1. Improving Control in Severe Asthma
Stanley Fineman, MD, MBA
Adjunct Assoc Professor of Pediatrics
Emory Univ School of Medicine
Atlanta Allergy & Asthma

2. Faculty Disclosures
Speakers’ Bureaus: AstraZeneca Pharmaceuticals LP, Boehringer Ingelheim Pharmaceuticals, Inc., Shire/Takeda
Contracted Research: Aimmune, BioCryst, DBV Technologies, Regeneron Pharmaceuticals

3. Learning Objectives
Describe clinical criteria for severe asthma and outline an approach to assessing symptom control and disease burden
Identify known phenotypes of severe asthma
Describe and identify severe asthma endotypes that can inform treatment selection
Develop an approach to the treatment of severe asthma that is personalized to the individual patient and describe the most recent clinical data on new and emerging therapies for severe asthma
Identify strategies for improving communication to promote collaborative decision-making and the ability to self-manage among patients with severe asthma

4. Overview of Severe Asthma

5. Overview of Severe Asthma
Asthma is a highly heterogeneous disease
Affects an estimated 10% to 15% of the asthma population
Characteristics of severe disease:
Not responsive to high-dose ICS with or without additional controller therapies (ie, LABAs, LAMAs, LTRAs, and/or theophylline)
Significantly impairs patient activity and QOL and increases patient risk for exacerbation
Optimal treatment remains challenging
Requires shift from guideline-directed management to a personalized approach to treatment in relation to disease characteristics
ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; QOL, quality of life.
Chung KF, et al. Eur Respir J. 2014;43(2): ; Katial R, et al. J Allergy Clin Immunol Pract. 2017;5(2S):S1-S14; Hossny E, et al. World Allergy Organ J. 2017;10(1):28.

6. Epidemiology of Uncontrolled Asthma
Prevalence of severe asthma is dependent on how it is defined
Under aggressive treatment schemes, both controlled and uncontrolled asthma are considered severe
Severe asthma symptoms are associated with:
Lack of, and noncompliance with, essential asthma medications
Poor patient education on asthma management
Failure to implement guidelines on asthma diagnosis and treatment
Severe asthma is associated with increased risk for hospitalization and death
CDC Fact Sheet on Asthma. Available at:
Poon AH, Hamid Q. Ann Am Thor Soc. 2016;13(suppl 1):68-77.

7. Economic Impact of Severe Asthma
Chastek B, et al. JMCP. 2016;22(7):

8. Definition of Severe Asthma

9. ATS/ERS (2014): Uncontrolled Asthma
One or more of the following:
Poor symptom control: ACQ consistently >1.5, ACT <20
Frequent severe exacerbations: ≥2 bursts of systemic CS in the previous year
Serious exacerbations: ≥1 hospitalization, ICU stay, or mechanical ventilation in the previous year
Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted
Controlled asthma that worsens on tapering of high doses of ICS, systemic CS, or additional biologics
ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; CS, corticosteroid; ICU, intensive care unit; FEV1, forced expiratory volume in 1 second.
Chung KF, et al. Eur Respir J. 2014;43(2):

10. ATS/ERS (2014): Severe Asthma
Patients ≥6 years of age who require GINA Step 4 or 5 treatment to prevent asthma from becoming “uncontrolled,” or asthma remains “uncontrolled” despite Step 4 or 5 treatment, eg, high-dose ICS/LABA
Consider low-dose ICS
LTRA or
low-dose theophylline
Medium to high-dose ICS or
low-dose ICS
and LTRA or low-dose ICS and theophylline
Add tiotropium* or high-dose ICS
and LTRA or
high-dose ICS and theophylline
Add tiotropium*; add low-dose OCS
Low-dose ICS
Low-dose
ICS/LABA
Medium- or high-dose ICS/LABA
Refer for add-on treatment
(eg, anti-IgE,
anti-IL-5)
STEP 1
STEP 2
STEP 3
STEP 4
STEP 5
Preferred Controller
Other
Controller
Options
Reliever
As needed SABA or low-dose ICS/LABA†
As needed short-acting
beta2-agonist (SABA)
ATS, American Thoracic Society; ERS, European Respiratory Society; GINA, Global Initiative on Asthma; IgE, immunoglobin E; IL, interleukin; OCS, oral corticosteroid.
*Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations; it is not indicated in children younger than 18 years old; †For patients prescribed beclomethasone/formoterol or budesonide/formoterol.
Chung KF, et al. Eur Respir J. 2014;43(2): ; Chipps BE, et al. Ann Allergy Asthma Immunol. 2017;118:

