COPD 2014

Alejandro C. Arroliga, M.D.Chairman and Professor

Dr. A. Ford Wolf and Brooksie Nell Boyd Wolf

Centennial Chair of Medicine

Organization of the talk

• A.- Inflammation

• B.- Brief review of therapy including for exacerbation (recent papers in red)

• COPD is a systemic disease

2

PLATINO: COPD in LatinAmerica

Brazil (São Paulo)

Uruguay (Montevideo)

Venezuela (Caracas)

Mexico (Mexico city)

Chile (Santiago)

Menezes A, et al. Lancet 2005

12,1%!!!

COPD is a progressive disease with inflammation as a key process

1. Snoeck-Stroband JB et al. Respir Res 2006; 7: 140. 2. Parr DG et al. Respir Research 2006; 7: 136 (online journal).

Understanding inflammation

• Airway inflammation negatively affects health status of COPD patients1

• Higher levels of certain inflammatory markers are associated with a decline in lung function and subsequent disease progression2

• Airway inflammation is characterised by increased numbers of neutrophils, macrophages and CD8+ lymphocytes1,2

• Infiltration of inflammatory cells into the airways occurs in both early and late stages of COPD3

• As the disease progresses, the small airways fill with inflammatory mucus exudates3

• The presence of inflammation in the airways provides a rationale for using inhaled corticosteroids and long-acting beta2-agonists to treat the disease

1. Gold Guideline http://goldcopd.com 2007. 2. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. 3. Hogg JC et al. New Eng J Med 2004; 350: 2645–2653.

Inflammation is present even in the early stages of COPD

Percentage change from baseline in biopsy and sputum endpoints

1. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743.

CD8p=0.001

CD68p=0.288

CD45p=0.001

CD4p=0.002

Mast cellsp=0.022

TNF-p=0.007

IFN-p=0.055

Ch

ang

e fa

vou

rsS

FC

Ch

ang

e fa

vou

rsp

lace

bo

30

20

10

0

-10

-20

-30

-40

-50

-60

-70

-80

SF

C 5

0/50

0 –

pla

ceb

o (

%)

The Anti-inflammatory Effect Is Associated With A Reduced Rate In

The FEV1 Decline

Ann Intern Med. 2009;151:517-527.

1. Bourbeau J et al. Thorax 2007; 62: 938–943. 2. Kardos P et al. Am J Respir Crit Care Med 2007; 175:144–149. 3. Mahler DA et al. Am J Respir Crit Care Med 2002 166: 1084–1091; 4. Calverley PMA et al. Lancet 2003; 361: 449–456. 5. Calverley PMA et al. New Eng J Med 2007; 356: 775–789. 6. Johnson M. Proc Am Thor Soc 2004; 1: 200–206 7. Adcock IM. J Allergy Clin Immunol 2002; 110(6 Suppl): s261–s268.

Synergistic effects of SFC

• Bourbeau et al suggest that combination therapy has anti-inflammatory effects, not seen with inhaled corticosteroids alone1

• Compared with monotherapy, enhanced effects for combination are consistent not only with clinical data but also with in vitro data2–5

• Bourbeau et al propose that the anti-inflammatory activity seen with SFC but not FP may be due to additive or synergistic effects at the receptor level1

• Corticosteroids may regulate 2 receptor function by increasing expression of the receptor, and inhibiting 2 receptor down-regulation6,7

COPD 2013

• “patients who benefit the most from inhaled bronchodilators seem to be those who have respiratory symptoms and airflow obstruction with an FEV1 less than 60% predicted”

• “monotherapy using either long acting inhaled anticholinergics or long acting beta agonists(but not inhaled steroids as monotherapy) for symptomatic patients with an FEV1 of less than 60% predicted is recommended

Courtesy of Frank Perez-Guerra, M.D.

Summary of data of different therapeutic studied in patients with COPD

• UPLIFT (Tiotropium achieves improvement in lung function over time, although rate of decline not reduced; reduction in frequency of exacerbations and in hospitalizations; no difference in mortality between tiotropium and placebo

• TORCH- reduction in the rate of decline in airflow limitation in the salmeterol/fluticasone arm compared to placebo

• INSPIRE – comparison of SFC versus tiotropium in severe COPD – no difference in exacerbation frequency between the two treatments. Question of better quality of life and reduced mortality risk with SFC.

