BPCO E PATIENT-RELATED OUTCOMES: IL VALORE AGGIUNTO DEI NUOVI TRATTAMENTI FARMACOLOGICI Pierluigi Paggiaro Dipartimento Cardio-Toracico e Vascolare, Università di Pisa Università degli Studi di Pisa Azienda Ospedaliera Pisana Ottica Respiro 2016 Verona, 6-7 maggio 2016

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4 Cazzola et al, ERJ 2008

Clinical outcomes for COPD Are they relevant ? Measurable by MRC scale, BDI/TDI, rescue med., … Impact on quality of life and mortality Are they improved by the pharmacologic treatment ? Bronchodilators Anti-inflammatory drugs Focus on LABA/LAMA combinations Are they better than single drug ? Which relevance for the patient ?

Global Strategy for Diagnosis, Management and Prevention of COPD Assessment of COPD  Assess symptoms  Assess degree of airflow limitation using spirometry  Assess risk of exacerbations  Assess comorbidities © 2014 Global Initiative for Chronic Obstructive Lung Disease

COPD Importance of symptoms Symptoms Dyspnea Cough Sputum Wheezing Mild Variability Day-by-day Morning/night

COPD Importance of symptoms Symptoms Dyspnea Cough Sputum wheezing Mild Variability Day-by-day Morning/night

Poor correlation between symptoms and FEV1

 Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities COPD Assessment Test (CAT) or Clinical COPD Questionnaire (CCQ) or mMRC Breathlessness scale Global Strategy for Diagnosis, Management and Prevention of COPD Assessment of COPD © 2014 Global Initiative for Chronic Obstructive Lung Disease

 Assess symptoms  Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities Use spirometry for grading severity according to spirometry, using four grades split at 80%, 50% and 30% of predicted value Global Strategy for Diagnosis, Management and Prevention of COPD Assessment of COPD © 2014 Global Initiative for Chronic Obstructive Lung Disease

 Assess symptoms  Assess degree of airflow limitation using spirometry  Assess risk of exacerbations Assess comorbidities Use history of exacerbations and spirometry. Two exacerbations or more within the last year or an FEV 1 < 50 % of predicted value are indicators of high risk. Hospitalization for a COPD exacerbation associated with increased risk of death. Global Strategy for Diagnosis, Management and Prevention of COPD Assessment of COPD © 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD  Assess symptoms  Assess degree of airflow limitation using spirometry  Assess risk of exacerbations Combine these assessments for the p urpose of improving management of COPD © 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD (C)(D) (A)(B) CAT < 10CAT > 10 Symptoms If CAT < 10 or mMRC 0-1: Less Symptoms/breathlessness (A or C) If CAT > 10 or mMRC > 2: More Symptoms/breathlessness (B or D) Assess symptoms first © 2014 Global Initiative for Chronic Obstructive Lung Disease Breathlessness mMRC 0–1mMRC > 2

Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD © 2014 Global Initiative for Chronic Obstructive Lung Disease Risk (GOLD Classification of Airflow Limitation)) Risk (Exacerbation history) ≥ 2 or > 1 leading to hospital admission 1 (not leading to hospital admission) 0 Symptoms (C) (D) (A) (B) CAT < CAT > 10 Breathlessness mMRC 0–1 mMRC > 2

The different components of COPD Different components of the disease: Airway obstruction and hyperinflation Responsable of: Increased work of breathing  limitation in exercise capacity Dyspnea, poor QoL  muscolo-scheletal consequences Airway and lung inflammation Responsable of: Progression of the airway and lung parenchima damage Rate and severity of exacerbations

The central role of airflow limitation in COPD Disability Disease progressionDeath Air trapping Expiratory flow limitation Hyperinflation DeconditioningInactivity Reduced exercise capacity Exacerbations COPD Breathlessness Quality of lifeExercise Bronchodilators improve symptom control and clinical outcomes

Old and new long-acting bronchodilators Beta2-agonists Over 12 hrs: salmeterol, formoterol Over 24 hrs: indacaterol, olodaterol, vilanterol Anticholinergic drugs Over 12 hrs: aclidinium Over 24 hrs: tiotropium, glycopirronium umeclidinium

Long-acting Anticholinergic drugs for COPD Common characteristics Highly selective for M3 receptor High affinity Long half life

How to measure the efficacy of anticholinergic drugs in COPD TiotropiumGlycopirroniumAclidinium FEV ml ml ml Exacerbations % (3 yrs)- 34% TFE (1 yr)- 35% (6 mts) Exercise tolerance+ 4 min ET+ 90 sec+ 116 sec PROs SGRQ- 3 SGRQ- 4 SGRQ FEV1 declineIn moderate COPD n.a. Mortality %n.a. SafetyLarge numbers Long follow-up CV AE (?) > 2000 pts Up to 1 yr No MAE > 1000 pts Up to 6 mts No MAE

Izquierdo et al, IJCOPD 2016 PDC: proportion of days covered

Clinical outcomes for COPD Symptoms and rescue medication Dyspnoea Measurable by MRC scale, BDI/TDI Cough and sputum Rescue medication use Short-acting beta2 Are they sensitive to pharmacologic treatment ? Single drugs vs combinations

Clinically significant improvement in QoL and dyspnea with aclidinium 400 mcg bid Kevin et al, JCOPD 2012