11. Identification of Patients with Severe Asthma

12. Case Evaluation: Patient Description
Kate is a 41-year-old female with worsening symptoms of asthma, including persistent cough, wheezing, chest tightness, and shortness of breath
Diagnosed with:
Sinusitis at age 30
Asthma at age 33
Recent discovery of nasal polyps
ACT: 17 (<20=not well-controlled)
2 exacerbations during the past year
Symptoms have limited normal activities and prevented Kate from sleeping through the night
Current treatment regimen includes a fluticasone/salmeterol (500/50 bid) therapy and albuterol (prn)
bid, twice daily; prn, as needed. 12

13. Case Evaluation: Discussion
What would you do to assess Kate’s asthma?

14. Assessments to Distinguish Uncontrolled Asthma from Severe Asthma
Watch patient use their inhaler
Show correct method
Identify poor adherence to ensure it does not contribute to lack of control
Confirm adherence and check correct use of inhalers
Confirm evidence of airflow obstruction
If no evidence of reversibility, consider challenge test
Confirm the diagnosis of asthma
Check for risk factors or inducers such as smoking, beta-blockers or NSAIDs, or allergen exposure
Check for and manage comorbidities
Identify potential risk factors and assess for comorbidities
Move step up to next slide.
GINA. Global Strategy for Asthma Management and Prevention. Available at:

15. Medical & Treatment History
Patient Assessment
Medical & Treatment History
Current medication use and adherence
Exacerbation history and need for systemic corticosteroids
Comorbidities
Clinical Assessment
ACT/ACQ/AIS
QOL/AQLQ
Laboratory Testing
Lung function (spirometry)
Blood eosinophils
Serum IgE
Allergy testing (skin or serological)
FeNO
Chest imaging
AIS, Asthma Impact Survey; AQLQ, Asthma Quality of Life Questionnaire.
Chung KF, et al. Eur Respir J. 2014;43(2):

16. Kate, 41-year-old Female: Assessment
Kate demonstrates correct use of inhaler
Reports adherence to treatment and regular medication refills
Confirm adherence and check correct use of inhalers
FEV1: 60%
16% improvement with bronchodilator
Evidence of airflow obstruction
Confirmed comorbid sinusitis and nasal polyps
No identifiable exposure to allergens or pollutants
Nonsmoker
Identify potential risk factors and assess and manage comorbidities
What is the next step in Kate’s management?
Consider treatment step-up 16

17. Differential Diagnosis
More Common
Less Common
Chronic obstructive pulmonary disease (COPD)
Gastroesophageal reflux disease (GERD)
Heart failure
Cystic fibrosis (CF)
Vocal cord dysfunction (VCD)
Congenital or acquired immunodeficiency
Primary ciliary dyskinesia
Trachea and mainstem bronchi obstruction
Recurrent aspiration
Bronchiolitis
Psychogenic hyperventilation
Drug side effects (eg, ACE inhibitor-induced cough)
Pulmonary embolism
ACE, angiotensin-converting enzyme.
Chung KF, et al. Eur Respir J. 2014;43(2):

18. Severe Asthma Phenotypes and Endotypes

19. Asthma Is Not One Disease
Heterogeneous Disease
Symptoms
Onset
Responsiveness
Severity

20. Inflammatory Mechanisms and Pathobiologic Features Leading to Severe Asthma
Th, T helper cell; TSLP, thymic stromal lymphopoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; PGD2, prostaglandin D2; ILC, innate lymphoid cells; TGF-β, transforming growth factor beta; CXCL8, CXC motif chemokine ligand 8; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor alpha; BLT2, leukotriene B4 receptor 2.
Israel E, Reddel HK. N Engl J Med. 2017;377:

