COPD: Over the Wall of the
Second Millennium
Bartolome R. Celli, M.D.
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
A Trip in Time
2000’s
Terrorism increases
Economic meltdown
Gulf War # 2
Chavez dies
Espana World
Champion!!!!
Pope Francis I
2000’s
# 1 Price
Social networks
# 2 Price
# 3 Price
High throughtput technology
What about COPD?
• Name recognition. Epidemiology and
guidelines
• The battle against smoking and pollution
• COPD, not just a lung disease
• Better treatment. Large pharmacological
trials. Different outcomes
• Phenotypes, comorbidities and complexity
• The future
What about COPD?
• Name recognition. Epidemiology and
guidelines
• The battle against smoking and pollution
• COPD, not just a lung disease
• Better treatment. Large pharmacological
trials. Different outcomes
• Phenotypes, comorbidities and complexity
• The future
Global Burden of Disease
Murray and Lopez NEJM 2013;369:448
Prevalence of COPD
Soriano J et al Lancet
Guidelines
Many!!!!
COPD: Numbers of papers over years
PubMed
What about COPD?
• Name recognition. Epidemiology and
guidelines
• The battle against smoking and pollution
• COPD, not just a lung disease
• Better treatment. Large pharmacological
trials. Different outcomes
• Phenotypes, comorbidities and complexity
• The future
Smoking: still a problem
E cigarettes
Vaping
Sales in USA in 2013 $ 1 billion
Zealots
Moderates
What about COPD?
• Name recognition. Epidemiology and
guidelines
• The battle against smoking and pollution
• COPD, not just a lung disease
• Better treatment. Large pharmacological
trials. Different outcomes
• Phenotypes, comorbidities and complexity
• The future
“COPD Homogeneity”
PT # 1
58 y
FEV1: 28 %
1
2
3
PT # 2
62 y
FEV1: 33%
4
PT # 3
69 y
FEV1: 35%
PT # 4
72 y
FEV1: 34%
FEV1 < 35%
Cote et al
Probability of Survival
1.0
1.0
0.8
0.6
Q1 0.8
Q2
Q3 0.6
I
II
0.4
0.4
III
0.2
Q4 0.2
#454 #273 #80
#625 #574
0.0
0
#625
0.0
26
BODE
52
0
#574 #454 #273 #80
26
ATS Staging
Celli et al. N Engl J Med. 2004;350:1005
52
Rehabilitation
Unbeatable
Evidence A
What about COPD?
• Name recognition. Epidemiology and
guidelines
• The battle against smoking and pollution
• COPD, not just a lung disease
• Better treatment. Large pharmacological
trials. Different outcomes
• Phenotypes, comorbidities and complexity
• The future
B Celli’s Trials type
Mega trials
> 10,000
1
After 2000
Trials
5K to10 K
4
Mini-trials
1K to 5K
26
Pico-trial
100 to 1000
Many
92 ml
difference
from
placebo
25% reduction in
exacerbations
St George’s
is 3.1 better
than placebo
and better
than baseline
UPLIFT
®
110 ml
difference
from placebo
16% reduction in
exacerbations
St George’s
is 3.3 units
better than
placebo and
better than
baseline
Ultra LABA
Ultra LABA
Ipratroprium
Aclidinium
LAMA
Glycopirronium
Tiotropium
Umeclidinium
Overview of inhaled LABA/LAMA
approved or in development
Drug
combinations
Frequency
Development
stage
Company
Formoterol/
aclidinium
Twice daily
Phase III*
Almirall/Forest
Formoterol/
glycopyrrolate
Twice daily
Phase II
Pearl
Therapeutics
Olodaterol/
tiotropium
Once a day
Phase III
BI
Umeclidinium/
vilanterol
Once a day
Phase III*
Theravance/GSK
Indacaterol/
glycopyrroniu
Once a day
m (QVA149)
*Detailed
data have not been presented publicly
Phase III
Novartis
How to approach?
ICS + LABA
LABA + LAMA
LABA
PDEI 4
LAMA
SABA
SAMA
Global Strategy for Diagnosis, Management and Prevention of COPD
C
GOLD 4
ICS + LABA
or
LAMA
GOLD 3
GOLD 2
GOLD 1
D
ICS + LABA
or
LAMA
A
>2
B
SAMA prn
or
SABA prn
mMRC 0-1
CAT < 10
LABA
or
LAMA
mMRC > 2
CAT > 10
1
0
Exacerbations per year
Manage Stable COPD: Pharmacologic Therapy
FIRST CHOICE
Global Strategy for Diagnosis, Management and Prevention of COPD
C
GOLD 4
D
LAMA and LABA
GOLD 3
GOLD 2
GOLD 1
ICS and LAMA or
ICS + LABA and LAMA or
ICS + LABA and PDE4-inh or
LAMA and LABA or
LAMA and PDE4-inh.
