Nuovi trattamenti per la COPD - Pazienti · PDF fileNUOVI TRATTAMENTI PER LA COPD. Leonardo M....

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

World COPD Day Roma, Hotel Una

16 Novembre 2011

Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena

Exacerbations in COPD

Current and future treatment

Futuristic treatments

Treatment of co-morbidities of COPD

NUOVI TRATTAMENTI PER LA COPD

Leonardo M. Fabbri

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

20%-24% (1 year)

2.5%-10% (5 days)

22%-32% (14 days)

13%-33% (14 days)

Hospital mortality

Hospital mortality

Relapse (repeat ER visit)

Treatment failure rate

OUTCOME OF COPD EXACERBATIONS

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.

In hospitalized patients

In ER patients

In ICU patients

In outpatients

LUNG FUNCTION IMPAIRMENT, COPD HOSPITALISATIONS AND

SUBSEQUENT MORTALITY

Garcia-Aymeric et al, Thorax 2011;66:585e590.

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 long-term all-cause mortality

COPD

Chronic disease

Tashkin D. N Engl J Med 2010; 363: 1184

Hurst et al, N Engl J Med 2010; 363: 1128-38

progressive nature

• lung function

• symptoms

• comorbidities

Exacerbations • typically 1 - 3 per year • frequency proportional to COPD severity • the frequent exacerbator • chronic decline resulting in poorer prognosis ↓ HRQL ↑ hospitalizations ↑ mortality

COPD exacerbations

PNEUMONIA

THROMBOEMBOLISM

ACUTE HEART FAILURE

METABOLIC ACIDOSIS

ANEMIA

CAUSES OF EXACERBATION OF

RESPIRATORY SYMPTOMS IN CHRONIC PATIENTS

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

All Breast Cancers

ER+ 65-75%

HER2+ 15-20%

Triple negative

15%

HER3+

IGFR1+

p95+ 4%

P53mut 30-40 %

FGFR1 Ampl 8%

PTENloss 30-50%

PI3Kmut 10%

BRCAMut 8%

TARGETED THERAPIES IN A-NSCLC Positive Phase III Studies

Monotherapy

ComboTherapy

Erlotinib BR.21

Bevacizumab ECOG 4599/AVAiL

Gefitinib IPASS/INTEREST/NEJG002

EGFR Mut+

1st Line

A-NSCLC

Cetuximab FLEX

2nd /3rd

Line

2005 2008 2009 2007

EGFR Mut+ All

lines

NUOVI TRATTAMENTI PER LA COPD

Leonardo M. Fabbri

Exacerbations in COPD

Current and future treatment

Futuristic treatments

Treatment of co-morbidities of COPD

NUOVI TRATTAMENTI PER LA COPD

Leonardo M. Fabbri

Add ICS OR/AND ROFLUMILAST in “exacerbators”

IV: Very Severe III: Severe II: Moderate I: Mild

Therapy at Each Stage of COPD

• FEV1/FVC < 70% • FEV1 > 80% predicted

• FEV1/FVC < 70% • 50% < FEV1 < 80% predicted

• FEV1/FVC < 70% • 30% < FEV1 <

50% predicted

• FEV1/FVC < 70% • FEV1 < 30%

predicted or FEV1 < 50%

predicted plus chronic respiratory failure

Add one or more long-acting bronchodilators (when needed); Add rehabilitation

Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed)

Add long term oxygen if chronic respiratory failure. Consider surgical treatments

Add ROFLUMILAST

2011 UPDATE OF THE GOLD GUIDELINES

2011 UPDATE OF THE GOLD GUIDELINES

Shanghai, October 2011

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

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

Alpert RK et al, New Engl J Med 2011; 365: 689-698

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

THE EFFECT OF TELITHROMYCIN IN ACUTE EXACERBATIONS OF ASTHMA

Johnston SL et al, NEJM 2006;354(15):1589-600

This study provides evidence of the benefit of telithromycin in

patients with acute exacerbations of asthma; the mechanisms of

benefit remain unclear

Corbetta L et al, 2011

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

Sciurba et al, N Engl J Med 2010; 363;13

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

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

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.

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 lung-function 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

Castro M et al. Am J Respir Crit Care Med 2010;181:116–24.

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.

EFFECTIVENESS AND SAFETY OF BRONCHIAL THERMOPLASTY IN THE TREATMENT OF

SEVERE ASTHMA

Momen M. Wahidi, MD, MBA and Monica Kraft, MD, AJRCCM, in press.