21. Asthma Pathophysiology
Normal
Eosinophilic Asthma
Noneosinophilic Asthma
Airway smooth muscle
Mast cell
Epithelium and reticular basement membrane
IgE
Allergic eosinophilic inflammation
Paucigranulocytic
B cells
Dendritic cell
IL4/13
IL5
Th2
Allergens
Pollutants, oxidative stress
Eosinophil
PGD2
Pollutants, microbes
Pollutants, oxidative stress, microbes
Dendritic cell
PGD2
IL23
Nonallergic eosinophilic inflammation
Th1/ Th17
Th1 + Th17 neutrophilic inflammation
IL33
IL17
IL5
TSLP
ILC3
ILC2
Goblet cell
CXCL8
PGD2
Macrophage
Mast cell
Neutrophil
Mixed granulocytic asthma
Papi A, et al. Lancet ;391(10122):

22. Asthma Phenotype vs. Endotype
The set of observable characteristics of an individual resulting from the interaction of its genotype with the environment
Endotype
A specific biologic mechanism that explains observable properties of an organism
Different asthma phenotypes and endotypes may respond differently to targeted therapies.

23. Asthma Phenotypes Category Phenotype Trigger-induced asthma Allergic
Nonallergic
Aspirin-exacerbated respiratory disease (AERD)
Infection
Exercise-induced
Occupational
Category
Phenotype
Trigger-induced asthma
Allergic
Nonallergic
Aspirin-exacerbated respiratory disease (AERD)
Infection
Exercise-induced
Occupational
Asthma patient characteristics
Smoking
Obesity
Elderly
Ethnicity
Category
Phenotype
Trigger-induced asthma
Allergic
Nonallergic
Aspirin-exacerbated respiratory disease (AERD)
Infection
Exercise-induced
Occupational
Asthma patient characteristics
Smoking
Obesity
Elderly
Black
Clinical presentation of asthma
Pre-asthma wheezing in infants
Episodic (viral wheeze)
Multi-trigger wheezing
Exacerbation-prone asthma
Asthma associated with apparent irreversible airflow limitation
Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.

24. Inflammatory Markers of Asthma
Type 2 asthma
Eosinophilic
High nitric oxide
High IgE
IL-4/IL-5/IL-13 mediated
Non-type 2 asthma
IL-6/IL-8/IL-17
IL-1/IL-6/IL-17/TNF-α mediated

25. Eosinophils Modulate the immune response
Promote airway hyper-responsiveness and remodeling
Cause bronchoconstriction
Release granular proteins (eg, ECP, EDN, and MBP)
Testing in blood or sputum
Blood eosinophil counts as low as 150 cells/µL may predict treatment response with targeted therapies
Associated cytokines:
IL-5
IL-4
IL-13
ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; MBP, major basic protein.
Douwes J, et al. Thorax. 2002;57(7): ; Eltboli O, Brightling C. Expert Rev Respir Med. 2013;1(7):33-42;
Ortega HG, et al. Lancet Respir Med. 2016;4(7): ; Carr T, et al. Am J Respir Crit Care Med. 2018;197(1):22-37.

26. Higher Eosinophils Correlate with Higher Risk for Exacerbation
Price Lancet Respiratory 2017
Adapted from: Price D, et al. J Asthma Allerg. 2016;9:1-12.

27. FeNO
Under physiological conditions, NO acts as a weak mediator of smooth muscle relaxation and protects against airway hyperresponsiveness
In the setting of asthma, NO may act as a proinflammatory mediator predisposing to airway hyperresponsiveness
Up-regulation occurs with inflammation
Associated with IL-13 cytokine
Picture showing that this is epithelial derived, 4-13 aspect on epithelium.
Show how this generated.
FeNO, forced exhaled nitric oxide; NO, nitric oxide.
Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.