• Tiotropium/formoterol (Foradil) vs salmeterol(Serevent)/fluticasone in moderate COPD – TF superior in lung function over the day compared to SF (this study appeals to me, Chest 2008;134:255)

• OPTIMAL (Tiotopium/placebo, T plus salmeterol, T plus salmeterol/fluticasone) – patients treated with T/F/S had significantly better disease specific quality of life and fewer hospitalizations compared to T/placebo, however these improvements in health outcomes were associated with increased costs. Monotherapy with T most economically attractive. Exacerbation rate did not differ

Summary of data of different therapeutic studied in patients with COPD

Others therapy

• Immunizations – both Pneumovax and influenza (this is an “accepted” recommendation)

• Testing for alpha-one-anti-trypsin deficiency –

• Lung volume reduction surgery (or “medical treatment utilizing valves”) - not a common procedure, but may be considered in very symptomatic patients with well documented predominant upper lobe emphysema with an FEV1 and DlCO of more than 20% of predicted

• Transplantation - LVRS may be a bridge to this. When to refer – BODE index of over 5, post dilator FEV1 of less than 20% predicted, resting hypoxemia, hypercapnia, secondary PH, accelerated decline in FEV1 – but…is there a survival benefit?

Global Strategy for Diagnosis, Management and Prevention of COPD

Manage Stable COPD: Non-pharmacologic

PatientGroup

Essential Recommended Depending on local guidelines

ASmoking cessation (can include pharmacologic

treatment)Physical activity

Flu vaccinationPneumococcal

vaccination

B, C, D

Smoking cessation (can include pharmacologic

treatment)Pulmonary rehabilitation

Physical activityFlu vaccinationPneumococcal

vaccination

© 2013 Global Initiative for Chronic Obstructive Lung DiseaseCourtesy of Shirley Jones, M.D.

COPD 2013

• Roflumilast – this is a PDE-4 inhibitor (PDE-4 inhibition decreases inflammation and promotes airway smooth muscle relaxation)

• Approved for COPD patients with a history of exacerbations – the experience is limited, but this agent may be useful perhaps not only in COPD, but in asthma, bronchiectasis, etc – time will tell

• Mucoactive agents- the jury is out, but some patients may improve, some even think that they are better than the inhaled medications (but this is doubtful)

GOLD Assessment

Sev

erity

of A

irflo

w

Obs

truc

tion

Worse obstruction

More severe

Exa

cerb

atio

ns

Frequent exacerbations

DSevere ObstructionSevere Symptoms++ Exacerbations

High

High

High

Risk

Risk

Risk

Symptoms

CSevere ObstructionMinimal Symptoms++ Exacerbations

AMild-Mod ObstructionMinimal SymptomsFew Exacerbations

BMild-Mod Obstruction

Severe SymptomsFew Exacerbations

GOLD Website. http://www.goldcopd.com. Updated December 2011

Survival shown as Kaplan-Meier curves

Lange et al AJRCCM 2012; 186: 975–981

Groups C and D experienced a higher incidence of exacerbations in the following year and a higher average number of exacerbations per year than groups A and B.

Exa

cerb

atio

ns p

er y

ear

> 2

1

0

mMRC 0-1CAT < 10

RiskFEV1

GOLD 4or

mMRC > 2CAT > 10

GOLD 3

GOLD 2or

GOLD 1

SAMA prnor

SABA prn

LABA or

LAMA

ICS + LABAor

LAMA

COPD: Pharmacologic Therapy(FIRST CHOICE)

A B

DCICS + LABA

or LAMA

• In alphabetical order

Symptoms

Risk

Exacerbations Are Not Random Events

Gold Stage AECOPD Rate in Yr 1

II 0.85

III 1.34

IV 2.00

Risks of COPD Exacerbations

Strongest predictor of an AECOPD in a given year was the presence of an exacerbation in the previous year

Hurst JR et al. N Engl J Med 2010; 363:1128-1138

22Agusti A, et al. Eur Respir J 2013; 42: 636

PA:A ratio of more than 1 at baseline was associated with future exacerbations of COPD, particularly those requiring hospitalization

23

The PA:A ratio also appears to outperform many established risk factors for exacerbation including GERD, SGRQ score, breathlessness, chronic bronchitis, and FEV1,as well as recently identified CT predictors.

