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The Use of Biomarkers in Asthma Clinical Research Trials
The Use of Biomarkers in Asthma Clinical Research Trials
Robert F. Lemanske, Jr., M.D.
Professor of Pediatrics and Medicine
Robert F. Lemanske, Jr., M.D.
Professor of Pediatrics and Medicine
University of Wisconsin
Madison
Disclosure Slide
• Employment
– University of Wisconsin-Madison
• Financial Interests
– Speaker: NIAID, GSK, Washington State Allergy Society, WSAAI Society, APAPARI
– Consultant: None
– Royalties: UpToDate, Elsevier, Inc.
• Research Interests– NHLBI
• Organizational Interests– AAAAI, ACAAI, ATS, AAP,
SPR
• Gifts– Nothing to Disclose
• Other Interests– Nothing to Disclose
Biomarker Definition• NIH definition - “a characteristic that is
objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”
� BP measurement for hypertension or HgβA1c for diabetes
• Non-invasive, reproducible, measures something relevant to a disease, cost-effective
How can (could) biomarkers be used clinically?
• Predictors of disease expression,
remission and/or progression
• Monitoring disease severity
• Predicting treatment response
• Evaluating/monitoring treatment response
Biomarkers
• Allergic sensitization (Ag-specific IgE)
• FeNO
• Sputum eosinophils
• Th2 High Signature
Allergic Sensitization
Early Identification of Atopy in the Prediction of Persistent
Asthma in Children
Sly P et al. Lancet 372:1100, 2008
RV Wheezing & Allergic Sensitizationin Year 3 and Asthma at Age 6 Years
Jackson DJ et al. AJRCCM, 178:667, 2008
Neither
Viral
Wheeze
Sensitized
Sensitized
and Viral
Wheeze
1 4
3
2
Does sensitization lead to viral wheezing, or does viral wheezing lead to sensitization?
Jackson et al. AJRCCM 185:281, 2012
Does sensitization lead to viral wheezing, or does viral wheezing lead to sensitization?
Neither
Viral
Wheeze
Sensitized
Sensitized
and Viral
Wheeze
1 4
3
2If viral wheeze causes sensitization:2→4 > 1→3
If sensitization causes viral wheeze:3→4 > 1→2
No causality:2→4 = 1→33→4 = 1→2
Jackson et al. AJRCCM 185:281, 2012
Sensitization Leads to Viral Wheeze (the reverse does not appear to be true)
Neither
Viral
Wheeze
Sensitized
Sensitized
and Viral
Wheeze
1 4
3
2
Virus Ratio
3→41→2
2→41→3
Any 1.9*(1.2, 3.1)
0.75(0.49, 1.1)
HRV 2.4*
(1.4, 4.3)
0.69(0.41, 1.2)
RSV 1.6 (0.9, 2.9)
0.8(0.52, 1.3)
Jackson et al. AJRCCM 185:281, 2012
Patterns of Sensitization and Asthma
Simpson A et al. AJRCCM 181:1200, 2010
Clusters and Risk of Hospitalization
Simpson A et al. AJRCCM
181:1200, 2010
FeNO
Biomarkers in Children with Mild-Moderate Asthma
Biomarker MedianLower and
upper quartile
Normal values
FeNO (ppb) 26.3 10.9, 52.3 10-20 ppb
IgE (kU/L) 154.3 53.5, 409.022 kU/L
(over age 10 yrs)
Peripheral blood eosinophils (cells
mm3)
266.6 150.0, 476.0 50-350
ECP (mg/ml) 15.9 8.8, 25.7 5.9 (18.1 = 95%)
Urinary leukotrieneE4 (pg/ml)
105 71, 134103 ± 9 pg
LTE/mg creatinine
Strunk R et al. JACI 112:883, 2003
FeNO: Influence of Atopy
Jackson DJ et al. JACI 124:949, 2009
FeNO to Guide Therapy
Smith AD et al. NEJM 352:2163, 2005
FeNO to Guide Therapy
Smith AD et al. NEJM 352:2163, 2005
AAsthma sthma CControl ontrol EEvaluation valuation
(ACE)(ACE)::
A BiomarkerA Biomarker--Based Based
Approach to Approach to
Improving Asthma Control Improving Asthma Control
in in
Inner City ChildrenInner City Children
NIAID Inner City Asthma NIAID Inner City Asthma
ConsortiumConsortiumSzefler S et al. Lancet 372:1065, 2008
ACE Primary ObjectiveACE Primary Objective
To determine whether asthma treatment To determine whether asthma treatment
based on exhaled nitric oxide and national based on exhaled nitric oxide and national
asthma guidelines (asthma guidelines (eNOeNO group) leads to group) leads to
better control than guidelines care alone better control than guidelines care alone
(Reference group).(Reference group).