28. Clinical Indications of FeNO
FeNO Levels
Clinical Indications
Low
<25 ppb in adults
<20 ppb in children
Eosinophilic inflammation and corticosteroid responsiveness is less likely
Medium
25-50 ppb in adults
20-35 ppb in children
Cautious interpretation necessary
High
>50 ppb in adults
>35 ppb in children
Eosinophilic inflammation and corticosteroid responsiveness likely
ppb, parts per billion.
Alving K, et al. Eur Respir J. 1993;6(9): ; Dwelk RA, et al. Am J Respir Crit Care Med. 2011;184(5):

29. IgE
Binds to FcεRI on mast cells, basophils, and antigen-presenting dendritic cells
Activates the release of inflammatory mediators
Associated cytokines:
IL-4
IL-13
Treatment with anti-IgE therapy is based on IgE ≥30 IU/mL
Anti-IgE therapy may be more effective in patients with high Th2-associated biomarkers
MHC, major histocompatibility complex.
Ahmad Al Obaidl AH, et al. J Asthma. 2008;45(8): ; Matsui EC, et al. Allergy. 2010;65(11): ; Hanania NA, et al. Am J Respir Crit Care Med. 2013;187(8):

30. Additional Biomarkers of Severe Asthma
Testing Method
Role in Allergic Pathway
Associated Cytokines
Neutrophil
Sputum
Significantly associated with severe asthma
Accumulates in the airways
Prominent in airway secretions during exacerbations
Associated with obesity, infections, and steroid resistance
IL-6, IL-8, IL-17
Periostin†
Serum, sputum
Regulates eosinophil recruitment and eosinophilic tissue infiltration
Active in Th2 mucosal inflammation, airway remodeling, and expression of inflammatory mediators
IL-13
DPP-4†
Serum
Stimulates the proliferation of bronchial smooth muscle cells and human fetal lung fibroblasts
Promotes fibronectin production
†Not commercially available.
DPP-4, dipeptidyl peptidase-4.
Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.

31. Case Evaluation: Discussion
How might biomarkers guide therapy?

32. Personalized medicine
Improved Understanding of Pathophysiologic Mechanisms May Guide Personalized Medicine
Empirical medicine
Stratified medicine
Personalized medicine
One treatment for all
Evidence-based
Different treatments for each group
Evidence-based
Biomarker-led
Individual treatments for each patient
Evidence-based
Patient-derived
Willis JCD, Lord GM. Nat Rev Immunol. 2015;15:

33. Traditional and Personalized Approaches to Treating Asthma
Personalized Approach to Asthma
Diagnosis
Determination of whether asthma is refractory
Characterize subtype
Phenotype
Endotype
Genotype
Gender
Age
Obesity
Ethnicity
Smoking Hx
Blood biomarkers
Sputum biomarkers
Other
IgE
Eosinophils
Periostin
Cytokines
Neutrophils
FeNO
Tailored therapy
Assess comorbidities
Traditional Guidance-Based Asthma Management
Diagnosis
Assessment of asthma severity
Avoidance of triggers and management of comorbidities:
Laryngopharyngeal reflux
Subacute bacterial infection
Sinus disease
Sleep apnea
Vocal cord dysfunction
Stepwise approach to therapy: SABA, ICS alone, ICS+LABA, ICS+LTRA, OCS, biologic therapy
Hx, history.
Katial R, et al. J All Clin Immunol In Practice. 2017;5(2):S1-S14.

34. Current Treatment Options

35. Kate, 41-year-old Female: Test Results
Serum IgE: 41 IU/mL (no antigen-specific IgE)
Blood eosinophil count: 215 cells/μL
FeNO: 41 ppb
Serum periostin level within normal limits.
What modifications to her current therapeutic regimen would you consider making?
What criteria would you use in selecting her treatment?

36. Place of Tiotropium in Severe Asthma
Significantly improves FEV1
Reduces exacerbations independent of T2 phenotype/endotype
Reduces overall risk for exacerbations requiring systemic glucocorticoids
May be added to high-dose ICS+LABA therapy prior to stepping up to other types of therapies
While phenotyping continues to emerge as an important component of evaluation, such information may not always be easily accessible (eg, for practices that lack access to experienced testing facilities). In general, tiotropium (which is known to reduce exacerbations and asthma worsening independent of T2 phenotype) may be added to high-dose ICS + LABA therapy prior to stepping up to other types of therapies (ie, OCS, newer biologics, or bronchial thermoplasty).
Kerstjens J. Allergy Clin Immunol. 2011;128(2): ; Casale TB, et al. J Allergy Clin Immunol Pract. 2018;6(3): e9.