0.029%SFC vs FP0.00212%SFC vs sal

<0.00125%SFC vs placebo

SFC significantly reduces exacerbations and severity of exacerbations over 3 years (TORCH)

p-valueTreatment effect

0

0.2

0.4

0.6

0.8

1

1.2

Placebo

An

nu

alis

ed e

xace

rbat

ion

rat

e

Sal FP SFC

25% (p<0.001)

1.13

0.97 0.930.85

1. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.

Treatment of ambulatory exacerbations of mild-moderate COPD is more effective with antibiotic vs. placebo

Primary and Secondary Outcomes

AMX (500/125 mg/8 hrs) %N=158

PBO %N= 152

P value

Clinical cure days 9-11* 74 59 0.016

Clinical cure at day 20 81 67 0.006

Days until exacerbation, median

233 (110-365) 160 (66-365) 0.015

Peak expiratory flow from basal , L/min

52 38 0.039

25

The NNT is seven

Llor C, et al Am J Respir Crit Care Med 2012; 186: 716

In patients presenting to the ER with acute exacerbation, 5-day treatment of prednisone (40mg daily) was noninferior to 14-day treatment

• Non inferiority was defined as a 15% absolute difference in % of patients with a re-exacerbation (6 months)

• Average FEV1 was 31% and 87% were GOLD 3 or 4

26

End point Conventional treatment (n=155)

Short- term (n= 156)

Comparison measure (95%CI)

P value

Reexacerbations (ITT)

36% 35% HR 0.95 (0.70-1.29) 0.006

Deaths follow up 8% 7% HR 0.93 (0.40-2.20) .87

Need for MV 13% 11% OR 0.78 (0.37-1.63) .49

Cumulative dose, median, mg

560 (560-773) 200 (200-310) <0.001

Leuppi JD, et al. JAMA 2013; 309: 2223-2231

COPD affects more than the lungs!

TORCH overall causes of death as adjudicated by the Clinical Endpoint Committee

Unknown7%

Cardiac 27%

Cancer21%

Other10%

Respiratory35%

1. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.

84% of COPD patients in TORCH study had comorbidities in at least one body system

53

34

2521

18 18 1714 14 12 11 10 10 9

4 4

% to

tal p

opul

ation

n=6112

Clinical consequences of osteoporosis

• Acute and chronic

pain

• Kyphosis

• Loss of height

• Loss of mobility

• Bulging abdomen, reflux and other GI

symptoms

• Breathing difficulties

• Depression

• Loss of independence

REDUCED QUALITY OF LIFECourtesy of Tony Anzueto, M.D.

What Do COPD Patients Die From?

Mannino et al. Thorax. 2003;58:388-393.

1000 20 40 60 80

Severe COPDGOLD Stage IIIGOLD Stage III

Moderate COPDGOLD Stage IIGOLD Stage II

No COPDGOLD Stage 0GOLD Stage 0

COPD ASCVD Lung Cancer Pneum/Inf Other

Patients (%)

Courtesy of Tony Anzueto, M.D.

Prevalence of CVD in COPD

Curkendall et al, AEP 2006

Angina Other Cardiovascular Disease

Pulmonary Embolism

StrokeAcute Myocardial Infarction

Arrhythmia

Odds ratio

Congestive Heart Failure

0

1

2

3

4

5

6

7

8

Courtesy of Tony Anzueto, M.D.

β-blockers can be used in patients with COPD and heart failure

• To explore the interaction of β-blocker selectivity and outcomes the authors queried the OPTIMIZE-HF registry

33Mentz RJ, Am J Cardiol 2013; 111: 582-87

34

β-blockers can be used in patients with COPD and heart failure

Mentz RJ, Am J Cardiol 2013; 111: 582-87

35

Mentz RJ, Am J Cardiol 2013; 111: 582-87

Conclusions

• The burden of COPD is high and is rising1

• COPD is a multicomponent disease with inflammation at its core2

• It is important to treat the underlying inflammation, which is present even in the early stages of the disease3,4

• Patients on SFC have significantly improved lung function and quality of life, and a significant reduction in exacerbations compared with components or placebo5

1. Murray CJL et al. Lancet 1997; 349:1498–1504. 2. Agusti AGN et al. Eur Respir J 2005; 99: 670–682. 3. Hogg JC et al. New Eng J Med 2004; 350: 2645–2653. 4. Barnes NC et al. Am J Respir Crit Care Med 2006; 173: 736–743. 5. Calverley PMA et al. New Eng J Med 2007; 356: 775–789.

