low dose ICS/LABA** Low dose ICS Other controller options Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) Add low dose OCS As-needed short-acting beta2-agonist (SABA) As-needed SABA or low dose ICS/formoterol# RELIEVER • Provide guided self-management education (self-monitoring + written action plan + regular review) • Treat modifiable risk factors and comorbidities, e.g. smoking, obesity, anxiety • Advise about non-pharmacological therapies and strategies, e.g. physical activity, weight loss, avoidance of sensitizers where appropriate • Consider stepping up if … uncontrolled symptoms, exacerbations or risks, but check diagnosis, inhaler technique and adherence first • Consider adding SLIT in adult HDM-sensitive patients with allergic rhinitis who have exacerbations despite ICS treatment, provided FEV1 is >70% predicted • Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations. Ceasing ICS is not advised. REMEMBER TO... SLIT added as an option GINA 2017, Box 3-5 (1/8) © Global Initiative for Asthma

4 Identifying new biological treatments to target molecular mechanisms of severe asthma
MONOCLONAL ANTIBODIES IgE, TNFalpha, IL5, IL13, IL4R, IL-17 NOVEL MOLECULES GATA-3-mRNA-specific DNAzyme CXCR2 antagonist PHARMACOLOGIC AGENTS Roflumilast, Tiotropium, Macrolides 4

5 INTERLEUKINS/CYTOKINES
Targetting INTERLEUKINS/CYTOKINES TSLP Th2 (ILC2) T2 Non-T2 AMG157 IL-13 IL-5 IL-4Rα IL-17 TNFα CXCR8 IgE IL-4 IL-13 IL-5Rα GSK679586 Lebrikizumab Tralokinumab Mepolizumab Reslizumab Brodalumab Benralizumab AMG317 Dupilumab Etanercept Golimumab CXCR2 Antagonist (SCH527123) Omalizumab QGE031 Quilizumab

6 Binding site of omalizumab to IgE
C3

7 Humbert M et al; Allergy 2005; 60:309-316
Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE P=0.042 Asthma exacerbations rate Clinically significant 0.91 1.0 0.8 0.68 0.6 0.4 0.2 omalizumab placebo 0.6 0.48 Severe asthma exacerbations rate P=0.002 0.4 0.24 0.2 omalizumab placebo Humbert M et al; Allergy 2005; 60:

8 TH2 IMMUNE PROCESSES IN THE AIRWAYS OF PEOPLE WITH ASTHMA
Wenzel S et al, Nat Med. 2012;18(5):716-25

9 Bel EH et al, N Engl J Med 2014; 371:1189-97
ORAL GLUCOCORTICOID-SPARING EFFECT OF MEPOLIZUMAB IN EOSINOPHILIC ASTHMA In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid sparing effect, reduced exacerbations, and improved control of asthma symptoms Bel EH et al, N Engl J Med 2014; 371:

10 CHANGE FROM BASELINE IN BLOOD EOSINOPHILS Adjusted ratio to baseline
4 8 12 16 20 24 Time (weeks) Placebo Mepolizumab 100mg SC 1.5 0.5 0.25 1 0.125 0.063 Bel EH et al, N Engl J Med 2014; 371:

11 MEDIAN OCS DOSE PERCENT REDUCTION Median OCS change from baseline (%)
40 -80 -40 20 -20 -60 Optimized dose Baseline - Week 4 Week 4 – Week 8 Week 8 – Week 12 Week 12 – Week 16 Week 16 – Week 20 Maintenance dose Placebo (N=66) Mepolizumab (N=69) Bel EH et al, N Engl J Med 2014; 371:

12 CUMULATIVE NUMBER OF EXACERBATIONS OVER TIME
Cumulative number of clinically significant exacerbations 4 8 12 16 20 24 Time (weeks) Placebo Mepolizumab 100mg SC 70 50 30 60 40 10 Bel EH et al, N Engl J Med 2014; 371:

13 Bel EH et al, N Engl J Med 2014; 371:1189-97
ORAL GLUCOCORTICOID-SPARING EFFECT OF MEPOLIZUMAB IN EOSINOPHILIC ASTHMA In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid sparing effect, reduced exacerbations, and improved control of asthma symptoms. Bel EH et al, N Engl J Med 2014; 371:

14 *P<0.05; **P<0.01; ***P<0.001.
aData for CALIMA from high-dosage ICS cohort Analysis via negative binomial model including covariates treatment group, region, number of exacerbations in the previous year, and use of maintenance oral corticosteroids. Values above bars represent 95% CI. AER=annual exacerbation rate; benra=benralizumab; CI=confidence intervals; eos=baseline blood eosinophil count; FAS=full analysis set; ICS=inhaled corticosteroid; Q4W=every 4 weeks; Q8W=every 8 weeks.

15 Early improvement in lung function were maintained
*P<0.05; †P<0.05; error bars represent 95% CIs Analysis via mixed-effect model repeat measurement (baseline, oral corticosteroid use, region, treatment, treatment duration) benra=benralizumab; CI=confidence interval;eos=baseline blood eosinophil count; FEV1=forced expiratory volume in 1 second; LS=least squares; ICS=inhaled corticosteriod; Q4W=every 4 weeks; Q8W=every 8 weeks

16 ANTI-IL-5 FOR SEVERE ASTHMA
Aiming High to Achieve Success We are moving into a new era of type 2 immunity mediated therapies that will bring new opportunities for clinicians and our patients, but with this opportunity comes new challenges Biomarkers will increase in importance to help drive precision medicine, but we need to understand how to use them, and in particular what cut points to apply For anti-IL-5 approaches we probably need to look toward elevated blood eosinophil counts, as aiming for a high cutoff is most likely the best way we shall achieve success Russell R et al., Chest 2016;150(4):

17 TH2 IMMUNE PROCESSES IN THE AIRWAYS OF PEOPLE WITH ASTHMA
Wenzel S et al, Nat Med. 2012;18(5):716-25

18

19 increases lung function reduces severe exacerbations
DUPILUMAB EFFICACY AND SAFETY IN ADULTS WITH UNCONTROLLED PERSISTENT ASTHMA DESPITE USE OF MEDIUM-TO-HIGH-DOSE INHALED CORTICOSTEROIDS PLUS A LONG-ACTING Β2 AGONIST Dupilumab increases lung function reduces severe exacerbations in patients with uncontrolled persistent asthma uncontrolled by optimal inhaled combination therapy, irrespective of baseline eosinophil count Wenzel S et al., Lancet Apr 26

20 IMPROVEMENT IN FEV1 IN LITERS (A, C, E) AND PERCENTAGE CHANGE (B, D, F) FROM BASELINE TO WEEK 24
769 severe asthmatics not controlled by inhaled LABA/highICS Treated with dupilumab mg sc every 2 or 4 weeks for 12 months Powered on FEV1 Dupilumab improves lung functions and reduces severe exacerbations irrespective of baseline eosinophil count Wenzel S et al., Lancet Apr 26

21 769 severe asthmatics not controlled by inhaled LABA/highICS
ADJUSTED ANNUALISED SEVERE EXACERBATION EVENT RATES ESTIMATED FROM THE 24-WEEK TREATMENT PERIOD IN THE OVERALL POPULATION (A) AND IN PATIENTS WITH BASELINE BLOOD EOSINOPHIL COUNTS OF AT LEAST 300 EOSINOPHILS PER ΜL (B) AND FEWER THAN 300 EOSINOPHILS PER ΜL (C) 769 severe asthmatics not controlled by inhaled LABA/highICS Treated with dupilumab mg sc every 2 or 4 weeks for 12 months Powered on FEV1 Dupilumab improves lung functions and reduces severe exacerbations irrespective of baseline eosinophil count Wenzel S et al., Lancet Apr 26