37. Kate, 41-year-old Female: Treatment & Discussion
Kate is initiated on tiotropium therapy, but continues to demonstrate poor symptom control after 4 weeks.
How long would you wait before recommending a switch in therapeutic approach?
What type of therapy would you consider for Kate at this point?

38. Targeted Biologic Therapies for Severe Asthma
Biologic Therapy
Target
Approval Date
Indication
Omalizumab
IgE
2003
≥6 years of age
Positive skin test or in vitro reactivity to a perennial aeroallergen
Mepolizumab
IL-5
2015
Add-on maintenance
≥18 years of age
Eosinophilic phenotype
Reslizumab
2016
Benralizumab
IL-5Rα
2017
≥12 years of age
Eosinophilic asthma
Dupilumab
IL-4/ IL-13
2018
Add-maintenance for moderate-to-severe asthma
Corticosteroid dependent asthma regardless of phenotype
At-home administration

39. Patients with Exacerbations (%)
IgE-targeted Treatment with Omalizumab Reduces Exacerbations and Systemic Corticosteroid Use * *
Patients with Exacerbations (%)
*P<.05.
BDP, beclomethasone dipropionate.
Busse W, et al. J Allergy Clin Immunol. 2001;108(2):

40. Reduction in Asthma Exacerbation Rates in Low- and High-biomarker Subgroups
–32
Asthma Exacerbation Rate (mean, 95% CI)
Percent Reduction in Protocol-Defined
n=193 n=201 n=383 n=414 n=279 n=255
P=.45* P=.001* P=.54* P=.005* P=.94* P=.07* 40 20
–20
–40
–60
–80
<19.5 ppb ≥19.5 ppb <260/µL ≥260/µL <50 ng/mL ≥50 ng/mL
FeNO Eosinophils Periostin
–16
–53 –9
–30 –3
*Exacerbation reduction P-values; omalizumab vs. placebo in each biomarker subgroup.
Hanania N, et al. Am J Resp Crit Care Med. 2013;187:

41. Cumulative Number of Exacerbations
Exacerbation Rates and FEV1 After 32 Weeks of Treatment with Mepolizumab
P<.001 for both comparisons.
Cumulative Number of Exacerbations
Week
250
200
150
100 50
Asthma Exacerbations
Placebo
Mepolizumab 75 mg, intravenously
Mepolizumab 100 mg, subcutaneously
FEV1
Week 75 70 65 60
Placebo
Mepolizumab 75 mg, intravenously
Mepolizumab 100 mg, subcutaneously
FEV1 (% of Predicted Value)
P=.02 in the intravenous-mepolizumab group. P=.03 in the subcutaneous-mepolizumab group.
Ortega HG, et al. N Engl J Med. 2014;371:

42. Probability of Not Having CAE (%)
IL-5-targeted Treatment with Reslizumab: Impact on Exacerbation Risk and Lung Function
LS Mean Change from
Baseline FEV1 (L)
0.40
0.30
0.20
0.10
End
point
Visit (week)
Reslizumab 3.0 mg/kg
Placebo † *
Probability of Not Having CAE (%)
100 80 60 40 20
Placebo
Reslizumab
Placebo; n=244
Reslizumab 3.0 mg/kg; n=245
HR .575 (95% CI )
P<.0001
Time to First CAE (weeks)
*P<·05. †P<·01.
CAE, clinical asthma exacerbation.
Castro M, et al. Lancet Respir Med. 2015;3:

43. IL-5-targeted Treatment with Benralizumab Reduces Exacerbations in Patients with Elevated Eosinophils
51%*
45%*
28%‡
36%†
SIROCCO
CALIMA
*P<.001; †P<.002; ‡P<.02
Q4W, every 4 weeks; Q8W, every 8 weeks.
FitzGerald JM, et al. Lancet. 2016;388(10056): ; Bleecker ER, et al. Lancet. 2016;388(10056):

