World COPD Day
Roma, Hotel Una
16 Novembre 2011
Nuovi trattamenti
per la COPD
Leonardo M. Fabbri
Clinica di Malattie dell’Apparato Respiratorio
Università degli Studi di Modena e Reggio Emilia
Azienda Ospedaliero-Universitaria - Policlinico di
Modena
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Leonardo M. Fabbri
Treatment of co-morbidities of COPD
Clinica di Malattie dell’Apparato Respiratorio
Università degli Studi di Modena e Reggio Emilia
Azienda Ospedaliero-Universitaria - Policlinico di
Modena
COPD EXACERBATION
GOLD 2011
An exacerbation of COPD is an
acute event characterized by a
worsening of the patient’s
respiratory symptoms that is beyond
normal day-to-day variations and
leads to a change in medication
OUTCOME OF COPD
EXACERBATIONS
In ICU patients
Hospital mortality
20%-24%
In hospitalized
patients
Hospital mortality
2.5%-10%
In ER patients
Relapse (repeat ER visit)
22%-32%
In outpatients
Treatment failure rate
13%-33%
(1 year)
(5 days)
(14 days)
(14 days)
Seneff et al. JAMA. 1995; 274:1852-1857; Murata et al. Ann Emerg Med. 1991;20:125-129;
Adams et al. Chest. 2000; 117:1345-1352; Patil et al. Arch Int Med. 2003; 163:1180-1186.
LUNG FUNCTION IMPAIRMENT, COPD
HOSPITALISATIONS AND
SUBSEQUENT MORTALITY
COPD severity was associated with a
higher rate of severe exacerbations
requiring hospitalisation, although severe
exacerbations at any stage were associated
with a higher risk of short-term and longterm all-cause mortality
Garcia-Aymeric et al, Thorax 2011;66:585e590.
COPD exacerbations
COPD
Chronic disease
progressive nature
Exacerbations
• typically 1 - 3 per year
• lung function
• frequency proportional
to COPD severity
• symptoms
• the frequent exacerbator
• comorbidities
• chronic decline resulting
in poorer prognosis
 ↓ HRQL
Tashkin D. N Engl J Med 2010; 363: 1184
Hurst et al, N Engl J Med 2010; 363: 1128-38
 ↑ hospitalizations
 ↑ mortality
CAUSES OF EXACERBATION OF
RESPIRATORY SYMPTOMS IN CHRONIC
PATIENTS
PNEUMONIA
THROMBOEMBOLISM
ACUTE HEART FAILURE
METABOLIC ACIDOSIS
ANEMIA
BIOCHEMICAL MARKERS OF CARDIAC
DYSFUNCTION PREDICT MORTALITY IN
ACUTE EXACERBATIONS OF COPD
Elevated levels of NT-proBNP and troponin T are strong
predictors of early mortality among patients admitted to
hospital with acute exacerbations of COPD independently of
other known prognostic indicators
The pathophysiological basis for this is unknown, but
indicates that cardiac involvement in exacerbations of COPD
may be an important determinant of prognosis
Chang CL et al, Thorax, available on line 9 june 2011
TARGETING THE LUNG
ATTACKS
Current management strategies for acute
asthma and ECOPD within and subsequent to
discharge from hospital are suboptimal
We suggest that the term ‘lung attack’ may
resonate more with patients and the broader
community
FitzGerald JM, Thorax, available on line 9 june 2011
Breast Cancer Diseases - 2015
ER+
65-75%
PI3Kmut
10%
HER3+
IGFR1+
All Breast Cancers
HER2+
15-20%
p95+
4%
P53mut
30-40 %
FGFR1
Ampl 8%
Triple
negative
15% PTENloss
30-50%
BRCAMut
8%
TARGETED THERAPIES IN A-NSCLC
Positive Phase III Studies
Gefitinib
IPASS/INTEREST/NEJG002
Erlotinib
BR.21
Monotherapy
2005
ComboTherapy
EGFR Mut+ EGFR Mut+
2nd /3rd
Line
All
lines
2007
2008
2009
1st Line
Bevacizumab
ECOG 4599/AVAiL
Cetuximab
FLEX
A-NSCLC
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
Therapy at Each Stage of COPD
I: Mild
II: Moderate
III: Severe
IV: Very Severe
• FEV1/FVC < 70%
• FEV1/FVC < 70%
• FEV1 > 80%
• FEV1/FVC < 70%
• FEV1/FVC < 70%
• 50% < FEV1 < 80%
• 30% < FEV1 <
predicted
50% predicted
predicted
• FEV1 < 30%
predicted
or FEV1 < 50%
predicted plus
chronic respiratory
failure
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
Add one or more long-acting bronchodilators (when
needed); Add rehabilitation
Add ICS OR/AND ROFLUMILAST
in “exacerbators”
Add long term
Add ROFLUMILAST
oxygen
if chronic
respiratory failure.
