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Evolving Definition of Severe vs. Uncontrolled Asthma
ACT = Asthma Control Test; ACQ = Asthma Control Questionnaire; ATAQ = Asthma Therapy Assessment Questionnaire; ERS/ATS = European Respiratory Society/American Thoracic Society; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GINA = Global Initiative for Asthma; ICS = inhaled corticosteroid; LABA = long‐acting b2‐agonist; NAEPP = National Asthma Education and Prevention Program; OCS = oral corticosteroid; SABA = short‐acting b2‐agonist.
Bernstein JA, et al. J Asthma. 2018;2:1–14; NAEPP. Guidelines for the Diagnosis and Management of Asthma (EPR‐3). www.nhlbi.nih.gov. Accessed 1/18/19; Chung KF, et al. Eur Repir J. 2014;43(2):343–373; GINA. Global Strategy for Asthma Management and Prevention: 2018 Update. www.ginasthma.org. Accessed 1/18/19.
• Severity and control are necessarily linked, and often used interchangeably– NAEPP guidelines
• Severity assessment is in patients who are not currently using long‐term control therapies• Severity and control have similar definitions contribute to confusion about how to accurately identify severe from uncontrolled asthma
– GINA guidelines• Severity assessment is in patients who have been using regular control medication for several months
• Field is evolving to conceptualize severity and control as separate facets of a patient’s asthma– Severity
• Intrinsic to the disease state and molecular mechanism of disease• Related to the pathophysiology that drives the observable symptoms • Defines how aggressive a patient’s treatment regimen must be in order to control symptoms
– Control• Extrinsic to the disease (independent of disease severity)• Related to the frequency and impact of symptoms• Impacted by external factors such as patient inhaler technique and adherence, and environmental triggers
Substances with a solid grey line have been or are currently being targeted for treatment of severe asthma. Please refer to the appendix for a list of the abbreviations.
Adapted from Israel, et al. N Engl J Med. 2017;377(10):965–976.
Type 2 Asthma Non‐Type 2 AsthmaAllergens
Mast cell
B cell
Th2 Cell
Eosinophil
IL‐25
IL‐4, 5, and 13
CXCL8
GM‐CSF
IL‐6
TGF‐ β
IL‐23
IL‐33TSLP
ILC2
Th 17 Cell
Neutrophil
Th 1 Cell
IL‐6
IL‐17GM‐CSF
Leukotrienes
PGD2
Histamine
IL‐3 and ‐9
IL‐5
IL‐4IFN‐γ
TNF‐α
Lipoxin
CXCR2
IL‐8
Leukotriene B4
IL‐13
IgE
CRTH2
GATA3GATA3
CRTH2
Irritants/pollutants/microbes/viruses
Airway Epithelium
ALX
BLT2
Hyperresponsiveness, remodeling, mucus production, and smooth‐muscle constriction and hypertrophy
Comparison of Type‐2 Inflammation Biomarkers in Asthma
ppb = parts per billion
Parulekar AD, et al. Curr Opin Pulm Med. 2016;22(1):59–68; Peters MC, et al. Curr Allergy Asthma Rep. 2016;16(10).
BiomarkerType 2 Levels
LimitationsLow Medium High
Total IgE (IU) <30 31–149 >150
Affected by age; poor predictor of response rate to biologic therapy. Does not correlate well with asthma severity. Elevations are not specific to asthma (also elevated in atopic dermatitis, allergic bronchopulmonary aspergillosis, etc.)
Blood eosinophils (cells/μL) <150 151– 399 >400Affected by weight, allergen exposure, steroids, and infection; optimal cut off value varies per therapy. Elevations are not specific to asthma (also elevated in allergic rhinitis, drug reactions, etc.)
Sputum eosinophils ‐ ‐ ≥3% Semi‐invasive; confined to research settings
FeNO (ppb) <25 26–49 >50 Affected by age, weight, sex, smoking, and respiratory infections
Investigational
Serum periostin (ng/mL) ‐ ‐ ≥50Unknown competing causes of systemic increases; unclear differences between asthma and healthy subjects; studied only in context of anti‐IL‐13 and anti‐IgE therapy
DPP‐4 ‐ ‐ >MedianOne of the newer biomarkers, lacks data from confirmatory studies in asthma
Comparison of Type‐2 Inflammation Biomarkers in Asthma
ppb = parts per billion
Parulekar AD, et al. Curr Opin Pulm Med. 2016;22(1):59–68; Peters MC, et al. Curr Allergy Asthma Rep. 2016;16(10).
BiomarkerType 2 Levels
LimitationsLow Medium High
Total IgE (IU) <30 31–149 >150
Affected by age; poor predictor of response rate to biologic therapy. Does not correlate well with asthma severity. Elevations are not specific to asthma (also elevated in atopic dermatitis, allergic bronchopulmonary aspergillosis, etc.)