44. Change From Baseline Least-Squares Means (L)
Change in FEV1 for Patients Receiving High-dose ICS+LABA According to Baseline Blood Eosinophils
Eosinophils ≥300 cells per µL
Eosinophils <300 cells per µL
Change From Baseline Least-Squares Means (L)
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05 * †
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
Change From Baseline Least-Squares Means (L)
Placebo
Benralizumab 30 mg Q4W
Benralizumab 30 mg Q8W
*P<.05 for benralizumab Q4W vs placebo and for benralizumab Q8W vs placebo; †P<.05 for benralizumab Q8W vs placebo.
FitzGerald JM, et al. Lancet. 2016;388(10056):

45. Dupilumab: IL-4/IL-13 Antibody Targeting T2/Th2 Pathway
Dupilumab is a fully human monoclonal antibody that targets the IL-4Rα of the IL-4 and IL-13 receptors
Impaired KC differentiation
Low AMPs production
Increased expression of TARC and oxtaxin-3 (CCL26)
↑Airway inflammation
↑Mucus production
↑ Airway hyperresponsiveness
↑Airway remodeling
Eosinophil recruitment
Eosinophil
IL-4
IL-13
Increased production of eotaxin-1 (CCL11)
Fibroblast
IgE production
Th2 differentiation and survival
AMPs, antimicrobial peptides; KC, keratinocyte; TARC, thymus- and activation-regulated chemokine.
D’Erme AM. Drug Design Dev Ther. 2017;11:

46. Relative Risk vs. Placebo (95% CI)
Dupilumab Reduced Risk of Severe Exacerbation Independent of Baseline Blood Eosinophil Count
Dupilumab, 200 mg Q2W vs. Matched Placebo
Number of Patients
Subgroup
Placebo
Dupilumab
Relative Risk vs. Placebo (95% CI)
Overall
317
631
.52 ( )
Eosinophil count
≥300 cells/mm3
148
264
.34 ( )
≥150 to <300 cells/mm3 84
173
.64 ( )
<150 cells/mm3 85
193
.93 ( )
FeNO
≥50 ppb 71
119
.31 ( )
≥25 to <50 ppb 91
180
.39 ( )
<25 ppb
149
325
.75 ( )
Dupilumab
Better
Placebo
Q2W, every 2 weeks.
Castro M, et al. New Engl J Med. 2018;378(26):

47. Relative Risk vs. Placebo (95% CI)
Dupilumab Reduced Risk of Severe Exacerbation Independent of Baseline Blood Eosinophil Count
Dupilumab, 300 mg Q2W vs. Matched Placebo
Number of Patients
Subgroup
Placebo
Dupilumab
Relative Risk vs. Placebo (95% CI)
Overall
321
633
.54 ( )
Eosinophil count
≥300 cells/mm3
142
277
.33 ( )
≥150 to <300 cells/mm3 95
175
.56 ( )
<150 cells/mm3 83
181
1.15 ( )
FeNO
≥50 ppb 75
124
.31 ( )
≥25 to <50 ppb 97
186
.44 ( )
<25 ppb
144
317
.79 ( )
Dupilumab
Better
Placebo
Better
Castro M, et al. New Engl J Med. 2018;378(26):

48. Change from Baseline FEV1 Over 52-week Treatment with Dupilumab
Least-Squares Mean Change from Baseline in FEV1 (liters)
Week
0.4
0.3
0.2
0.1
0.0
Dupilumab, 300 mg
Dupilumab, 200 mg
Placebo, 2.00 mL
Placebo, 1.14 mL
Patients received dupilumab at a dose of 200 mg or 300 mg every 2 weeks, or a matched-volume placebo. For the lower dose of dupilumab, the matched placebo had a volume of 1.14 mL. For the higher dose of dupilumab, the matched placebo had a volume of 2.00 mL.
Castro M, et al. New Engl J Med. 2018;378(26):