22 increases lung function reduces severe exacerbations
DUPILUMAB EFFICACY AND SAFETY IN ADULTS WITH UNCONTROLLED PERSISTENT ASTHMA DESPITE USE OF MEDIUM-TO-HIGH-DOSE INHALED CORTICOSTEROIDS PLUS A LONG-ACTING Β2 AGONIST Dupilumab increases lung function reduces severe exacerbations in patients with uncontrolled persistent asthma uncontrolled by optimal inhaled combination therapy, irrespective of baseline eosinophil count Wenzel S et al., Lancet Apr 26

23 THEORETICAL RANGE OF FACTORS THAT MAY BE INVOLVED IN THE DEVELOPMENT OF NON-TH2 ASTHMA
Wenzel S et al, Nat Med. 2012;18(5):716-25

24 INTERLEUKINS/CYTOKINES
Targetting INTERLEUKINS/CYTOKINES TSLP Th2 (ILC2) T2 Non-T2 AMG157 IL-13 IL-5 IL-4Rα IL-17 TNFα CXCR8 IgE IL-4 IL-13 IL-5Rα GSK679586 Lebrikizumab Tralokinumab Mepolizumab Reslizumab Brodalumab Benralizumab AMG317 Dupilumab Etanercept Golimumab CXCR2 Antagonist (SCH527123) Omalizumab QGE031 Quilizumab

25 Effect of golimumab, anti-TNFα antibody, in severe asthma
Symptomatic asthma despite >1,000µg fluticasone + LABA ± OCS ≥ 2 exacerbations per year FEV1 Severe exacerbations SAE’s in up to 30% vs 20% in placebo: pneumonia, cellulitis and sepsis; 8 malignancies. Wenzel AJRCCM 2009

26 Effect of golimumab, anti-TNFα antibody, on severe exacerbations
Patients with > 12% reversibility Patients with < 12% reversibility Wenzel AJRCCM 2009

27 A randomized, double-blind, placebo controlled study of tumor necrosis factor-α blockade in severe persistent asthma Overall, treatment with the anti tumor necrosis factor-α golimumab did not demonstrate a favourable risk-benefit profile in this study population of patients with severe persistent asthma Wenzel SE et al. AJRCCM 2009; 179:549-58

28 IL-17 IN HUMAN ASTHMA Cytokines from T-helper 2 cells are believed to be critical contributors of asthma. IL-17, another T-helper lymphocyte-associated cytokine, has been put forward as another potentially important mediator of asthma Several drugs that target IL-17 signaling aim to find whether there are any specific features of asthma that could be relieved by the use of IL-17-targeting drugs Silverpil E, Lindén A. Expert Rev Respir Med Apr;6(2):173-86

29 Effect of brodalumab, an anti-IL-17R antibody, in asthma
ICS: µg/day fluticasone Inadequate control ACQ≥1.5 FEV % Reversibility measured (> or <12%) No other medication Low reversibility High reversibility Busse et al AJRCCM 2013

30 Identifying new biological treatments to target molecular mechanisms of severe asthma
MONOCLONAL ANTIBODIES IgE, TNFalpha, IL5, IL13, IL4R, IL-17 NOVEL MOLECULES GATA-3-mRNA-specific DNAzyme CXCR2 antagonist PHARMACOLOGIC AGENTS Roflumilast, Tiotropium 30

31 GATA-3 IS CONSIDERED A KEY TRANSCRIPTION FACTOR IN
TH2-DRIVEN INFLAMMATORY DISEASES Barnes P, JCI 118 (2008):

32 DNAzyme-based GATA-3 antagonist for the treatment of moderate to severe Th2-driven asthma
DNAzymes are single-stranded DNA molecules comprising a catalytic domain flanked by two binding domains The binding domains attach to a specific sequence of targeted mRNA (antisense), in case of SB010 GATA-3 Mrna After binding to the target, the catalytic domain then cleaves the mRNA, thereby inhibiting relevant cytokine expression SB010 significantly reduces expression of key cytokines interleukin (IL)-4, IL- 5, and IL-13, and is safe and well-tolerated in toxicological studies with negligible side-effects. 32

