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 baseline4 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

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