49. Percentage Reduction in Oral
Dupilumab Reduces Oral Corticosteroid Use in Glucocorticoid-dependent Severe Asthma
Percentage Reduction in Oral
Glucocorticoid Dose
Week
–20
–40
–60
–80
Placebo
Dupilumab
Primary
endpoint
P<.001
In the intention-to-treat population, the least-squares mean (±SE) percentage change in the oral glucocorticoid dose from baseline to week 24, while asthma control was maintained, was -70.1±4.9% in the dupilumab group vs ±4.6% in the placebo group.
Rabe KF, et al. New Engl J Med. 2018;378(26):

50. Least-Squares Mean Difference P-value for Interaction
Dupilumab Percent Reduction in Oral Steroid Use According to Blood Eosinophil Group
Subgroup
Placebo
(n=107)
Dupilumab
(n=103)
Least-Squares Mean Difference
(95% CI)
P-value for Interaction
Number of Patients
Percentage Points
≥300 or <300 cells/mm3
.24
≥300 41 48
-36.8 (-54.7 to -18.9)
<300 66 55
-21.3 (-38.8 to -3.9)
≥150 or <150 cells/mm3
.71
≥150 69 81
-29.4 (-43.1 to -15.7)
<150 38 22
-26.9 (-54.5 to -.7)
10 0 –10 –20 –30 –40 –50
Placebo
Better
Dupilumab
Better
Only the patients whose glucocorticoid dose was 30 mg per day or less at baseline were included in the analysis of the endpoint regarding the elimination of glucocorticoid use.
Rabe KF, et al. New Engl J Med. 2018;378(26):

51. Case Evaluation: Discussion
In addition to the currently available biologic therapies, what other treatment approaches may be appropriate for a patient like Kate?

52. Targeted Biologics for Severe Asthma: Overview of Efficacy
Agent
Exacerbations
Asthma Control
FEV1
QOL
OCS Use
Mepolizumab* ↓
ACQ-5 NS ↑
Reslizumab*
ACQ-7  —
Benralizumab*
ACQ-6 
Omalizumab ↑↓
Dupilumab*
ACQ-5 
Under Development
Tezepelumab*
ACQ-6
NS, not statistically significant; , statistically significant.
*No strong safety signals for any biologic vs. placebo in clinical trials.

53. Other Therapies

54. Effect of Azithromycin on Exacerbations and QOL in Adults with Uncontrolled Asthma: Introduction
Macrolide antibiotics have antibacterial, antiviral, and anti-inflammatory effects
Reported benefit in eosinophilic and noneosinophilic subtypes
Systematic reviews of randomized controlled trials report benefits of macrolides on asthma symptoms
Unable to draw conclusions about the effects on other endpoints, including exacerbations, due to lack of data, heterogeneity of results, and inadequate study design and sample size
Trial tested hypothesis that azithromycin reduces asthma exacerbations and improves QOL in patients with symptomatic asthma on inhaled maintenance therapy
Gibson PG, et al. Lancet. 2017;390:

55. Add-on Azithromycin in Uncontrolled Asthma Despite ICS and Long-acting Bronchodilator Therapy
AMAZES Study
Exacerbations per Person Year Incidence Rate
Placebo Azithromycin Ratio (95% CI)
Noneosinophilic asthma ( )
Eosinophilic asthma ( )
Inhaled corticosteroid ( ) dose adjustment
Frequent exacerbators ( )
Cough and sputum VAS ( )
Bacteria–negative ( )*
Bacteria–positive ( )*
Add-on azithromycin reduces asthma exacerbations in adults with
uncontrolled asthma despite maintenance ICS and a long-acting bronchodilator therapy
Favors Azithromycin
Favors Placebo
*P<.05
VAS, Visual Analog Scale.
Gibson PG, et al. Lancet. 2017;390:

56. Impact of Bronchial Thermoplasty (BT) on Asthma Control
Rates of Severe Exacerbations
(Events/Subject/Year)
1.2 1
0.8
0.6
0.4
0.2
Rates of Emergency Room Visits
12 months before BT
Year 1
Year 2
Year 3
Year 4
Year 5
Average over 5 years
12 months before BT
Year 1
Year 2
Year 3
Year 4
Year 5
Average over 5 years
At 5 years, BT was associated with durable improvements in asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms).
Wechsler ME, et al. J Allergy Clin Immunol. 2013;132(6):

