Terapia della Bronco Pneumopatia Cronica Ostruttiva e dell Asma Bronchiale: quali novità?

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1 Università della Campania - L.Vanvitelli Dip. Scienze Cardio-Toraciche e Respiratorie AORN Monaldi - Napoli Terapia della Bronco Pneumopatia Cronica Ostruttiva e dell Asma Bronchiale: quali novità? Andrea BIANCO

2 Asma & BPCO Malattie Respiratorie Croniche Ostruttive Caratteristiche Fisio-patologiche differenti Caratteristiche Sintomatologiche differenti Approccio Terapeutico diversificato

3 Global Initiative for Asthma

4 Global Initiative for Asthma

5 Asma Bronchiale & BPCO Terapia Inalatoria Cardine del Trattamento Dove si localizza la malattia? Dove veicolare la terapia? Come veicolare il farmaco?

6 Asma Bronchiale & BPCO n Sede di Malattia n Caratterizzazione pato-fisiologica n Localizzazione Recettoriale u Beta-2 agonisti u Muscarinici u Steroidei

7 Different distribution of muscarinic and β 2 -adrenergic receptors along the bronchial tree Muscarinic receptors are more abundant in central airways β 2 -adrenergic receptors are more abundant in peripheral airways

8 Dove sono localizzati i recettori steroidei? Generazione " Alveoli " Endotelio vascolare " Muscolatura liscia vascolare " Epitelio delle vie aeree " Cellule infiammatorie Adcock I.M. et al; Am J Respir Crit Care Med 1996

9 Beta-2 receptors are located: Generation Bronchial smooth muscles Epithelium cells Vasculair endothelium and smooth muscles Presynaptic nerve endings Inflammatory cells (eos, lymphocyts, mastcells, macroph) Barnes P J et al. Nature 1982:299;

10 Definizione di asma L asma è una malattia eterogenea, caratterizzata normalmente da un infiammazione cronica delle vie aeree. Viene definita dalla storia dei sintomi respiratori come sibili, dispnea (respiro corto), costrizione toracica e tosse che variano nel tempo e nell intensità associati ad una limitazione al flusso aereo. GINA 2015 Global Initiative for Asthma

11 Symptoms ASTHMA

12 ASTHMA INFLAMMATION BRONCHOCONSTRICTION AIRWAY REMODELLING

13 Major goal of asthma management ASTHMA TREATMENT ACHIEVING AND MAINTAINING OPTIMAL ASTHMA CONTROL FUTURE RISK MANAGEMENT SYMPTOMS LIMITATION of PHYSICAL ACTIVITY NOCTURNAL SYMPTOMS RESCUE MEDICATION EXACERBATIONS ADVERSE EVENTS LUNG FUNCTION DECLINE

14 Ciclo di gestione dell asma basato sul controllo Diagnosi Controllo dei sintomi e fattori di rischio (incluso la funzionalità respiratoria) Tecnica inalatoria e aderenza terapeutica Preferenze del paziente Sintomi Riacutizzazioni Effetti collaterali Soddisfazione del paziente Funzionalità respiratoria Farmaci per asma Strategie non farmacologiche Trattamento dei fattori di rischio modificabili GINA 2015, Box 3-2 Global Initiative for Asthma

15 Step 1 as-needed inhaled short-acting beta 2 -agonist (SABA) STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS GINA 2016, Box 3-5, Step 1 (4/8) *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations Global Initiative for Asthma

16 Step 2 low-dose controller + as-needed inhaled SABA STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 2 (5/8) Global Initiative for Asthma

17 Step 3 one or two controllers + asneeded inhaled reliever STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 3 (6/8) Global Initiative for Asthma Global Initiative for Asthma

18 Step 4 two or more controllers + as-needed inhaled reliever STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 4 (7/8) Global Initiative for Asthma Global Initiative for Asthma

19 Residual Disease burden in optimally treated asthma Anderson GP. Lancet 372: , 2008

20 Studio prospettico nella vita reale sul controllo dell asma in Italia: Risultati della fase trasversale Allegra L et al, Respir Med , ,8 % Non controllato 15,9 % Controllo Parziale 64,2% Controllato

21 Uncontrolled and Severe Asthma Poor Inhaler Technique (up to 80% of Community patients) Poor medication adherence Comorbidities and complicating conditions (e.g. Rhinosinusitis, gastroesophageal reflux obesity, obstructive sleep apnea, chronic Airway infections includin intracellular pathogens) Incorrect Diagnosis of Asthma with Symptoms due to alternative conditions (e.g. upper airway disfunction cardiac failure, other Ongoiing exposure to irritant or sensitizing agents

22 Step 5 higher level care and/or add-on treatment STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Add tiotropium* Low dose ICS+LTRA High dose ICS (or + theoph*) + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 5 (8/8) Global Initiative for Asthma

23 X X

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25 BPCO Targets Terapeutici Limitazione Persistente del Flusso Aereo Iperinflazione Polmonare Infiammazione