Blood eosinophils (cells/μL) <150 151– 399 >400Affected by weight, allergen exposure, steroids, and infection; optimal cut off value varies per therapy. Elevations are not specific to asthma (also elevated in allergic rhinitis, drug reactions, etc.)
Sputum eosinophils ‐ ‐ ≥3% Semi‐invasive; confined to research settings
FeNO (ppb) <25 26–49 >50 Affected by age, weight, sex, smoking, and respiratory infections
Investigational
Serum periostin (ng/mL) ‐ ‐ ≥50Unknown competing causes of systemic increases; unclear differences between asthma and healthy subjects; studied only in context of anti‐IL‐13 and anti‐IgE therapy
DPP‐4 ‐ ‐ >MedianOne of the newer biomarkers, lacks data from confirmatory studies in asthma
*Off‐label, data only with budesonide‐formoterol; †Off‐label, separate or combination ICS and SABA inhalers; $Low‐dose ICS‐formoterol is for patients prescribed budesonide‐formoterol maintenance and reliever; #Consider adding HDM SLIT for sensitized patients with allergic rhinitis and FEV >70% predictedLTRA = Leukotriene Receptor Agonist; SABA = Short‐Acting Beta2 Agonist; ICS = Inhaled Corticosteroid; OCS = Oral CorticosteroidGINA. Global Strategy for Asthma Management and Prevention: 2019 Update. www.ginasthma.org. Accessed 4/11/19.
As needed low dose ICS‐formoterol*
Daily low‐dose inhaled ICS or as needed low dose
ICS‐formoterol*
Low‐dose ICS/LABAMedium dose ICS/LABA
High dose ICS/LABA
Refer for phenotypic assessment ± add‐on
therapy, e.g.tiotropium,anti‐IgE,
anti‐IL5/5RAnti‐IL4R
STEP 1
STEP 2
STEP 3
STEP 4
STEP 5
Low dose ICS whenever SABA is
taken†
LTRA, orlow dose ICS whenever SABA
taken†
Medium dose ICS, orlow dose ICS + LTRA#
High dose ICS, add‐on tiotropium,
or add‐on LTRA #
Add low dose OCS, but consider side effects
PREFERRED CONTROLLER
PREFERRED RELIEVER
Other controller options
As needed low dose ICS‐formoterol* As needed low dose ICS‐formoterol$
Weighing the Potential Risks and Benefits ofIncreasing ICS Dose to Control Asthma Exacerbations
Rate of Annual Asthma Exacerbations*
0.48
0.37
0
0.2
0.4
0.6
0.8
Intervention Control
P = 0.30
Time to First Severe Asthma Exacerbation
* Severe exacerbation that was treated with systemic corticosteroids1Jackson DJ, et al. N Engl J Med. 2018;378(10):891‐901; 2McKeever T, et al. N Engl J Med. 2018:NEJMoa1714257; 3Kew KM, et al. Cochrane Database Syst Rev. 2016;6:CD007524
5x Dose in Children (5 – 11 years old)1 4x Dose in Adolescents & Adults (≥16 years)2
↓ growth rate among children ↑ treatment‐related adverse effects
Cochrane Review3 = increasing ICS dose to treat asthma exacerbations in adults and children does not reduce use of oral corticosteroids, hospitalizations, or recovery time.
Available and Emerging Targeted Therapies for Asthma Control
Biologic Target Key Trials
Administration
Age (years)
Route Frequency Considerations
Approved
Omalizumab IgE Study 008/009/ALTO ≥6 SCQ2WQ4W
• Powder in single‐dose vial for reconstitution • PFS available in two doses:150 mg/mL and 75 mg/0.5 mL• Dose determined by: age, weight, and baseline IgE levels• Administered by: HCP only
Mepolizumab IL‐5 MENSA/SIRIUS ≥12 SC Q4W• Powder in single‐dose vial for reconstitution• Fixed dose for all patients: 100mg/injection• Administered by: HCP only
Reslizumab IL‐5 BREATH trials ≥18 IV Q4W• Solution in single‐dose vial for infusion• Dose determined by: weight (3mg/kg)• Administered by: HCP only, patients‡
Efficacy of Omalizumab by Biomarker Status in Patients with Asthma: PROSPERO Study
*P <0.0001 for comparison of Before Study Entry to Through 12 Months on Study. †Baseline: mean±SD; through month 12: least squares (mean). ‡P values reflect adjustments for differences in baseline characteristics.
Placebo 75 mg Mepolizumab IV 100 mg Mepolizumab SC
*Eosinophil count ≥150/μL at screening or ≥300/μL within previous year; **Includes ICS, LABA, tiotropium, and others with the exception of other biologics.
Ortega HG, et al. N Engl J Med. 2014;371(13):1198–207.
