Νεότερεσ θεραπείεσ για το άςθμα Μίνα Γκάγκα ΝΝΘΑ
COI Disclosure Ερευνητήσ ςε μελζτεσ των εταιριών GSK, AZ, Novartis, Cephalon, Schering Plough, BI, Βιανεξ, Elpen. Ομιλητήσ ςε διαλζξεισ για τισ Chiesi, GSK, AZ, Novartis, Cephalon, Schering Plough, BI, Βιανεξ, Merck.
Θεραπεία άςθματοσ Τρζχουςα θεραπευτική προςζγγιςη Νεότερεσ θεραπευτικζσ προςεγγίςεισ Μελλοντικζσ θεραπείεσ βαςιςμζνεσ ςε φαινοτφπουσ
Φαινότυποι Brittle, near-fatal, premenstrual, steroid-dependent/steroid-resistant, severe occupational, AIA Το ςύνολο των κλινικών χαρακτηριςτικών του ϊςθματοσ Αςθενεύσ με ςυνεχό ςυμπτώματα και ςυχνϋσ παροξύνςεισ, αςθενεύσ με μόνιμη ςτϋνωςη αεραγωγών, παχυςαρκύα, πρώιμη/όψιμη ϋναρξη, ατοπύα, ηωςινοφιλύα, ςυννοςηρότητα... (παρϊ την αγωγό με υψηλϋσ δόςεισ φαρμϊκων)
Χξεηαδόκαζηε θαηλνύξγηα θάξκαθα ζην άζζκα; Τα θάξκαθα πνπ έρνπκε έωο ηώξα ζην άζζκα (ICS/BΓ) είλαη απνηειεζκαηηθά ζηνπο πεξηζζόηεξνπο αιιά όρη ζε όινπο ηνπο αζζκαηηθνύο Πξόβιεκα ζπκκόξθωζεο Σνβαξό/δπζάγωγν άζζκα: ζνβαξό πξόβιεκα, ρωξίο ιύζε κε ηα ππάξρνληα θάξκαθα Φαηλόηππνη άζζκαηνο: δηαθνξεηηθά πξόηππα αληαπόθξηζεο ζηε ζεξαπεία
Τρζχουςα θεραπευτική προςζγγιςη Χώροσ για βελτίωςη?
Νεόηεξα εηζπλεόκελα θνξηηθνεηδή κε θαιύηεξε απόδνζε/αζθάιεηα, εύθνιν δνζνινγηθό ζρήκα.
Severe Asthma Response to sytemic corticosteroids Bioair Study, change in FEV 1 Αντοχή? 0,4 Placebo, n=35 Steroid, n=34 Open steroid after placebo, n=35 0,4 Placebo, n=24 Steroid, n=20 Open steroid after placebo, n=24 FEV 1.0 (L) 0,2 0,0 ** * FEV 1.0 (L) 0,2 0,0 ns ns -0,2 double-blind steroid/placebo open steroid -0,2 double-blind steroid/placebo open steroid -0,4 pre 1 post 1 pre 2 post 2-0,4 pre 1 post 1 pre 2 post 2 Severe Asthma COPD
Treating to Achieve Asthma Control Step 5 Reliever medication plus additional controller options Addition of oral glucocorticosteroids to other controller medications may be effective (Evidence D) but is associated with severe side effects (Evidence A) Addition of anti-ige treatment to other controller medications improves control of allergic asthma when control has not been achieved on other medications (Evidence A)
Omalizumab in Severe Asthma Humbert et al Allergy 2008 Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4/5 treatment): INNOVATE Βελτίωςη κλινική, μείωςη παροξφνςεων
Νέα καθξύηεξεο δξάζεο βξνγρνδηαζηαιηηθά Ultra-long acting β 2 -agonists (24ωξεο δξάζεο β 2 -δηεγέξηεο) Indacaterol (Novartis). Carmoterol (Chiesi), GSK159797 Βξνγρνδηαζηαιηηθά κε δξάζε > 24 ωξώλ, γξήγνξε έλαξμε δξάζεο, θαηάιιεια γηα ρνξήγεζε άπαμ εκεξεζίωο Φαίλεηαη λα κπνξνύλ λα απμήζνπλ θαη ηελ δηάξθεηα δξάζεο ηωλ ICS - ζπκκόξθωζε
Ερωτήματα Η θεραπεία των ςυννοςηροτήτων βελτιώνει το άςθμα? Υπάρχουν προγνωςτικοί δείκτεσ για την εμφάνιςη παροξφνςεων? Μακρολίδεσ, ανοςοκαταςταλτικά (ΜΤΧ) ζχουν θζςη? Υπάρχουν προγνωςτικοί δείκτεσ για την ανταπόκριςη ςτη θεραπεία?