No < airway hyperresponsiveness or > FEV1 > quality of life

< severe exacerbations < emergency department visits < days lost from school or work

bronchospasm

occasionally hospitalization

BRONCHIAL THERMOPLASTY FOR SEVERE ASTHMA

Exacerbations in COPD

Current and future treatment

Futuristic treatments

Treatment of co-morbidities of COPD

NUOVI TRATTAMENTI PER LA COPD

Leonardo M. Fabbri

EMERGING PHARMACOTHERAPIES FOR COPD

Barnes PJ. Chest 2008; 134:1278-1286

Barnes JACI 2007

Expression of CXCR2 on Neutrophils

Pharmacol Rev 56:515-548, 2004

Goblet Cell (discharging)

Ciliated Epithelial

Cells Alveolus

Type I Type II

Smooth Muscle

Neutrophil

Blood Vessel

Capillary

collagen

CXCR2

Macrophage

Eosinophil T-cell

Mast Cell

Contraction Migration

Goblet cell hyperplasia Mucus secretion

Chemotaxis

Microvascular leakage VCAM-1 expression

Fibroblast myofibroblast

Angiogenesis

Airway Epithelium

Blood Vessel

CXCR2 Biology

fibroblast neutrophil

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Sput

um n

eutr

ophi

ls

Cel

ls X

106

/mL

P = 0.001

P < 0.001

P < 0.001

Screening

Pre ozone Post ozone Placebo SCH 527123 Prednisolone

Effect of 50 mg of SCH527123 on Ozone-Induced Airway Neutrophilia in Healthy Subjects

Holz et al Eur Respir J. 2010: 564-70

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

Up to 6 weeks Start optimized COPD therapy *

N = 492

Safety Follow-Up

Period

4 Weeks

2-year Double-blind Treatment Period

N = 160 Placebo p.o. + optimized COPD therapy

N = 329 Palovarotene (5 mg qd) 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

490 patients

2 patients not treated (0.4%)

Placebo 159 patients

Palovarotene 5 mg 329 patients

29 % withdrawals • 15 % due to safety • 14 % non-safety

Dose reduction 3 (2 %) permanent

dose reduction

Dose reduction 28 (9%) permanent

dose reduction

32 % withdrawals • 22 % due to safety • 10 % non-safety

Placebo 114 patients (71 %)

Palovarotene 225 patients (68 %)

Safety pop

Completers

ITT pop Placebo 160 patients Palovarotene 329 patients

1 patient (no efficacy FUP)

1 patient received palovarotene for 28 days

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

Incidence of COPD exacerbations (% of patients)

% of COPD exacerbations leading to:

COPD Exacerbations*

* 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

Corren J et al, N Engl J Med 2011

Results: change in FEV1

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

Miotto D, Boschetto P, Mapp C et al Eur Respir J 2003; 22: 602–608

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.

INTERLEUKIN-13 AND -4 EXPRESSION IN THE CENTRAL AIRWAYS OF SMOKERS WITH

CHRONIC BRONCHITIS

Exacerbations in COPD

Current and future treatment

Futuristic treatments

Treatment of co-morbidities of COPD

NUOVI TRATTAMENTI PER LA COPD

Leonardo M. Fabbri

Barnes PJ et al., Eur Respir J 2009;33:1165–1185

SYSTEMIC EFFECTS AND COMORBIDITIES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Clinical Case Report

• Man

• 60 years old

• Occupation trader of fruit

• No familiarity for lung disease

• No occupational/environmental exposures

• Smoker (90 p/y)

Symptoms and signs reported:

♦ fatigue

♦ Chest: reduced murmur

♦ increasing dyspnea (even at rest)

♦ ankle edema

♦ 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

Rutten FH et al, Arch Intern Med. 2010 May 24;170(10):880-7

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

Exacerbations in COPD

Current and future treatment

Futuristic treatments

Treatment of co-morbidities of COPD

NUOVI TRATTAMENTI PER LA COPD

Leonardo M. Fabbri

Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena

World COPD Day Roma, Hotel Una

16 Novembre 2011

Nuovi trattamenti per la COPD

Rossi A, Centanni B, Cerveri I, Gulotta C, Foresi A, Cazzola M, BrusascoV. Respiratory Medicine (2011) xx, 1e7

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

ACUTE EFFECTS OF INDACATEROL ON LUNG HYPERINFLATION IN MODERATE COPD:

A COMPARISON WITH TIOTROPIUM