33 ALLERGEN-INDUCED ASTHMATIC RESPONSES MODIFIED BY A GATA3-SPECIFIC DNA-ZYME
SB010 significantly attenuates both late and early asthmatic responses after allergen provocation in patients with allergic asthma Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses Krug N et al. N Engl J Med 2015;372:

34 A GATA3-SPECIFIC DNA-ZYME INHIBITS
ALLERGEN-INDUCED ASTHMATIC RESPONSES Figure 2 Lung Function after Allergen Challenge. Panels A shows the forced expiratory volume in 1 second (FEV1) as a percentage of the baseline FEV1 after allergen challenges performed before initiation of the study drug (pretreatment), and Panel B shows these values after completion of the 28-day study period (post-treatment). After an allergen challenge, lung function was recorded for 7 hours. Mean (±SE) values are shown. Both the early asthmatic response (EAR) and the late asthmatic response (LAR) were significantly attenuated after treatment with SB010 (solid line) as compared with placebo (dashed line). ANCOVA denotes analysis of covariance. Panel C shows the individual patient values for changes from pretreatment to post-treatment in the area under the curve (AUC) for the late allergic response. Panel D shows individual patient values for the changes in the maximum decline in FEV1 during the late allergic response. The thick black lines represent the mean values. Negative values reflect improvement and positive values reflect worsening after 4 weeks of receipt of the study drug. Each symbol represents an individual patient in the SB010 or placebo group. The complete data set for each patient is shown in Tables S5A and S5B in the Supplementary Appendix. Krug N et al. N Engl J Med 2015;372:

35 ALLERGEN-INDUCED ASTHMATIC RESPONSES MODIFIED BY A GATA3-SPECIFIC DNA-ZYME
SB010 significantly attenuates both late and early asthmatic responses after allergen provocation in patients with allergic asthma Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses Krug N et al. N Engl J Med 2015;372:

36 Expression of CXCR2 on Neutrophils
Pharmacol Rev 56: , 2004 Barnes JACI 2007 36

37 CXCR2 Biology Airway Epithelium Ciliated Epithelial Cells Goblet Cell (discharging) Alveolus Type I Type II Goblet cell hyperplasia Mucus secretion Smooth Muscle Contraction Migration Macrophage CXCR2 Angiogenesis Neutrophil Chemotaxis Eosinophil T-cell Fibroblast myofibroblast Microvascular leakage VCAM-1 expression Blood Vessel receptors for the 7 structurally related ELR chemokines; IL-8, gro alpha, beta; leukocyte/neutrophil migration to sites of inflammation; other cells/tissues; implication for respiratory diseases; CXCR2 picture neutrophil has central role but other players are important as well Mast Cell Capillary Blood Vessel collagen fibroblast neutrophil

38 Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial The SCH caused a mean reduction of 36.3% in sputum neutrophil percentage compared to a 6.7% increase in the placebo arm (P = 0.03). The mean absolute neutrophil count in blood was reduced by 14% at the end of 4 weeks, but recovered by the 5th week. There were no differences in the overall rates of adverse events among the groups. There were fewer mild exacerbations (1.3 vs. 2.25, P = 0.05) and a trend towards improvement in the ACQ score (P = 0.053). No statistically significant changes were observed FEV 1, sputum myeloperoxidase, IL8 or elastase. Nair P et al, Clin Exp Allergy 2012;42:

39 Identifying new biological treatments to target molecular mechanisms of severe asthma
MONOCLONAL ANTIBODIES IgE, TNFalpha, IL5, IL13, IL4R, IL-17 NOVEL MOLECULES GATA-3-mRNA-specific DNAzyme CXCR2 antagonist PHARMACOLOGIC AGENTS Roflumilast, Tiotropium, Macrolides 39