Consider surgical
treatments
2011 UPDATE OF THE
GOLD GUIDELINES
2011 UPDATE OF THE GOLD GUIDELINES
First choice
Second choice
Alternative choice
A
SABA or SAMA prn
SABA and SAMA
LABA or LAMA
Theophylline
B
LABA or LAMA
LABA and LAMA
Theophylline
SABA and/or SAMA
C
ICS/LABA
or LAMA
LABA and LAMA
ICS and LAMA
Theophylline
SABA and/or SAMA
Consider PDE4-inh*
D
ICS/LABA
or LAMA
ICS/LABA and LAMA
ICS/LABA and PDE4-inh*
LAMA and PDE4-inh
Theophylline
SABA and/or SAMA
Carbocysteine
Shanghai, October 2011
FIGURE 2. PROPORTION OF PARTICIPANTS FREE FROM
ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE
PULMONARY DISEASE (COPD) FOR 1 YEAR, ACCORDING
TO STUDY GROUP
Albert RK Et Al, NEJM ,August 25, 2011 vol. 365 no. 8
CHRONIC AZITHROMYCIN DECREASES THE
FREQUENCY OF CHRONIC OBSTRUCTIVE
PULMONARY DISEASE EXACERBATIONS
When added to usual treatment,
azithromycin, 250 mg taken daily for
one year decreases COPD
exacerbations and improves quality of
life but also causes hearing decrements
in a small fraction of subjects
Alpert RK et al, New Engl J Med 2011; 365: 689-698
THE EFFECT OF TELITHROMYCIN IN ACUTE
EXACERBATIONS OF ASTHMA
This study provides evidence of
the benefit of telithromycin in
patients with acute exacerbations
of asthma; the mechanisms of
benefit remain unclear
Johnston SL et al, NEJM 2006;354(15):1589-600
TC DEL POLMONE DI PAZIENTE CON ENFISEMA
PREVALENTE AI LOBI INFERIORI
Lobi inferiori
Corbetta L et al, 2011
TC DEL POLMONE DI PAZIENTE CON ENFISEMA
PREVALENTE AI LOBI SUPERIORI
Lobi superiori
Corbetta L et al, 2011
VALVOLE UNIDIREZIONALI ZEPHYR A BECCO D'ANATRA:
PORZIONE ENDOBRONCHIALE CHE ADERISCE ALLA
PARETE BRONCHIALE
Corbetta L et al, 2011
VALVOLA SPIRATION AD OMBRELLINO
Corbetta L et al, 2011
A RANDOMIZED STUDY OF
ENDOBRONCHIAL
VALVES FOR ADVANCED EMPHYSEMA
Endobronchial-valve treatment for advanced
heterogeneous emphysema induced modest
improvements in lung function, exercise
tolerance, and symptoms
at the cost of
more frequent exacerbations, pneumonia, and
hemoptysis after implantation
Sciurba et al, N Engl J Med 2010; 363;13
TRACHEOBRONCHOPLASTY FOR SEVERE
TRACHEOBRONCHOMALACIA*
A PROSPECTIVE OUTCOME ANALYSIS
In experienced hands, surgical central
airway stabilization with posterior
tracheobronchial splinting using a
polypropylene mesh improves respiratory
symptoms, health-related quality of life,
and functional status in highly selected
patients with severe symptomatic TBM.
