Asthma Heterogeneity: Endotypes, Phenotypes and Choosing the Right Treatment Michael Wechsler, MD MMSc Director, NJH Cohen Family Asthma Institute Professor of Medicine National Jewish Health [email protected]Property of Presenter Not for Reproduction
65
Embed
Asthma Heterogeneity: Endotypes, Phenotypes and Choosing ... · Asthma Defined • Asthma is a heterogeneous disease, Healthycharacterized by chronic airway inflammation and history
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Asthma Heterogeneity: Endotypes, Phenotypes and
Choosing the RightTreatment
Michael Wechsler, MD MMScDirector, NJH Cohen Family Asthma
InstituteProfessor of MedicineNational Jewish Health
Dr. Wechsler has received consulting honoraria from AstraZeneca, Boehringer Ingelheim, Glaxosmithkline, Novartis, Regeneron, Sanofi, Teva
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Asthma Defined
• Asthma is a heterogeneous disease, characterized by chronic airway inflammation and history of respiratory symptoms such as
• Wheeze
• Shortness of breath
• Chest tightness
• Cough that varies over time and in intensity
• Variable airflow limitation
Global strategy for asthma management and prevention. Global Initiative for Asthma website. https://ginasthma.org/wp‐content/uploads/2018/04/wms‐GINA‐2018‐report‐tracked_v1.3.pdf. Updated 2018. Accessed September 2018.
•Smoking•Obesity•Age •Psychosocial issues (eg, lower income, poor health literacy)
•Poor treatment adherence•Inadequate inhaler technique•Heterogeneity of treatment response
•Failure to follow self-management plan
•Side effects of other medications (eg, NSAIDs)
Patient-Related Factors
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
The Asthma Patient Population is Segmented Based on Disease Severity
Asthma Patient Population
Intermittent Mild Moderate Severe
Persistent Asthma
National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute website. https://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf. Published October 2007. Accessed September 2018.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Evolution of Asthma Classification
1980’s-1990’s
Inflammation
Early 2000’s
Identification of phenotypes and
clusters
Late 2000’s
Precision medicine:
identification of endotypes and mechanisms of
disease including T2 vs. non-T2
Present
Precision therapy by endotype
Desai M, Oppenheimer J. Ann Allergy Asthma Immunol. 2016;116(5):394-401.
1960’s-1970’s
Bronchoconstriction
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
1. Assess adherence and make sure it’s asthma
2. Characterize the asthma-what type of asthma is it?
3. Treat the Asthma
Approach to Asthma Mangement
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Asthma Phenotype vs Endotype
Phenotype
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
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Understanding Severe Asthma Heterogeneity Through Phenotyping and Endotyping
1. Chung KF et al. Eur Respir J. 2014;43:343-373.
Severe Asthma Phenotype
and Endotype
GenesGene
expression
Airway epithelium,
smooth muscle
Environment:Infections/
Irritants
Patient factors
Comorbid disease
Environment: Allergies
Meds/Adherence
CytokinesImmune
cells
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Asthma Phenotypes
Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.
Inflammation PredominantLate onset, greater proportion of males; few daily symptoms but active eosinophilic inflammation
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
The Transition from Phenotyping and Endotyping to Genotyping
16
Personalized approach to asthmaDiagnosis
Refractory asthma?
Characterize subtype
Phenotype/Cluster approach
Endotypes (Th2 high vs. low) Genotype
GenderAge
ObesityEthnicity/RaceSmoking Hx
Early vs. Late Onset
Blood biomarkers
Sputum biomarkers
Other
IgEEosinophils
PeriostinCytokines
EosinophilsNeutrophilsCytokines
FeNO
TAILORED THERAPYDunn and Wechsler 2015
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Asthma is Not Just One Disease
Howard R, Rattray M, Prosperi M, Custovic A. Curr Allergy Asthma Rep. 2015;15(7):38. Lötvall J, Akdis CA, Bacharier LB, et al. J Allergy Clin Immunol. 2011;127(2):355‐60.
Asthma SyndromeSymptoms of asthma, variable airflow obstruction
Allergy Lung function
Exacerbations
Airway inflammatio
n
Wheeze, cough, other symptoms
Asthma Phenotype CharacteristicsBased on observable features with no direct relationship to a disease process (e.g., gender, age, obesity, ethnicity, smoking history, early vs. late onset, etc.)