40 TIOTROPIUM IN ASTHMA POORLY CONTROLLED
WITH STANDARD COMBINATION THERAPY Kerstjens H.A.M. et al., N Engl J Med 2012; 367(13): Days 60 20 40 50 30 10 Severe exacerbations 225 25 125 75 100 150 175 200 250 275 300 325 454 453 319 339 435 430 367 378 412 409 338 401 379 389 356 363 353 332 348 303 331 290 282 308 272 298 Placebo Tiotropium Patients with at least one severe asthma exacerbation (%) No. At risk

41 severe exacerbation and provided modest sustained bronchodilation
TIOTROPIUM IN ASTHMA POORLY CONTROLLED WITH STANDARD COMBINATION THERAPY In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation Kerstjens H.A.M. et al., N Engl J Med 2012; 367(13):

42 ROFLUMILAST IN CLINICAL PRACTICE
Clinical benefits Roflumilast is an anti-inflammatory drug and not a bronchodilator In patients with severe COPD with chronic bronchitis and increased risk of exacerbations it reduces exacerbations improves lung function Add-on to bronchodilatory maintenance treatment with additive effects Dia 2961 COPD is a chronic inflammatory condition leading to physiological changes in the lungs that cause the typical signs and symptoms of the disease. The precise causes of inflammation in COPD are not clearly defined but it is thought that cigarette smoke and other inhaled irritants may initiate the inflammatory response in susceptible individuals. In COPD, there is debate as to whether the airflow obstruction is primarily due to obstruction of the lumen of the small airways, as a result of chronic inflammation of the bronchioles (chronic bronchitis), or whether it is due to loss of elasticity and closure of the small airways as a result of enzymatic destruction of the alveolar walls (emphysema). PDE4 inhibition Calverley, et al. Lancet 2009; 374:685–9 Fabbri, et al. Lancet 2009; 374:695–703 Martinez FJ et al. Lancet 2015; published online on 12 February 42

43 ROFLUMILAST: CELLULAR TARGETS IN ASTHMA AND COPD
& N-OXIDE Endothelial cells permeability; E-/P-selectin; PMN adhesion, apoptosis Smooth muscle cells proliferation, migration; GM-CSF; Rantes; eotaxin relaxation, ET1 Neutrophil ROS; LTB4; NE, CD11b, Chemotaxis T-lymphocyte (CD4+ / CD8+) proliferation; cytokines (IL-2, -4, -5, -13, IFN) Granzyme B Monocyte/M Dendritic cell TNF; IL-12; ROS Airway Epithelial cells MUC5AC CFTR, CBF Fibroblast proliferation, chemotaxis; myofibroblast transition, ECM, cytokines, ICAM-1 STRUCTURAL REMODELING (Enphysema, Fibrotic) MUCOCILIARY MALFUNCTION COPD-RELATED INFLAMMATION

44 Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects
Gauvreau GM J et al. Respir Res 2011;12:140

45 CHRONIC AZITHROMYCIN DECREASES THE FREQUENCY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS
When added to usual treatment, azithromycin, 250 mg taken daily for one year decreases COPD exacerbations and improves quality of life but also causes hearing decrements in a small fraction of subjects Alpert RK et al, NEJM 2011; 365: Siafakas NM. Preventing exacerbations of COPD--advice from Hippocrates. N Engl J Med Aug 25;365(8):753-4.

46 Identifying new biological treatments to target molecular mechanisms of severe asthma
MONOCLONAL ANTIBODIES IgE, TNFalpha, IL5, IL13, IL4R, IL-17 NOVEL MOLECULES GATA-3-mRNA-specific DNAzyme CXCR2 antagonist PHARMACOLOGIC AGENTS Roflumilast, Tiotropium, Macrolides 46

47 Pulmonary integrated care: from bench to bedside in asthma
PneumoTrieste 2017 Trieste 3 Aprile 2017 Pulmonary integrated care: from bench to bedside in asthma Leonardo M. Fabbri, MD, FERS, AE Professor of Respiratory and Internal Medicine (-2016) University of Modena and Reggio Emilia


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