Aclidinio Bromuro 400 µg BID (n=171) Tiotropio 18 µg QD (n=158) Run in 6 settimane Placebo (n=85) Giorni 1 & 2: − TFP seriati 24 ore Giorni 42 & 43 – TFP seriati 24 ore – Preferenza per il device Farmaco di salvataggio e sintomi quotidiani della BPCO -EXACT-RS -Altri sintomi Randomizzazione: 2:2:1 EXACT-RS,: EXAcerbations of Chronic Pulmonary Disease Tool-Respiratory Symptom)s; TFP, test di funzionalità polmonare LAS 39: study design Studio multicentrico di Fase IIIb, randomizzato, in doppio cieco, double-dummy, controllato con placebo e con confronto attivo, della durata di 6 settimane, su pazienti (n=414) con BPCO da moderata a grave Dopo lo screening e un run-in di 2-3 settimane, i pazienti sono stati randomizzati (2:2:1) a ricevere il trattamento con Aclidinio Bromuro 400 μg b.i.d. al mattino e alla sera mediante l’inalatore multidose a polvere secca Genuair,Tiotropio 18 μg u.i.d. al mattino mediante l’inalatore HandiHaler, oppure placebo per 6 settimane Beier J et al. COPD 2013

Clinically significant improvement in through FEV1 with aclidinium 400 mcg bid Beier et al, JCOPD 2013

Aclidinium bid improves diurnal and nocturnal symptoms better than tiotropium od Beier et al, JCOPD 2013

Symptom variability in COPD patients Partidge, CMRO 2009 Online survey in COPD patients Kessler, ERJ 2011 Clinic-based survey (GPs and specialists) Agusti, ERR 2011 Nocturnal symptoms in COPD patients of different severity «unreported exacerbations» Asthma COPD Overlap Syndrome (ACOS)

Pazienti (%) Al risveglio Più tardi nel mattino Nel pomeriggio A sera Di notte Mancanza di fiato (n=1769) Respiro sibilante (n=1018) 25.1 Respiratory symptoms are more frequent at early morning Al risvegli o Più tardi nel mattino Nel pomeriggio A sera Di notte Pazienti (%) Costrizione toracica (n=690) Al risveglio Più tardi nel mattino Nel pomeriggio A sera Di notte Pazienti (%) Kessler R et al. Eur Respir J 2011 Pazienti (%) Al risveglio Più tardi nel mattino Nel pomeriggio A sera Di notte Tosse (n=1433)

PRESENZA DI SINTOMI NOTTURNI SECONDO LA GRAVITÀ DELLA BPCO Agusti A et al Eur Respir Rev 2011; 20: 121, 183–194 % del VEMS predetto più recente Prevalenza percentuale dei pazienti Incremento percentuale Intervalli di confidenza al 95% COPD: nocturnal symptoms Uno studio condotto su pazienti ha mostrato che i sintomi notturni sono presenti in tutti gli stadi di gravità della malattia (presenti nel 67 % dei pazienti) La percentuale di pazienti che presentano sintomi notturni aumentava con il peggiorare della gravità della BPCO.

Santus et al, Pulm Pharm & Ther 2015

Marth et al, Respir Med 2015

32 Clinical outcomes for COPD Exercise tolerance Important impact on daily life activities «vicious cyrcle» of COPD Measurable with different tests 6MWT, SWT, daily activity Improvement may strongly impact on non- respiratory manifestations of COPD Muscolo-skeletal function Cardiovascular consequences

Poor physical activity is associated with high risk of hospitalization and mortality in COPD patients Garcia-Rio et al, Chest 2012 MortalityHospitalization

Long-lasting brochodilation improves systemic consequences of COPD o Allowing a better physical activity o Additional doses of bronchodilators on top on regular treatment o Bronchodilators on top of rehabilitation o Reducing systemic consequences of inactivity o As demonstrated in rehabilitation programmes o Increasing physical activity o Reducing cardiovascular events, osteoporosis, muscular disfunction, etc

Beeh et al, BMC Pulm Med 2015

Pre-clinical data Studied in normal subjects up to 6000 mcg Single doses No relevant side effects Rapidly converted in two inactive metabolites by plasma hydrolysis Maximum plasma concentration in 5-7 min T1/2: hours Steady state plasma concentration at 7th day No accumulation Predominantly renally excreted

Aclidinium is rapidly hydrolyzed in human plasma (in vitro) % remaining compound Time (minutes) Sentellas et al, Eur J Pharm Sci Aclidinium Ipratropium Tiotropium Aclidinium half-life 2.4 mins

 Long-acting inhaled bronchodilators are convenient and more effective for symptom relief than short-acting bronchodilators.  Long-acting inhaled bronchodilators reduce exacerbations and related hospitalizations and improve symptoms and health status.  Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator. Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Bronchodilators © 2013 Global Initiative for Chronic Obstructive Lung Disease

New LABA-LAMA combinations Singh, B J Clin Pharm 2015

Oba et al, Thorax 2016

Maximizing bronchodilation with LABA/LAMA Which advanteges for patients ? o Improving symptoms and symptom-free days o Improving exercise capacity o Reducing exacerbations  Improving quality of life o Prevention of FEV1 decline ? o Small signal with monotherapy o Suggestions from experimental models

Effects of mechanical stress o On several airway structures o Epithelial cells o Smooth muscle cells o Through various mechanisms o Release of pro-inflammatory cytokines (IL-8) o Neoangiogenesis and globet cell increase o Actin-myosin changes o Potential role in remodelling o Persistent airway obstruction o Progression of the disease

Repeated mechanical stress induces neo-angiogenesis and VEGF production from human airway smooth muscle cells Hasaneen et al, AJPLCMP 2007

Which patient for LABA/LAMA combination ? Singh, B J Clin Pharm 2015

COPD: multiple targets for intervention Bronchodilators –Effective on airway calibre and hyperinflation –Positive effects on symptoms, exercise tolerance and quality of life –Positive effect on exacerbation rate LAMA are first choise –Depending on additional findings (nocturnal and early morning symptoms, comorbidities, …) LABA/LAMA fixed combinations may be used –In alternative to LABA or LAMA, when poorly effective –In more severe patients (MRC >2, FEV1 <50%)