Post on 22-Feb-2016
description
transcript
Grazie per aver scelto di utilizzare a scopo didattico questo materiale
delle Guidelines 2011 libra.Le ricordiamo che questo materiale è
di proprietà dell’autore e fornito come supporto didattico per uso
personale.
Targeted Therapies in Difficult-to-Control Asthma
Paul M O’ByrneEJ Moran Campbell Professor of MedicineFirestone Institute for Respiratory Health,
St. Joseph’s Healthcare and McMaster University, Hamilton, Ontario, Canada
Phenotyping
Empiric Treatment
GINA Guidelines 2011
Age 39.3 (12-73) 39.0 (12-74)Duration of asthma (years) 20.6 (1-61) 22.7 (2-60)BDP dose (mean [(μg/day) 570 (420-1008) 568 (336-840)Serum total IgE (IU/mL) 172.5 (20-860) 186.3 (21-702)FEV1 % predicted 64.6 (12.5) 64.1 (11.6)FEV1 reversibility (%) 26.9 25.9Puffs of rescue medication per day during run-in 4.9 (2.65) 4.8 (2.51)
Total asthma symptom score during run-in 4.31 (1.17) 4.24 (1.17)
Omalizumab and Difficult-to-Control Asthma
Omalizumab and Difficult-to-Control Asthma
Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90
Omalizumab and Difficult-to-Control Asthma
Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90
7
Bronchial Thermoplasty• Catheter has an expandable wire
array at the tip Radiofrequency energy that is
converted to heat in the airway wall
Monopolar radiofrequency (RF) energy Temperature controlled: 65 °C 10 seconds Signal for successful activation
Multiple safety algorithms to ensure controlled energy delivery
Miller J D et al. Chest 2005;127:1999-2006
Bronchial Thermoplasty
Bronchial Thermoplasty
Cox PG, et al. Am J Respir crit Care Med 2006; 173:965-9
Bronchial Thermoplasty
BRONCHIAL THERMOPLASTY CONTROLS
Age 39.4 41.7BDP dose (mean [(μg/day) 1351+963 1264+916Seasonal Allergies 62% 65%FEV1 % predicted 72.6+10.4 76.1+9.6Asthma SeverityModerate Persistent 38% 47%
Asthma SeveritySevere Persistent 62% 53%
Phenotyping
Empiric Treatment
GINA Guidelines 2011
Induced Sputum
O’Byrne PM, Nair P. Lancet 2006; 368:794-308
0
20
40
60
80
100
120
BTSmanagement group
Sputummanagement group
SevereExacerbations
(number)
2 4 6 8 10 120
GREEN R, et al . LANCET 2002; 360: 1715-21
Time (months)
Num
ber/e
xace
rbat
ions
/yea
r(m
edia
n)
Clinical StrategySputum Strategy
Very Mild - Mild
Moderate - Severe
All subjects
0
1.5
1.0
0.5
0.77
0.46
1.0
0.50
p=0.01
p=0.03
Pizzichini MMM et al. ERS meeting 2003
LOMA study
Jayaram L, et al. Eur Respir J 2006; 27:483-94
Effect of SCH55700, a Humanized Anti-Human Interleukin-5 Antibody, in Severe Persistent Asthma
Blood Eosinophils FEV1
Kips J, et al. Am J Respir Crit Care Med 2003; 167:1655-9
26 severe asthmatics. FEV1 49-61% predicted.
All on high dose ICS or oral corticosteroids.
Mepolizumab in asthma
• Subjects: – moderate/severe asthma– inhaled corticosteroids up to 1000 mcg/day– symptoms mean 5 on 12 point scale– FEV1 68% predicted
• Treatment:– SB 240563 250 mg or 750 mg or placebo
Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71
Mepolizumab in asthma
AsthmaExacerbations
(% patients)
Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71
p=0.06
Subject characteristics
101059.359.3
nnAge, y (gender, M)Age, y (gender, M)
FEVFEV11 % predicted % predictedYears of symptomsYears of symptoms
ΔΔ FEV FEV11, exacerbation %, exacerbation %
9957.957.9
MepolizumabMepolizumab PlaceboPlacebo
9.29.211.811.8(7M)(7M)(4M)(4M)
68.268.265.565.545.045.043.743.7
ΔΔ FEV FEV11, SABA % , SABA % 27.427.417.117.1
LABA, nLABA, n
10101010Prednisone, mg (years )Prednisone, mg (years ) (8.0)(8.0)(9.7)(9.7)1000100010001000ICS, ICS, gg
9988 NAIR P, et al. N Engl J Med 2009; 360:985-93
Sputum and Blood Eosinophils
NAIR P, et al. N Engl J Med 2009; 360:985-93
0
20
40
60
80
100
mepolizumab placebo
prednisone reduction as % of maximum possible
reduction
n=9 n=10
Prednisone Reduction
p<0.05
NAIR P, et al. N Engl J Med 2009; 360:985-93 .