A
>2
B
LAMA or
LABA or
SABA and SAMA
LAMA and LABA
1
0
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Exacerbations per year
Manage Stable COPD: Pharmacologic Therapy
SECOND CHOICE
State of the Art in Hypertension
Chobanian A NEJM 2009;361:878
Analogy with Hypertension
0
MI
CVA
CHF
% decrease
-10
-20
-30
-40
-50
-60
“Blood-pressure
differences as small as
3/2 mm Hg (2-3 %)
between treatment
groups have been
associated with
significant differences
in certain outcomes”
Chobanian A . Shattuck Lecture NEJM 2009; 361:878
Analogy with Hypertension
0
-2
FEV1
AE
QoL
Mortality
% decrease
-4
-6
-8
-10
-12
-14
-16
“FEV1 differences as
small as 100ml (10 %)
between treatment groups
have been associated with
significant differences in
certain outcomes”
What about COPD?
• Name recognition. Epidemiology and
guidelines
• The battle against smoking and pollution
• COPD, not just a lung disease
• Better treatment. Large pharmacological
trials. Different outcomes
• Phenotypes, complexity and comorbidities
• The future
Genome and Epigenetics
Inflammation
Enhanced
tissue repair
Impaired
tissue repair
Airflow Limitation
CRP
IL-6
IL-8
Slow decliner
FEV1
Fast decliner
Normal or High
BMI
Low
Normal
FFM
Low
CT scan
Normal
Lung volumes
High
Minimal or no
emphysema
Normal
DLCO
Low
Slightly impaired
Exercise
Severely impaired
Yes
Chronic
bronchitis
No
CAD
Diabetes
Metabolic
Syndrome
Co-morbidities
Inflammation
Biomarkers
CT scan
Significant
Emphysema
SPD
Osteoporosis
Skin wrinkling
Renal dysfunction
Lung Cancer
PVD
Repair and ageing
CC-16
SRAGE
Complexity is not new
Garden of Earthly Delights
Hieronymus Bosch (1450-1516)
COPD complexity
Agusti A and Vestbo AJRCCM 20122;184:507
COPD complexity
Epidemiology
Phenotyping
OMICS
Agusti A and Vestbo AJRCCM 20122;184:507
COPD complexity
Epidemiology
Phenotyping
Genomics
Proteomics
Metabolomics
Visiomics
Agusti A and Vestbo AJRCCM 20122;184:507
What about COPD?
• Name recognition. Epidemiology and
guidelines
• The battle against smoking and pollution
• COPD, not just a lung disease
• Better treatment. Large pharmacological
trials. Different outcomes
• Phenotypes, comorbidities and complexity
• The future
Genome
Environment
Transcriptome
Proteome
Metabolome
Modified from Loscalzo et al Mol Sys Bio 20007;3:124
Genome
Environment
Transcriptome
Proteome
Metabolome
Thrombosis
Inflammation
Hemorrhage
Fibrosis
Immune
Cell
Apoptosis
response
proliferation
Necrosis
Modified from Loscalzo et al Mol Sys Bio 20007;3:124
Genome
Environment
Transcriptome
Proteome
Metabolome
Thrombosis
Inflammation
Hemorrhage
Fibrosis
Immune
Cell
Apoptosis
response
proliferation
Necrosis
Intermediate phenotype
Distinct phenotype: Syndrome and clinical disease
Modified from Loscalzo et al Mol Sys Bio 20007;3:124
Genome
Environment
Transcriptome
Proteome
Metabolome
Thrombosis
Inflammation
Hemorrhage
Fibrosis
Immune
Cell
Apoptosis
response
proliferation
Necrosis
Abnormal lung function
COPD
Modified from Loscalzo et al Mol Sys Bio 20007;3:124
Predictions
• The complexity of COPD will be parceled
• Genes play a role but a significant portion of
COPD goes beyond that so epigenetics and the
mRNA complex will be researched
• The “omics” revolution will help
• Clinical phenotypes are already identifiable.
Pathobiological phenotypes will come
• Smoking cessation and judicious use of current
therapies will decrease the impact of COPD
• The Future is for us to Forge
“Querer es poder”
Dinorah Croquer
“No hay nada como sonar
para crear el futuro”
Victor Hugo