Reduced Exacerbation Rate vs Placebo at Week 32
P <0.001
Annualized
Exacerbation Rate
↓74% ↓80%
↓47% ↓53%
P <0.001
576 patients ≥12 years with severe, eosinophilic asthma received mepolizumab add‐on therapy to ICS + ≥1 controller regimen
Efficacy of Benralizumab (anti‐IL‐5R) in Patients ≥12 Years Old with Severe, Uncontrolled Asthma: SIROCCO and CALIMA Phase 3 Trials
AER = annual exacerbation rate
Bleecker ER, et al. Lancet. 2016;388(10056):2115–2127; FitzGerald JM, et al. Lancet. 2016;388(10056):2128–2141; Goldman M, et al. Curr Med Res Opin. 2017;33(9):1605–1613; FitzGerald JM, et al. Lancet Respir Med. 2017;Epub ahead of print.
1.5
1.1
0.90.7
0
0.4
0.8
1.2
1.6
SIROCCO CALIMA
n = 306 n = 325 n = 315 n = 300
↓42%↓36%
Rate Estim
ate
Blood eosinophils ≥150 cells/μL
1.33
0.93
0.70.60.65 0.66
0
0.4
0.8
1.2
1.6
SIROCCO CALIMA
n = 267 n = 275
↓51% ↓ 28%
n = 267 n = 248 n = 241 n = 239
↓ 36%↓45%
Blood eosinophils ≥300 cells/μL
48 weeks 48 weeks56 weeks 56 weeks
Placebo
Benralizumab Q4W
Benralizumab Q8W
Benralizumab (30mg Q4W or Q8W) as add‐on therapy to high‐dose ICS/LABA (SIROCCO) or medium‐to‐high dose ICS/LABA (CALIMA)
Efficacy of Dupilumab (anti‐IL‐4/‐13R) in Patients with Uncontrolled Asthma: LIBERTY ASTHMA Phase 3 Trials
* P <0.001. BL = Baseline. Castro M, et al. N Engl J Med. 2018. Epub ahead of print; Rabe KF, et al. N Engl J Med. 2018. Epub ahead of print.
0.87
0.46
0
0.2
0.4
0.6
0.8
1
Placebo 1.14mL Dupilumab 200mg
QUEST Phase 3 Trial 1,902 patients ≥12 years with
uncontrolled, moderate‐to‐severe asthma
0.39–0.53
0.72–1.05 ↓48%
*
0.97
0.52
Placebo 2.00mL Dupilumab 300mg
0.45–0.61
0.81–1.16 ↓46%
*
n = 317 631 321 633
Annualized Rate of Severe Asthma Exacerbations (52 weeks)
‐42
‐70‐80
‐60
‐40
‐20
0
Placebo 2.00mL Dupilumab 300mg
VENTURE Phase 3 Trial 210 patients ≥12 years with oral
corticosteroid‐dependent severe asthma
Change in OCS Dose from BL (24 weeks)
±5%
±5%
n = 107 103
*
• 48% of patients with corticosteroid‐dependent severe asthma no longer needed OCS after 24 weeks of dupilumab – vs. 25% of patients in placebo group (P=0.002)
• Dupilumab also improved FEV1 outcomes and ACQ‐5 scores, and reduced hospitalization/ED visit rates.
GINA 2019: Identifying Patients and Selecting Treatment
*Baseline IgE levels do not predict likelihood of response
GINA. Difficult‐to‐Treat Severe Asthma in Adolescents and Adult Patients: Diagnosis And Management. Available at: www.ginasthma.org. Accessed 4/12/19
Type 2 airway inflammation if:
Meets ≥ 1 of the following criteria while on high‐dose ICS (before OCS):
• Blood eosinophils ≥150 cells/µL• FeNO ≥20 ppb• Sputum eosinophils ≥2%• Asthma is clinically allergen‐driven• Need for maintenance OCS
Start with anti‐IgE therapy if:
• Ages ≥6 years • Severe allergic asthma• Sensitization on skin prick testing or specific IgE• Total serum IgE* and weight within dosage range• Exacerbations in the last year
Predictors of good response:• Blood eosinophils ≥260 cells/µL• FeNO ≥20 ppb• Allergen‐driven symptoms• Childhood‐onset asthma
Start with anti‐IL5 or –IL5R therapy if:
• Ages ≥12 or ≥18 years • Severe eosinophilic asthma• Exacerbations in the last year• Blood eosinophils ≥300 cells/µL
Predictors of good response:• Higher blood eosinophils• More exacerbations in previous year • Adult‐onset of asthma• Nasal polyps
Start with Anti‐IL4 if:
• Ages ≥12• Severe eosinophilic asthma or need for
maintenance OCS• Exacerbations in last year• Blood eosinophils ≥150 cells/µL or FeNO ≥25 ppb
Predictors of good response:• Higher blood eosinophils• Higher FeNO
May also be used to treat:• Moderate‐to‐severe atopic dermatitis• Nasal polyps (investigational)