Majid A et al, Chest 2008; 134:801–807
DYNAMIC AIRWAY CT
Majid A et al, Chest 2008; 134:801–807
SILICONE STENT
Majid A et al, Chest 2008; 134:801–807
SKETCH SHOWING THE PLICATION OF THE POSTERIOR
MEMBRANOUS WALL OF THE TRACHEA AND MAINSTEM
BRONCHUS USING A MARLEX MESH
Majid A et al, Chest 2008; 134:801–807
TRACHEOBRONCHOPLASTY FOR SEVERE
TRACHEOBRONCHOMALACIA*
A PROSPECTIVE OUTCOME ANALYSIS
In experienced hands, surgical central
airway stabilization with posterior
tracheobronchial splinting using a
polypropylene mesh improves respiratory
symptoms, health-related quality of life,
and functional status in highly selected
patients with severe symptomatic TBM.
Majid A et al, Chest 2008; 134:801–807
TIOTROPIUM IMPROVES LUNG FUNCTION
IN PATIENTS WITH SEVERE ASTHMA:
a randomised controlled trial
The addition of once-daily tiotropium to asthma
treatment including high dose ICS plus LABA,
provides significant improvements in lungfunction over 24 hours in patients with
inadequately controlled, severe, persistent
asthma
Long-term studies are needed to assess patient
reported outcomes and exacerbation rates.
Kerstjens HAM et al, JACI, August 2011
EFFECTIVENESS AND SAFETY OF BRONCHIAL
THERMOPLASTY IN THE TREATMENT OF
SEVERE ASTHMA
This study demonstrates that BT provides clinically
meaningful improvements in severe exacerbations requiring
corticosteroids, ED visits, and time lost from work/school
during the post-treatment period in patients with severe
and inadequately controlled asthma, together with
improvements in quality of life.
We conclude that the increased risk of adverse events in
the short-term after BT is outweighed by the benefit of BT
that persists for at least 1 year. BT offers clinicians a novel,
procedure-based, add-on therapy beyond the current use of
high-dose ICS and LABA to decrease the morbidity of
severe asthma.
Castro M et al. Am J Respir Crit Care Med 2010;181:116–24.
BRONCHIAL THERMOPLASTY FOR
SEVERE ASTHMA
No < airway hyperresponsiveness or > FEV1
> quality of life
< severe exacerbations
< emergency department visits
< days lost from school or work
bronchospasm
occasionally hospitalization
Momen M. Wahidi, MD, MBA and Monica Kraft, MD, AJRCCM, in press.
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
EMERGING PHARMACOTHERAPIES
FOR COPD
Barnes PJ. Chest 2008; 134:1278-1286
Expression of CXCR2 on Neutrophils
Pharmacol Rev 56:515-548, 2004
Barnes JACI 2007
CXCR2 Biology
Airway Epithelium
Ciliated
Epithelial
Cells
Goblet
Cell
(discharging)
Alveolus
Type I
Type II
Goblet cell hyperplasia
Mucus secretion
Smooth Muscle
Macrophage
Contraction
Migration
CXCR2
Neutrophil
Angiogenesis
Chemotaxis
Eosinophil
Fibroblast
myofibroblast
Blood Vessel
T-cell
Microvascular leakage
VCAM-1 expression
Mast Cell
Capillary
collagen
Blood Vessel
fibroblast
neutrophil
Effect of 50 mg of SCH527123 on Ozone-Induced
Airway Neutrophilia in Healthy Subjects
P = 0.001
Screening
P < 0.001
3.5
Sputum neutrophils
Cells X 106/mL
3.0
2.5
2.0
P < 0.001
1.5
1.0
0.5
0.0
Pre ozone
Holz et al Eur Respir J. 2010: 564-70
Post ozone
Placebo
SCH 527123
Prednisolone
TESRA (Treatment of Emphysema
with a Selective Retinoid Agonist)
study results
Paul Jones on behalf of TESRA
Steering Committee Members and
Investigators
Study design
Screening
Period
2-year Double-blind Treatment
Period
Safety
Follow-Up
Period
Up to 6 weeks
Start optimized
COPD therapy *
N = 329 Palovarotene (5 mg qd) p.o
+ optimized COPD therapy
4 Weeks
N = 492
N = 160 Placebo p.o.