Conclusions

• Exacerbations are common. Patients with previous exacerbations are more likely to have more. Presence of cough and sputum production are associated with more exacerbations

• Antibiotics are useful to treat exacerbations in patients with mild to moderate COPD

• Prednisone 40 mg daily for 5 days is enough

• Use of β-blockers in patients with HF, even non selective are well tolerated and may be associated with improve survival

38

COPD : a vision for the next 10 years

Understanding airway obstruction

Improved drug delivery

New LABAs and LAMAs

Combinations LAMA + LABA

Ultra long-acting β2 agonists under development

Vilanterol

Olodaterol

Abediterol (LAS-100977)

AZD3199

PF-610355 (?)

NEW LABAs

Cazzola M, et al. Respir Med 2013

Disease Severity: BDs +/- ICS

Decramer M, et al. Respir Med 2013

New LABA’s

van Noord JA, et al. Pulm Pharmacol Ther 2011

n=35FEV1: 37 ± 9%TBD: 21 ± 8%Respimat

n=35FEV1: 37 ± 9%TBD: 21 ± 8%Respimat

Long-acting antimuscarinic agents

Glycopyrronium (NVA-237)Umeclidinium (GSK-573719)

Aclidinium

TD-4208 CHF 5407QAT370

BEA-2180BR Trospium

DexpirroniumAZD8683

PF-3715455 or PF-3635659

New LABA - NAV 237

Kerwin E, et al; GLOW2. Eur Respir J 2012

n=1066FEV1: 55,7 ± 13%TBD: 16 ± 15%Breezhaler

n=1066FEV1: 55,7 ± 13%TBD: 16 ± 15%Breezhaler

New LAMA’s

Jones PW, et al; ATTAIN. Eur Respir J 2012

n=828FEV1: 53 ± 14%TBD: –Genuair

n=828FEV1: 53 ± 14%TBD: –Genuair

COPD : a vision for the next 10 years

Understanding airway obstruction

Improved drug delivery

New LABAs and LAMAs

Combinations LAMA + LABA

The present and future

LAMAs

• Tiotropium

• Glycopyrronium (NVA237)

• Umeclidinium bromide

• Aclidinium bromide

LABAs

• Oledanterol

• Indacaterol

• Vilanterol

• Carmoterol

• Formoterol

• Salmeterol

Fixed - Combinations- Olodaterol/ tiotropium-Umeclidinium/ vilanterol -- Indacaterol/ glycopyrronium - Formoterol/aclidinium-Formoterol/glycopyrrolate

Rationale for combining long-acting bronchodilators

• Inhaled bronchodilators are the foundation of COPD treatment

• Most patients with COPD improve with bronchodilation

• Maximal bronchodilation is not achieved using clinically approved doses of 1 class of bronchodilator alone

• There could be synergistic interactions between 2-agonists and anticholinergics

Cazzola M, Molimard M. Pulm Pharmacol Ther 2010;23:257-67

Ipratropium + Albuterol

Combination short acting therapy

40

50

60

70

80

90

100

0 15 30 45 60 75 90 105 120

% R

esp

ond

ing

Albuterol Ipratropium

Minutes post-drug administration

Dorinsky PM, et al. Chest. 1999;115:966–971.

Combining tiotropium and formoterol (dosed once or twice daily): FEV1

1.5

1.4

1.3

1.2

1.1

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 249 AM 3 PM 9 PM 3 AM 9 AM

FEV

1 (

L)

van Noord JA et al. Chest 2006;129:509-17

Time (hours)

Tiotropium qd + formoterol bidTiotropium qd + formoterol qd

Tiotropium qd + placebo bid24-hour base

Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPDtime to exercise intolerance FEV1

Berton et al. Respiratory Medicine 2010; 104: 1288-96

Combination: LABA + LAMA

Nuevas evidencias en LABA-LAMA2

Bateman E, et al; SHINE. ERS Congress 2012

5m 1h 2h 4h 8h 16h 22h 24\912h

Time

1.601.551.551.451.401.351.301.251.201.151.101.051.00

LS

me

an

of

FE

V1(

L)