Szefler S et al. Lancet 372:1065, 2008
0
1
2
3
4
5
6
0 3 9 17 25 33 41 49
Study Week
Mea
n s
ymp
tom
day
s / 2
wee
ks eNO
Reference
ACE Primary Outcome ACE Primary Outcome –– Symptom DaysSymptom Days
P-value: NS
Run-in Randomized Trial
P-value: NS
Szefler S et al. Lancet 372:1065, 2008
ExacerbationsExacerbations
Outcomes Outcomes
(% with (% with ≥≥≥≥≥≥≥≥ 1)1)
FeNOFeNO
GroupGroup
ReferenceReference
GroupGroup
PP--
valuevalue
Prednisone burstsPrednisone bursts 32%32% 42%42% 0.020.02
Unscheduled visits Unscheduled visits 11 21%21% 23%23% NSNS
Hospitalizations Hospitalizations 11 3%3% 4%4% NSNS
1 Self-reported, based on two-month recall
Szefler S et al. Lancet 372:1065, 2008
FeNOFeNO MetaMeta--analysisanalysis
•• MetaMeta--analysis (4 studies met criteria):analysis (4 studies met criteria):
–– no difference between groups for the primary outcome no difference between groups for the primary outcome
of asthma exacerbations or for other outcomes (clinical of asthma exacerbations or for other outcomes (clinical
symptoms, symptoms, FeNOFeNO level and level and spirometryspirometry).).
–– In postIn post--hoc analysis, a significant reduction in mean hoc analysis, a significant reduction in mean
final daily dose ICS was found in the group where final daily dose ICS was found in the group where
treatment was based on treatment was based on FeNOFeNO in comparison to clinical in comparison to clinical
symptomssymptoms
–– There was no difference in ICS dose between the There was no difference in ICS dose between the
groups in the overall daily dose in the adult studies or in groups in the overall daily dose in the adult studies or in
the the paediatricpaediatric studies.studies.
Petzky H.L. Cochrane Database Syst Rev, CD006340, 2008
•• CONCLUSIONS:CONCLUSIONS:–– Tailoring the dose of ICS based on Tailoring the dose of ICS based on FeNOFeNO
in comparison to clinical symptoms was in comparison to clinical symptoms was carried out in different ways in the four carried out in different ways in the four studies that were found, and the results studies that were found, and the results show only modest differences.show only modest differences.
–– The role of utilizing exhaled The role of utilizing exhaled FeNOFeNO to tailor to tailor the dose of inhaled corticosteroids is the dose of inhaled corticosteroids is currently uncertaincurrently uncertain
Petzky H.L. Cochrane Database Syst Rev, CD006340, 2008
FeNOFeNO MetaMeta--analysisanalysis
Factors Influencing Factors Influencing FeNOFeNO ValuesValues
•• AtopyAtopy
•• Height (+ correlation)Height (+ correlation)
•• Age (+ correlation)Age (+ correlation)
•• Sex (boys > girls)Sex (boys > girls)
•• Infection (URI)Infection (URI)
•• Food (nitrite containing foods)Food (nitrite containing foods)
•• Medications (ICS and LTRA Medications (ICS and LTRA ↓↓))
•• Smoking (active and passive Smoking (active and passive ↓↓))
•• ExerciseExercise
Jartti T et al. Ped Respir Rev 13:178, 2012
Sputum Eosinophils
Treatment Strategy and Measures of Response:
Guidelines approach Vs. Inflammation-Based Approach
Ref. Green, RH et al.