+ optimized COPD therapy
* Optimized COPD therapy = SABA prn + Tiotropium + ICS+LABA (either Advair® or
Symbicort® at highest registered dose)
Outcomes (measured every 6 months)
• Post-bronchodilator FEV1 (primary outcome)
• Diffusing capacity
• CT densitometry (15% percentile) measured yearly
• 6-MWD
• SGRQ
• TDI
TESRA Patient Disposition
492 randomized patients
2 patients not treated (0.4%)
490 patients
ITT pop
1 patient (no efficacy FUP)
Placebo 160 patients
Palovarotene 329 patients
Placebo
159 patients
Palovarotene 5 mg
329 patients
29 % withdrawals
Dose reduction
3 (2 %) permanent
dose reduction
Dose reduction
28 (9%) permanent
dose reduction
Completers
Placebo
114 patients (71 %)
Palovarotene
225 patients (68 %)
1 patient received
palovarotene for 28 days
Safety pop
• 15 % due to safety
• 14 % non-safety
32 % withdrawals
• 22 % due to safety
• 10 % non-safety
Summary
• Palvoratene appears to have low toxicity
• In placebo treated patients, 2 regions of interest in the lower lung (lower half
and lowest quartile) showed faster disease progression across most measures
• ITT analysis in whole lung
– Palvarotene efficacy did not differ from placebo
• Post hoc analysis in the lower lung
– Palvarotene was associated with less worsening over time in most
outcomes
• These observations require confirmation using more detailed analysis of
emphysema progression in different parts of the lung
• If confirmed, the observations from this hypothesis-generating study require
testing in patients with lower lung emphysema
COPD Exacerbations*
Incidence of COPD exacerbations
(% of patients)
% of COPD exacerbations leading to:
* Defined as worsening of COPD symptoms requiring either orals steroids and/or antibiotics
Reported as Adverse Events by Investigator
44
Clustering by expression levels of periostin, CLCA1 and
serpinB2 in epithelial brushings identifies two groups of
subjects with asthma
Woodruff et al. AJRCCM 2009
LEBRIKIZUMAB TREATMENT IN ADULTS
WITH ASTHMA
Jonathan Corren, Robert F. Lemanske, Jr., Nicola A. Hanania, Phillip E.
Korenblat, Merdad V. Parsey, Joseph R. Arron, Jeffrey M. Harris, Heleen
Scheerens, Lawren C. Wu, Zheng Su, Sofia Mosesova, Mark D. Eisner,
Sean P. Bohen, and John G. Matthews.
August 3, 2011
Results: change in FEV1
Corren J et al, N Engl J Med 2011
Conclusions


Lebrikizumab treatment was associated with
improved lung function.
Patients with high pretreatment levels of
serum periostin had greater improvement in
lung function with lebrikizumab than did
patients with low periostin levels.
Corren J et al, N Engl J Med 2011; August 3, 2011
GATA-3 IS THE MASTER TRANSCRIPTION FACTOR IN
TH2-DRIVEN INFLAMMATORY DISEASES
Barnes P, JCI 118 (2008): 3546-3556
THE TRANSCRIPTION FACTORS GATA-3 AND TBET
PLAY A CRUCIAL ROLE IN INFLAMMATION
Ansel KM, et al. Annu. Rev. Immunol. 24 (2006): 607-56
SB010: MECHANISM OF ACTION
INTERLEUKIN-13 AND -4 EXPRESSION IN
THE CENTRAL AIRWAYS OF SMOKERS WITH
CHRONIC BRONCHITIS
T-helper-2 and -1 protein expression is
present in the central airways of
smokers and interleukin-4 and -13
could contribute to mucus
hypersecretion in chronic bronchitis.