26 Terapia Broncodilatatrice e Desuflazione Polmonare BPCO DESUFLAZIONE Flusso aereo BRONCODILATATORE Aumento del flusso FEV 1 Aumento dei volumi FVC e CI Aumento della tolleranza all esercizio Mahler et al, ERS 2009

27 Aclidinio vs Tiotropio 27 Broncodilatazione sostenuta per 24 ore al Giorno 1: LAS 23 Aclidinio 400 µg b.i.d. Tiotropio 18 µg QD Placebo Variazione del VEMS dal basale [L] A. Giorno 1 0,5 0,4 0,3 0,2 0,1 0,0-0,1 Somministrazione serale serale Aclidinio 400 μg b.i.d. Tiotropio 18 μg q.d. Placebo Tempo dopo la prima dose (ore) Studio randomizzato, in doppio cieco, a doppia simulazione, crossover a tre periodi, controllato con placebo e farmaco attivo su pazienti (n=30) con BPCO da moderata a grave. I pazienti sono stati randomizzati (1:1:1) al trattamento con Aclidinio Bromuro 400 µg BID, Tiotropio 18 µg QD o placebo. Endpoint primario è stato la variazione rispetto al basale nel VEMS 1 AUC 0-12/12 al giorno 15 di trattamento Fuhr R, et al, Chest 2012;141:

28 Doppia Broncodilatazione LAMA + LABA LAMA Long-acting anticholinergics LABA Long-acting beta 2 -agonists

29 Shine study: Trough FEV1 at week 26 Glycopyrronium/Indacaterol vs. placebo and Tiotropium Bateman ED, et al. Eur Respir J. 2013;42:

30 Mean change from baseline in trough FEV 1 at Day ml * LS mean change from baseline in trough FEV 1 (ml) Umeclidinium/Vilanterol 62.5/25 µg (n=413) Umeclidinium 62.5 µg (n=418) Vilanterol 25 µg (n=421) Placebo (n=280) *p<0.001 vs. placebo; p<0.01 vs. Umeclidinium; p<0.001 vs. Vilanterol UMEC/VI: Umeclidinium/Vilanterol 1. Donohue et al. Resp Med Donohue. Supplement Materials 2013

31 Phase III pivotal studies design - TONADO Tio-Olo Statistically significant improvements in trough FEV 1 were observed on all test days compared with mono-components Trough FEV 1 response (ml) p<0.001 for all comparisons of TIO/OLO (2.5/5µg and 5/5µg) vs TIO (2.5µg and 5µg) and OLO 5µg on all test days X X X X X X X Test day X X TIO/OLO 5/5µg TIO/OLO 2.5/5µg TIO 5µg TIO 2.5µg OLO 5µg Buhl R. Eur Respir J 2015;45: FEV 1 : forced expiratory volume in one second; TIO: tiotropium; OLO: olodaterol.

32 Augment Combinazione aclidinio/formoterolo Variazione vs basale del FEV1 1 ora post-dose alla settimana 24 *p<0,05 vs placebo; p<0,05 vs aclidinio, formoterolo e placebo 32 Ada@ata da D Urzo et al. Respir Res 2014;15:123

33 Pooled ACLIFORM/AUGMENT:Aclidinium / formoterol impact on daily symptoms over 24 weeks 0,0 Breathlessness Cough & sputum Chest Total score LS mean change from baseline in symptom score -0,5-1,0-1,5-2,0-2,5-3,0 * * **** **** **** Placebo Formoterol 12 µg Aclidinium 400 µg AB/FF 400/12 µg n=525 n=716 n=722 n=720 * * **** * * AB/FF 400/12 µg improves daily symptoms of COPD (assessed by E-RS total score) compared with placebo, aclidinium and formoterol (all p<0.05) ****p<0.001 vs placebo, p<0.01 vs formoterol; p<0.05, p vs aclidinium Bateman E et al. Respir Res 2015;16:92

34 Pooled ACLIFORM/AUGMENT: Aclidinium / formoterol impact on nighttime symptom severity over 24 weeks LS mean change from baseline in symptom severity scores 0,00-0,05-0,10-0,15-0,20-0,25-0, (-12.7%) Overall symptom (-18.2%) (-14.5%) (-21.6%) Placebo Formoterol 12 µg Aclidinium 400 µg FDC 400/12 µg n=525 n=716 n=722 n=720 ***p<0.001 vs placebo, p<0.05 vs formoterol, p<0.001 vs aclidinium The score is out of 5 points scale (0-4) * *** FDC 400/12 µg improves overall night time symptoms of COPD, compared with placebo, aclidinium and formoterol (all p<0.05) Bateman E et al. Respir Res 2015;16:92 Singh D. et al. ERS 2014

35 ASMA BPCO Conclusions Malattie Croniche delle Vie Aeree Meccanismi Patogenetici Differenti Caratteristiche Fisio-patologiche Differenti Espressione Clinica Differente Terapia Inalatoria: cardine del trattamento Farmacologico

36 Asma /BPCO Terapia Inalatoria: Quali Criticità? Dove si localizza la malattia? Dove veicolare la terapia? Come veicolare il farmaco?