Lancet 2002; 360:1715-1721
Periostin and Th2 High
Signatures
Sensitivity of Biomarkers to Predict Airway Eosinophilia
Jia G et al. JACI 130:647, 2012
Expression Levels of 3 IL-13-induced Genes Define Two Subgroups of
Asthma Patients
Woodruff PG et al. AJRCCM 180:388, 2009
Th2 High and Low Signature
Woodruff PG et al. AJRCCM 180:388, 2009
Characteristics of Th2 High Individuals
• ↑ Methacholine reactivity
• ↑ Blood eosinophils
• ↑ Biopsy eosinophils
• ↑ Serum IgE
• ↑ Improvement in FEV1 following ICS treatment
Woodruff PG et al. AJRCCM 180:388, 2009
Biomarkers and Treatment Response to Omalizumab
Hanania NA et al. AJRCCM 187:804, 2013
Use of Biomarkers in Asthma
Clinical Research
Categories of Outcomes
•Core
•Supplemental
•Emerging
Core Outcomes
• A core outcome is identified as a selective set of asthma outcomes to be considered by participating NIH institutes and other federal agencies as requirements for institute/agency-initiated funding of clinical trials and large observational studies in asthma
Supplemental Outcomes
• Supplemental outcomes are asthma outcomes for which standard definitions can or have been developed, methods for measurement can be specified, and validity has been proved but whose inclusion in funded clinical asthma research is optional.
Emerging Outcomes
• Emerging outcomes are asthma outcomes that have the potential to expand and/or improve for which standard definitions can or have been developed, methods for measurement can be specified, and validity has been proved but whose inclusion in funded clinical asthma research is optional.
A S T H M A O U T C O M E SW O R K S H O P
A S T H M A O U T C O M E SW O R K S H O P
M a r c h 15 - 16 , 2 0 10
B e t h e s d a , M D
Agency for Healthcare Research and Quality AHRQ ı National Heart, Lung and Blood Institute NHLBI ı National Institute of Allergy and Infectious Diseases NIAID ı National Institute of Child Health and Human Development NICHD ı National Institute of Environmental Health Sciences NIEHS ı Merck Childhood Asthma Network MCAN
ı RW Johnson Foundation.
National Institute of Allergy and Infectious Diseases
Recommendations
Characterization of Study
Population for Prospective
Clinical Trials
Prospective Clinical
Trial
Efficacy/Effectiveness
Outcomes
Observational Study
Outcomes
Core Outcome Multiallergen screen (IgE) to
define atopy
None None
Supplemental CBC (total eosinophils)
FENO
Sputum eosinophils
Total IgE
Allergen-specific IgE
FEeNO
Sputum eosinophils
Total IgE
Allergen-specific IgE
Urinary LTE4
CBC (total eosinophils)
FENO
Sputum eosinophils
Total IgE
Allergen-specific IgE
Emerging Allergen skin testing
Sputum PMNs and analytes
Airway imaging
‘omics’ studies;
Breath markers – pH,
isoprostanes
Allergen skin testing
Sputum PMNs, and
analytes
Airway imaging
‘omics’ studies
Cortisol measures
Breath markers –pH
isoprostanes
Sputum PMNs and
analytes
Airway imaging
‘omics’ studies
Biomarkers and Asthma
• None yet found that have acceptable sensitivity and specificity to aid in:
–Prognosis
–Diagnosis
–Assessment of severity
–Monitoring and/or predicting response to therapy