Asthma EndotypesDistinct functional or pathophysiologic mechanisms that may be present in clusters of
Type 2 inflammation is prevalent in patients with uncontrolled persistent asthma, and these patients have the highest disease burden
Endotype
Phenotype
Comorbidities
Biomarker
Obesity, infections, smokers
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Targeted Pathways for Biologic TherapiesTargeted PathwaysIgE Inhaled allergens stimulate production of IgE by B lymphocytes and bind to mast
cellsdegranualationIL-5 Pro-eosinophilic cytokine; cytokine that regulates proliferation, maturation, migration, and
effector functions of eosinophilsIL-4
IL-13
Cytokine found in increased levels in airways and sputum of asthma patients and involved in eosinophil trafficking and B cell production of IgECytokine associated with eosinophil trafficking and production of eNO from epithelial cells
TSLP Novel target; epithelial-cell-derived cytokine; drives allergic inflammatory responses by activating dendritic cells and mast cells
Non-Type 2 Inflammatory Pathways IL-17 Cytokine produced by Th17 cells; plays important role in the immunologic responses seen in
asthmaCXCR2 Potent chemoattractant for neutrophils; under investigation in asthma and COPD
Novel Asthma Therapies Anti IL5: mepolizumab, reslizumab, benralizumab Anti IL4- R alpha/Anti IL13: dupilumab Anti IL13 lebrikizumab, tralokinumab Other Novel therapies:
• Anti TSLP• Anti IL33• Anti IL17• Anti IL6• Anti M1’• Anti Gata3 DNAzyme• TLR9 agonists• CRTH2 Antagonists• Antibiotics• Vitamin D
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
What is your approach to treating patients with severe asthma?
Treat with personalized approach Identify asthma type by phenotype or endotype Treat with the most appropriate therapeutic
strategy based on underlying asthmatic mechanism of inflammation
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
What can we achieve with biologics?
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
What can we achieve with biologics?
Reduced exacerbation Reduced steroid dose and side effects Improved symptoms and quality of life Disease modification to prevent asthma over long
term
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Which therapy is best for a specific patient? How do you choose between biologics?
George L, et al. Ther Adv Chronic Dis. 2016;7:34-51.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Which therapy is best for a specific patient? How do you choose between biologics?
• Biomarkers help predict therapeutic responses Phenotype patients and choose most appropriate therapy Goal of personalized or “precision medicine” Potential need to measure different biomarkers to determine
endotype/phenotype
George L, et al. Ther Adv Chronic Dis. 2016;7:34-51.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
BLOCKING EOSINOPHILS WITH ANTI IL5
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Eosinophilic asthma
• Asthma can be classified phenotypically as eosinophilic (40–60% of cases) or non-eosinophilic
• Symptom severity is increasedin eosinophilic asthma
• Interleukin-5 (IL-5) regulates proliferation, maturation, migration and effector functions of eosinophils
• IL-5 mRNA is increased in patients with asthma, correlates with asthma severity, and is inducible by allergen exposure
Corren J. Discov Med 2012;13:305–12Kouro T & Takatsu K. Int Immunol 2009;21:1303–9
Miranda C, et al. J Allergy Clin Immunol 2004;113:101–8Wenzel SE. Lancet 2006;368:804–13
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
epithelialcell
basophil
smoothmusclecell
mast cell
neutrophil
dendriticcell
macrophage
monocyte
eosinophil
endothelialcell
B cell neuronmyofibroblast
TH2
TH1TH0
IL-3, IL-6IL-8, ECPRANTESMBP
IL-8GM-CSF
IL-6IL-8LTECP
IL-3IL-4GM-CSFTNF-
IL-4TNF-
IL-4IL-5
IL-1IL-2IL-4IL-10IL-16 IL-4
RANTES
RANTESIL-3, IL-5GM-CSF
Eosinophilic cytokines contribute to the chronic inflammatory process
allergen/irritant
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
IL‐5
BenralizumabMepolizumabReslizumab
The targets: IL‐5 or eosinophils (IL‐5Rα)
Eosinophil
IL, interleukin
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Total exacerbations over time are reduced with mepolizumab vs. placebo
Pavord I, et al. Lancet 2012;380:651–9
Inclusion criteria • sputum eos >3%,• FeNO>50, • blood eos >300,• deterioration of
asthma after <25% reduction in ICS or OCS
• AND
>2 asthma exacerbations in previous year
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
MEPOLIZUMAB NEJM 2014
ORTEGA NEJM 2014 BEL NEJM 2014
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Reslizumab Effects on Exacerbations and Lung Function
Castro et al. Lancet Respir Med 2015; Epub ahead of print 36
1009080706050403020100
0 10 20 30 40 50 60 70 80
Pro
babi
lity
of n
ot h
avin
g C
AE
(%)
244 169 138 112 107 97 0 0 0PlaceboNumber at risk
245 207 177 158 146 136 1 0 0Reslizumab
0.40
0.30
0.20
0.10
00
LS m
ean
chan
ge fr
om b
asel
ine
in F
EV
1(L
)
4 8 1216202428323640444852 Endpoint
Visit (week)
PlaceboReslizumab
PlaceboReslizumab 3.0 mg/kg
Placebo; n=244Reslizumab 3.0 mg/kg; n=245HR 0.575 (95% CI 0.440–0.750)p<0.0001
††
†
*
†† † † † †
† †*
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Benralizumab and Exacerbations
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Reduction in ExacerbationEosinophils ≥300 cells per μL
Bleecker ER, et al. FitzGerald JM, et al.
