the use of biomarkers in asthma clinical research trials€¦ · –aaaai, acaai, ats, aap, spr •...

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


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)


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

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

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


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


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


Characteristics of Th2 High Individuals

• ↑ Methacholine reactivity

• ↑ Blood eosinophils

• ↑ Biopsy eosinophils

• ↑ Serum IgE

• ↑ Improvement in FEV1 following ICS treatment


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


Urinary LTE4

CBC (total eosinophils)

FENO

Sputum eosinophils

Total 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

the use of biomarkers in asthma clinical research trials€¦ · –aaaai, acaai, ats, aap, spr •...

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