Miotto D, Boschetto P, Mapp C et al Eur Respir J 2003; 22: 602–608
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
SYSTEMIC EFFECTS AND COMORBIDITIES OF
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Barnes PJ et al., Eur Respir J 2009;33:1165–1185
Clinical Case Report
• Man
• 60 years old
• Smoker (90 p/y)
• Occupation  trader of fruit
• No familiarity for lung disease
• No occupational/environmental
exposures
Symptoms and signs reported:
♦ increasing dyspnea (even at rest)
♦ fatigue
♦ ankle edema
♦ Chest: reduced murmur
♦ SaO2 (supine, air) 94%; ABP 130/80
Previous clinical history
• COPD (1990) with severe emphysema  GOLD III
• Major depression (2000)
• Hypertension (1990)
• Diabetes mellitus type II (2006)
• Chronic pulmonary heart failure(2010)
• Congestive heart failure (2010)
• Obstructive sleep apnea syndrome (2011)
• Obesity (BMI 36)
Home Therapy
- Bisoprolol 2,5 mg/day
- Valsaltan 80 mg/day
- Furosemide 250 mg/day
- Canrenoato potassium 100 mg/day
- Venlafaxine 150 mg/day
- Pregabalin 300 mg/day
- Triptych 150 mg/day
- Metformin 1000 mg/day
- Salmeterol/Fluticasone 50/500 1
inhalation/bid
- Tiotropium 18 mcg 1 in./day
- O2 therapy 1 L/min. at night
Diagnostic tests performed
• Blood examination  normal [in particolar normal ESR (10
mm), PCR (0.58 mg/dl) and D-dimer (370 ng/ml)] but with
mild increase in glycemia (138 mg/dl)
• Arterial blood gas analysis  hypoxemia (pH 7.43, pO2
63 mmHg, pCO2 49 mmHg, sO2 92%)
• Respiratory function tests  severe obstructive ventilatory
failure [FEV1 48% (1.71 L), FVC 71% (3.32 L), TLC 108%,
RV/TLC 136%; TLCO(Va) 68%]
• Polysomnography  A+H 7,8 / h; mean oxygen saturation
86,8%
• Echocardiogram (August 2011)  nothing significant to
report, except for a slight increase in PAPs; EF 45%.
Pulmonary emphysema on CT-scan
micronodule of 4 mm
REDUCTION OF MORBIDITY AND MORTALITY
BY STATINS, ACE INHIBITORS, AND ARBS IN
PATIENTS WITH COPD
These agents may have dual cardiopulmonary
protective properties, thereby substantially
altering prognosis of patients with COPD.
These findings need confirmation in
randomized clinical trials.
Mancini JB et al. J Am Coll Cardiol 2006;47(12):2554-60
Β-BLOCKERS MAY REDUCE MORTALITY AND RISK
OF EXACERBATIONS IN PATIENTS WITH
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Treatment with beta-blockers may
reduce the risk of exacerbations and
improve survival in patients with
COPD, possibly as a result of dual
cardiopulmonary protective
properties
Rutten FH et al, Arch Intern Med. 2010 May 24;170(10):880-7
NUOVI TRATTAMENTI PER LA COPD
Leonardo M. Fabbri
Exacerbations in COPD
Current and future treatment
Futuristic treatments
Treatment of co-morbidities of COPD
World COPD Day
Roma, Hotel Una
16 Novembre 2011
Nuovi trattamenti per la
COPD
Leonardo M. Fabbri
Clinica di Malattie dell’Apparato Respiratorio
Università degli Studi di Modena e Reggio Emilia
Azienda Ospedaliero-Universitaria - Policlinico di
Modena
ACUTE EFFECTS OF INDACATEROL ON LUNG
HYPERINFLATION IN MODERATE COPD:
A COMPARISON WITH TIOTROPIUM
Diagnosis of moderate (as classified by the Global Initiative
for Chronic Obstructive Lung Disease [GOLD] Guidelines,
2007) chronic obstructive pulmonary disease (COPD) and:
Smoking history of at least 10 pack-years
Forced expiratory volume in 1 second (FEV1
< 80% and ≥ 50% of the predicted normal value
Post-bronchodilator FEV1/Forced Vital capacity (FVC) < 0.7
Rossi A, Centanni B, Cerveri I, Gulotta C, Foresi A, Cazzola M, BrusascoV.
Respiratory Medicine (2011) xx, 1e7