QVA149 Indacaterol Glycopyrronium Open-label tiotropium Placebo

54/46

LABA + LAMA vs ICS/LABA

Vogelmeier CF, et al; ILLUMINATE. Lancet 2012

Four weeks once daily treatment with tiotropium + olodaterol fixed dose combination compared with tiotropium in COPD patients

0

50

100

150

200

250

300

350

400

450

T 5μg T+O 5/2μg T+O 5/5μg T+O 5/10μg

Peak FEV1 response (mL)

Trough FEV1 response (mL)

* *

*

*

Maltais et al, ERS Congress 2010

FEV1 after 4 weeks of treatment

aMean values adjusted for baseline, treatment and centre

1.20

1.30

1.40

1.50

1.60

-1 0 1 2 3 4 5 6Time (hours)

FE

V1

(L)a

T+O (5 / 10 µg)T+O (5 / 5 µg)

T+O (5 / 2 µg)

T (5 µg)

Maltais F et al. P5557 presented at ERS 2010

28-day safety and tolerability of umeclidinium incombination with vilanterol in COPDChange from baseline in 0–6 h weighted mean pulse rate

Feldman et al, Pulm Pharmacol Ther 2012

(Ultra) LABA/ICS combinations in clinical development

Formoterol + mometasone (MFF258)Formoterol + fluticasone propionate

Formoterol + ciclesonideIndacaterol + mometasone (QMF-149)

Indacaterol + QAE-397Vilanterol + fluticasone furoate

GS-424020 (novel mutual prodrug of salmeterol and desisobutrylciclesonide)

Cazzola et al, Expert Opin Pharmacother 2012

Triple combination therapies in Phase I and II clinical trials

COPD: Drug Combinations (in alphabetical

order)

Patient

First choice Second choiceAlternative

Choices

ASAMA prn

or SABA prn

LAMA or

LABA or

SABA and SAMA

Theophylline

BLAMA

or LABA

LAMA and LABASABA and/or

SAMATheophylline

C

ICS + LABAor

LAMALAMA and LABA

PDE4-inh.SABA and/or

SAMATheophylline

D

ICS + LABAor

LAMA

ICS and LAMA orICS + LABA and LAMA

or ICS+LABA and PDE4-

inh. orLAMA and LABA or

LAMA and PDE4-inh.

CarbocysteineSABA and/or

SAMATheophylline

MABA: LABAS + LAMALABA

Long-acting beta agonistLABA

Long-acting beta agonistLAMA

Long-acting muscarinic antagonistLAMA

Long-acting muscarinic antagonist

MABAMuscarinic antagonist and beta agonist

Hughes AD, et al. Prog Med Chem 2012

Astra Zeneca – PATHOS Study• Objectives:– To investigate exacerbation rates in primary care patients with COPD treated with BF vs FS.• Methods:– Data from primary care medical records.– Pairwise (1:1) propensity score matching.• Results– Matching of 9893 patients (7155 BF; 2738 FS yielded two cohorts of 2734 patients), comprising 19,170 patient-years.– The exacerbation rates were 0.80 and 1.09 per patient-year BF and FS – Yearly rates for COPD-related hospitalizations were 0.15 and 0.21, respectively• Conclusions– Long-term treatment with fixed-combination BF was associated with fewer exacerbations than FS in patients with moderate and severe COPD.

Journal of Internal Medicine 2013 in press.

New ICS-LABAS combination

Martinez F et al Respiratory Medicine 2013; 107: 550

Inhibition of release ofinflammatory mediators by p38 inhibitors

- Signalling through p38 mitogen-activated protein kinase (p38-MAPK) is required for the expression of a range of inflammatory mediators associated with COPD such as tumor necrosis factor α, interleukin-1 (IL-1), IL-6 and IL-8.- PH-797804 is a potent, selective p38-MAPK

MacNee W, et al. Thorax 2013

Novel classes of bronchodilators

• Selective phosphodiesterase inhibitors

• K+ channel openers

• Vasoactive intestinal peptide analogs

• Rho kinase inhibitors

• Brain natriuretic peptide and analogs

• Nitrix oxide donors

• E-prostanoid receptor 4 agonists

• Bitter taste receptor agonists

Cazzola et al, Pharmacol Rev 2012

COPD : a vision for the next 10 years

• Further understanding of the impact of long acting bronchodilators.

• Demonstrate the efficacy of intervention in milder disease.

• New delivery systems

• Provide maximum bronchodilation - combination therapy – LABA-LAMA

• New molecules