(1.12‐1.58)
p<0.0001(0.60‐0.89)
(0.77‐1.12)
p=0.0018(0.48‐0.74)
p=0.0188(0.54‐0.82)
Percentage reduction relative to placebo‐45% ‐51%
Percentage reduction relative to placebo
‐36% ‐28%
FitzGerald J et al. Lancet Online Publishing, thelancet.com. September 2016.
Bleecker E et al. Lancet Online Publishing, thelancet.com. September 2016.
Annu
al asthm
a exacerbatio
n rate ra
tio (9
5% CI)
Annu
al asthm
a exacerbatio
n rate ra
tio (9
5% CI)
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
P NAIR ET AL, NEJM MAY 2017
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Does Broader Blockade of Type 2 Cytokines Improve Outcomes?
Dupilumab
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Anti IL4/13 and Asthma
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Dupilumab in Asthma
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Improvement in Lung Function, On Top ofCombination Rx
P < 0.001
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Dupilumab Significantly Lowers Rates of Severe Exacerbation in a Phase 3 Trial
Castro M, Corren J, Pavord ID, et al. N Engl J Med. 2018;378(26):2486‐2496.
*Exacerbation reduction P‐values; omalizumab versus placebo in each biomarker subgroup.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Tezepelumab treatment reduced the annualised AER vs placebo at Week 52
53
• Significant reduction in annualised AER for all tezepelumab treatment groups compared with placebo; P<0.001
***P<0.001, compared with placebo group. Sequential testing approach was used to adjust for the multiplicitycaused by the multiple dose‐placebo comparisons. The hierarchy was tezepelumab 280 mg, 210 mg, and70 mg vs placebo
• We now have multiple novel biologic therapies that may treat patients with severe eosinophilic asthma
• How will we decide which therapies work best in which patients?
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Treating Severe Asthmatics Now
• Do extensive workup• Endotype your patients
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Asthma Biomarkers
• IGE• FENO• EOS
– Sputum– Blood
• Periostin• DPP4 (Dipeptidyl Peptidase 4 / CD26;
an adipokine)Prop
erty o
f Pres
enter
Not for
Rep
roduc
tion
• Other factors influencing the decision: patient comfort with a new agent vs older treatment with more experience
Selecting Treatment for Severe Asthma: Anti-IgE Versus Anti‒IL-5
1. Papathanassiou E et al. Eur Clin Resp J. 2016;3:31813. 2. Magnan A et al. Allergy. 2016;71:1335-1344.
Head-to-head studies are needed
Anti-IgE or Anti‒IL-5 or Anti IL4/13
Patients with allergic noneosinophilic asthma
Anti-IgE or Anti IL4/13 if eNO high
Patients with allergic eosinophilic asthma
Patients with eosinophilic asthma who:• Are nonallergic
OR• Do not respond to anti-IgE treatment
OR• Are out of range of dosing
for anti-IgE treatment
Anti‒IL-5 or Anti iL4/13
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Conclusions
• Asthma is a spectrum of diseases, with different pathologic and clinical phenotypes
• There has been an increased understanding of the immunology of asthma, leading to new therapeutic options
• Defining phenotypes and endotypes in asthma is a young field, but it is making progress
• Tailoring treatment to phenotypes and endotypes is the ultimate goal Prop
erty o
f Pres
enter
Not for
Rep
roduc
tion
Conclusions
• Patients with severe asthma may require additional evaluation and referral
• Patients with allergic asthma not well controlled with high‐dose ICS and an additional controller can be considered for treatment with omalizumab
• Patients with severe eosinophilic asthma not controlled with ICS/LABA may benefit from an inhibitor of IL‐5 (mepolizumab, reslizumab, or benralizumab)
• Consider Dupilumab with eosinophilic or type 2moderate severe asthma or on systemic steroids
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Understanding Disease Mechanisms May Guide Therapy to a More Personalized Approach
Willis JC, Lord GM. Nat Rev Immunol. 2015;15(5):323‐329.
One Size Fits All Personalized MedicineStratified Medicine
• Evidence‐based• One treatment for all
• Evidence‐based• Different treatments for groups of patients
• Evidence‐based• Individualized treatment for each patient
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Providing Asthma Care is a Team Sport
Patient
Nurse Practitioner
AllergistPediatrician
Pulmonologist
Otolaryngologist
Pulmonary Rehabilitation Specialist
Case Manager
Immunologist
Primary care physician
School personnel
Pharmacist
Nurse/APN
Your Asthma Care Team. University of Rochester Medical Center website. https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=134&contentid=253. Accessed September 2018.
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
FUTURE QUESTIONS• How will clinicians and payers decide between different
biologics based on existing biomarkers?
• Can we use combinations of biologics?• Are there biomarkers that should be studied other than
blood eosinophils, IgE, FeNO?
• What are best therapies for nontype 2 severe asthma?• What about Asthma COPD overlap Syndrome???
63
Propert
y of P
resen
ter
Not for
Rep
roduc
tion
Drug Phase Dosing Frequency Route Exacerbation Reduction Rate