Asthma Exacerbations
NAIR P, et al. N Engl J Med 2009; 360:985-93.
Mepolizumab and Difficult-to-Control Asthma
MEPOLIZUMAB PLACEBOAge 48 50
BDP dose (mean [(μg/day) 2038 1711
Oral Prednisone 57% 53%
Seasonal Allergies 67.9% 68.8%
Post-BD FEV1 % predicted 78.1+20.9 77.6+24.1
Sputum eosinophils 6.84% 5.46%
ACQ score 1.98+1.07 2.38+1.35
Mepolizumab in Difficult-to-Control Asthma
Haldar P et al. N Engl J Med 2009; 360:973-984
New Drugs for Asthma• Modifications of existing drugs:
– Untra-longacting inhaled β2-agonists– Modified inhaled corticosteroids– Glucocorticosteroid receptor agonists– New ICS/LABA combinations
• New approaches– Anti-sense against IL-3, IL-3, GM-CSF and CCR– Anti-sense IL-4R– Anti-IL-9 – Anti-IL-13– Anti-C5a– Anti-Ox 40L– CXCR2 antagonist– CRTH2 antagonists
Transcription
Nucleus
DNA(GENE)
RNA
1. Antisense(ssDNA)
RNAseH
2. siRNA(dsRNA)
RISC
Promoter
4. Decoy(dsDNA)
Transcription factor
5. Aptamer(DNA or RNA)
Translation
3. ISS/ CpG motif(ssDNA)
TLR9
Immuno-stimulation
mRNAdegradation
PROTEIN
“Blocks”receptorfunction!
Competition for TF“Blocks” transcription!
Oligonucleotide Therapeutic Approaches
RNAseH
Paolo Renzi MD.
Rationale:
• By down-regulating the expression of the eotaxin receptor (CCR3) and the common beta chain for IL-3, IL-5, and GM-CSF, – an inhaled anti-sense, ASM8 will inhibit the
migration and survival of eosinophils, basophils, mast cells.
– and thereby inhibit allergen-induced airway responses.
Effect of ASM8 on βc and CCR-3 mRNA in sputum cells
% c
hang
e fr
om p
re-a
llerg
en le
vels
% c
hang
e fr
om p
re-a
llerg
en le
vels
Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.
SPUTUM TOTAL CELLS COUNTPRE-DOSE (DAY 1) & 7 HRS POST-ALLERGEN (DAY 3)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0 PLACEBO
ASM8
PRE POST PRE POST
TOTA
L C
ELL
S C
OU
NT
(X10
6 CE
LLS
)(M
ean
+/-
SE
M)
SPUTUM EOSINOPHILS CELL COUNTPRE-DOSE (DAY 1) & 7 HRS POST-ALLERGEN (DAY 3)
0.00
0.25
0.50
0.75
1.00
1.25
1.50 PLACEBO
ASM8
PRE POST PRE POST
* * p= 0.0059 (Placebo vs ASM8)
**
EO
SIN
OPH
ILS
CE
LL C
OU
NT
(X10
6 CE
LLS
)(M
ean
+/-
SE
M)
Sputum Cell CountsPre-dose vs Post Allergen
Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.
Allergen-Induced Sputum Eosinophilia
pre 7h 24h0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
Baseline
8 mg OD
1 mg BID2 mg BID4 mg BID
Time Post Allergen Challenge
Sput
um E
osin
ophi
ls (X
106 c
ells
)
screen 1 mg BID 2 mg BID 4 mg BID 8 mg OD0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
Dose Level
Sput
um E
osin
ophi
ls (X
106 )
7 h
post
alle
rgen
screen 1 mg BID 2 mg BID 4 mg BID 8 mg OD0.0
0.2
0.4
0.6
0.8
1.0
1.2
Dose Level
Sput
um E
osin
ophi
ls (X
106 )
24 h
pos
t alle
rgen
p=0.005
p=0.043
Allergen-induced Fall in FEV1
0 1 2 3 4 5 6 7
-5
0
5
10
15
20
25
30
35
40
Baseline 4 mg BID 8 mg OD1 mg BID 2 mg BID
Time (h)
Fall
in F
EV1 (
%)
Summary
• Phenotyping is important to identify the best choice of treatment in difficult-to-control asthma.
• Bronchial thermoplasty is the only novel treatment recently approved for severe asthma.
• Anti-IL-5 mAbs appear very promising for asthma with a persisting airway eosinophilia
• Many other therapeutic approaches are being studied for the management of difficult-to-control asthma.