57. Approach to Treatment Selection

58. Step Therapy for Adult Patients with Asthma
Consider low-dose ICS
LTRA or
low-dose theophylline
Medium to high-dose ICS or
low-dose ICS
and LTRA or low-dose ICS and theophylline
Add tiotropium* or high-dose ICS
and LTRA or
high-dose ICS and theophylline
Add tiotropium*; add low-dose OCS
Low-dose ICS
Low-dose
ICS/LABA
Medium- or high-dose ICS/LABA
Refer for add-on treatment
(eg, anti-IgE,
anti-IL-5)
Step 1
Step 2
Step 3
Step 4
Step 5
Preferred Controller
Other
Controller
Options
Reliever
As needed short-acting beta2-agonist
or low-dose ICS/LABA†
As needed short-acting
beta2-agonist
Step therapy for adult patients with asthma adapted from the 2015 Global Initiative for Asthma guidelines.1 *Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations; it is not indicated in children younger than 18 years old. **For patients prescribed beclomethasone/formoterol or budesonide/formoterol. IL indicates interleukin; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid.
*Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations; it is not indicated in children younger than 18 years old; †For patients prescribed beclomethasone/formoterol or budesonide/formoterol.
Chipps BE, et al. Ann Allergy Asthma Immunol. 2017;118:

59. Therapeutic Options for Severe Asthma by Inflammatory Phenotype
IgE (allergic)
Eosinophilic
Preferred: 3-month trial of anti-IgE (omalizumab) 
determine responsiveness
Alternatives: newer targeted biologics, or BT
Preferred: 3-month trial of anti-IL-5 (mepolizumab, reslizumab, or benralizumab) 
Alternatives: BT or newer biologics*† (currently in development)
Preferred:
Either biologic type with observation 
switch if non-responsive
Alternatives: BT
Noneosinophilic/Non-IgE (allergic)
Preferred: BT
Alternatives: theophylline or biologics in development*
Note: Although chronic OCS is an accepted therapy in the National Asthma Education and Prevention Program (NAEPP) and GINA guidelines, the panel recommends that all other therapies be considered prior to employing maintenance OCS.
*Dupilumab; †Benralizumab.
Blaiss MS, et al. Allergy Asthma Immunol. 2017;119(6):

60. Considerations for Long-term Asthma Management

61. Patient Education
Review the status of the patient’s asthma control regularly
Teach and reinforce at every opportunity
Basic facts about asthma
What defines well-controlled asthma and patient’s current level of control
Roles of medications
Skills (eg, inhaler technique, use of a spacer, self-monitoring)
When and how to handle signs and symptoms of worsening asthma
When and where to seek care
Measures to prevent or limit exposure to asthma triggers
Develop an active partnership with the patient and provide a written action plan
Jones MA. Respir Care. 2008;53(6):778-84;discussion

62. Patient-reported Topics Discussed During Routine Visits
Topics discussed during routine visits with managing healthcare providers in the past 12 months (as reported by patients with severe asthma):
Topic
Patients (%)
Current medications
65%
Symptoms
44%
Steps to better control symptoms
28%
Daily life limitations
27%
Technique used to take medication
24%
Personal asthma action plan
17%
Fears or feelings associated with asthma
13%
Adapted from: Allergy & Asthma Network. OPEN Asthma Survey: Observations of Patient Experience in the Nation. Available at:

63. Summary
Despite increased understanding of asthma pathophysiology and a corresponding expansion of available therapies, a subset of affected patients continue to report severe uncontrolled disease
Many clinically important phenotypes and endotypes have now been identified and can provide valuable guidance in personalizing treatment for patients with severe asthma
A wide range of targeted therapies have demonstrated good efficacy in the treatment of patients demonstrating different severe asthma phenotypes
Severe asthma management should include implementation of strategies for improving disease awareness, increasing collaborative decision-making, and promoting self-management among patients to ensure optimal health outcomes

64. Thank You!