Asthma Phenotypes Cluster Analysis-SARP 5 phenotypes-clinical heterogeneity Moore W, AJRCCM 2010
Cluster analysis of clinical asthma phenotypes Haldar et al., Am J Respir Crit Care Med 2008
Lotvall et al, JACI 2011
Lotvall et al, JACI 2011
Severe Asthma 5-10 % of asthmatic patients >50% of asthma costs Severe impact on health Gaga et al, ENFUMOSA Cohort, Clin Exp Allergy 2005 Gaga et al. Severe asthma in adults: an orphan disease? Clin Chest Med. 2012
Έρευνα - νεότερα υάρμακα στο άσθμα
AntiIL-5 (Mepolizumab) and Exacerbations of Refractory Eosinophilic Asthma Reduced exacerbations Improved AQLQ, reduced eos Haldar et al, NEJM 2009
Mepolizumab for Prednisone-Dependent Asthma with Sputum Eosinophilia Nair P, NEJM 2009 Reduced exacerbations, eosinophils and OCS dose
Masitinib in Severe Asthma c-kit & PDGFR tyrosine kinase inhibitor, 3, 4.5 and 6 mg/kg/day, 16 w Humbert et al Allergy 2009 0,0-0,2-0,4-0,6-0,8-1,0 0 4 8 12 16 Time (weeks) Masitinib Placebo No difference in OCS dose. ACQ improved, no difference in FEV 1
Etanercept in Severe Asthma Berry et al. N Engl J Med 2006 Βελτίωςη FEV 1 Βελτίωςη AQLQ
Percent of Subjects 100 80 60 40 20 0 Etanercept in Severe Asthma Wenzel et al, AJRCCM 2009 Number of Severe Exacerbations per Subject from Baseline through Week 24 p = 0.354 p = 0.557 p = 0.731 p = 0.636 (n=78) (n=77) (n=76) (n=78) (n=154) Placebo 50 mg q4 wks 100 mg q4 wks Treatment Group 200 mg q4 wks Combined 100 mg & 200 mg # of severe exacerbations = 0 # of severe exacerbations = 1 # of severe exacerbations = 2 # of severe exacerbations = 3 to 5 # of severe exacerbations = 6 or more
Anti-interleukin 13 (lebrikizumab) therapy in adults with asthma Corren et al NEJM 2011 Periostin Interleukin-13 induces bronchial epithelial cells to secrete periostin, a matricellular protein Th 2 type of airway inflammation Woodruff et al, AJRCCM 2009
Anti-interleukin 13 (lebrikizumab) therapy in adults with asthma Improved FEV 1, compared to placebo, with greatest changes in high levels of periostin or FeNO group (post hoc analyses). No effect on ACQ5 or diary measures. Exacerbations were 60% lower in treated group with high Th2. Corren et al NEJM 2011
Blood Sputum Reduction in blood and sputum neutrophils. Reduction in mild exacerbations. No reduction in ACQ score (p=0.053)
Author Treatment Summary Results Kips et al, 2003 SCH55700, anti-il-5, 12 w Reduced blood sputum eos No other significant outcomes Castro et al 2011 Reslimuzab, anti-il-5, 12 w Improved ACQ score Greater fall in sputum eosinophils. improved FEV1 Corren et al, 2010 AMG317, anti-il-4ra blocks IL-4 and IL-13, 12 weeks No effect on ACQ or exacerbations
Author Treatment Summary Results Busse et al, 2008 Daclizumab, IL- 2Ra chain antibody, 20 weeks Improved FEV 1 Reduction in day-time asthma scores, use of SABA. Prolonged time to severe exacerbations. Reduction in blood eosinophils. Piper et al, 2012 Pavord et al, 2012 Tralokinumab (150/300/600), IL-13 neutralising mab, 3 months Mepolizumab (75, 250 or 750 mg infusions at 4 weeks), anti- IL-5, 52w No change in ACQ-6 at 13 weeks. FEV 1 increase of 0.21L versus 0.06L with placebo (p=0.072) b 2 -agonist use decrease of -0.68 versus - 0.10 with placebo (p=0.020) Better response in those with higher IL-13 levels in sputum All doses reduced exacerbations by 39 to 52%. No effect on ACQ, AQLQ or FEV 1.
Thermoplasty in Severe Asthma Castro et al AJRCCM 2010 Decreased Frequent exacerbations and severity of exacerbations, Decreased rescue medications, effect on airflow obstruction, Improved quality of life No
Number of Events Healthcare Utilization over 5 Years Post BT Pavord, ERS 2012 12 Heathcare Utilization Events 10 8 6 6 4 2 2 3 3 2 4 2 P = 0.08 0 1 1 1 Baseline Year 1 Year 2 Year 3 Year 4 Year 5 ER Visits Hospitalizations Numbers within bars represent Number of subjects
Πξνηάζεηο γηα ζεξαπεπηηθά ζρήκαηα βαζηζκέλα ζην θαηλόηππν ERS/ATS Task Force on severe asthma:
Characteristic Associations Specifically-targeted treatments Severe allergic asthma High eosinophil High IgE High TH2??? Anti-IgE Anti-IL4/IL-13 IL4Receptor Eosinophilic asthma High IgE Recurrent exacerbations Anti-IL5, Anti-IL-4/-13 IL-4R BT? Neutrophilic asthma Corticosteroid insensitivity Bacterial infections Anti-IL-8 CXCR2 antagonists Anti-LTB4 Macrolides
Characteristic Associations Specifically-targetted treatments Chronic airflow obstruction Airway wall remodelling (increased smooth muscle, fibrosis) Anti-IL13 BT? Recurrent exacerbations High eosinophils Reduced response to ICS ± OCS Anti-IL5 Anti-IgE Corticosteroid insensitivity High neutrophils p38 MAPK inhibitors Theophylline PDE4 inhibitors Macrolides
Τν άζζκα πνπ δελ ειέγρεηαη κπνξεί λα έρεη θαηαζηξνθηθέο ζπλέπεηεο
Γελ κπνξνύκε λα πξνθπιάμνπκε ηνπο αξξώζηνπο καο από ην πεξηβάιινλ, κπνξνύκε όκωο λα ρνξεγήζνπκε ζηνρεπκέλα ζεξαπεία Royal Deluxe, Nantes 2009
Πξνηάζεηο γηα ζεξαπεπηηθά ζρήκαηα βαζηζκέλα ζην θαηλόηππν Αλάγθε γηα καθξνρξόληεο θαη ζηνρεπκέλεο ζε θαηλόηππνπο κειέηεο, θπξίωο ζην ζνβαξό άζζκα, ώζηε λα δηαιεπθαλζνύλ νη κεραληζκνί θαη λα εμεηαζζνύλ ζηξαηεγηθέο αληηκεηώπηζεο