Transcript Document 7169704

Upper Airways Research Laboratory
Department of Otorhinolaryngology
Advanced treatments of nasal
polyposis: Anti-IL-5 and Anti-IgE
Which for whom?
Prof. Dr. Philippe Gevaert
Department of Otorhinolaryngology
Ghent University Hospital, Belgium
Advanced medical treatments in
recurrent nasal polyposis
Surgery =
removing
immunological
memory
Eotaxin
IgE
IL-5
ECP
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Advanced medical treatments in
recurrent nasal polyposis
Eotaxin
IgE
Corticosteroids
Anti-IL-5
IL-5
ECP
Antibiotics
Upper Airways Research Laboratory
Department of Otorhinolaryngology
J Allergy Clin Immunol 2005;116:1275-81
N=354
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Nasal corticosteroid DROPS in nasal polyps
double-blind, placebo-controlled study with nasal GCS drops
After 12-weeks:
 nasal blockage,  peak nasal inspiratory flow
 polyp volume (CT score)
 need for sinus surgery
Aukema, Mulder, Fokkens; JACI 2005
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Oral steroids in nasal polyps: a 3-month double
blind, randomized, placebo-controlled trial
DBPC in 32 patient with nasal polyps, 20days methylprednisolon
(Day 1-5 32 mg, day 6-10 16 mg, day 11-20 8 mg)
Participating centers: ENT Dept: University Hospital Ghent, Belgium, University Hospital
St. Rafael Leuven Belgium; University Hospital Erlangen, Germany, Adelaide University
Hospital, Australia, Academic Medical Center, Amsterdam, the Netherlands
Primary endpoint: endoscopic scoring with a five grade system
Secoundary endpoints
symptoms
2
grade 0 1
3
evaluation of local and systemical biological activity and efficacy
measurement of IgE, IL-5 and ECP on nasal secretions (merocell)
measurement of blood eosinophilia
daily measurement of nasal peak inspiratory flow
Upper Airways Research Laboratory
T Van Zele, Gevaert P (in preparation)
Department of Otorhinolaryngology
4
Oral steroids in nasal polyps: a 3-month double
blind, randomized, placebo-controlled trial
DBPC in 32 patient with nasal polyps, 20days methylprednisolon
(Day 1-5 32 mg, day 6-10 16 mg, day 11-20 8 mg)
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Thibaut Van Zele, Philippe Gevaert, Gabriele Holtappels, Achim
Beule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter
Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert
Methylprednisolone has mild local anti-inflammatory effects
Placebogroup: n=18
Methylprednisolone group: n=14
Upper Airways Research Laboratory
Department of Otorhinolaryngology
T Van Zele, Gevaert P (in preparation)
Advanced medical treatments in
recurrent nasal polyposis
Eotaxin
IgE
Anti-IL-5
Corticosteroids
IL-5
ECP
Antibiotics
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Long term antibiotic treatment in NP
•
DBPC study in 90 patients:
•
•
•
3m low-dose erythromycin, nasal douche,
nasal GCS vs. sinus surgery
50% Improvement of symptoms
no difference vs sinus surgery
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Doxycycline reduces MMP9, ECP, MPO and nasal polyp size, in a
double-blind, randomized, placebo controlled, multicenter trial.
20 days doxycycline (100mg/d) reduces PND
*
Post Nasal drip
1.0
Congestion
Chnage in Congestion
1.0
Change in Post Nasal Drip
*
0.5
0.5
0.0
0.0
-0.5
p=0.8
-p=0.7
-0.5
Placebo
doxy
-1.0
0
7 14 21 28 35 42 49 56 63 70 77 84
Days
p=0.2
p=0,04
p=0.1
Placebo
doxy
-1.0
0
7
14 21 28 35 42 49 56 63 70 77 84
Days
Philippe Gevaert, Thibaut Van Zele, Gabriele Holtappels, Achim
Upper Airways Research Laboratory
Beule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter
Department of Otorhinolaryngology
Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert
Oral doxycycline reduces
neutrophilic and eosinophilic inflammation
MPO (ng/ml)
10.000
750
0
-5.000
p=0.005
p=0.2
-10.000
p=0.06
p=0.04
-15.000
ECP (µg/l) in nasal secretion
MPO (ng/ml) in nasal
5.000
500
250
0
-250
p=0.8
p=0.033
p=0.035
-500
-750
p=0.004
p=0.18
p=0.009
-1.000
-20.000
0
7
14
21
28
35
42
49
Placebo
56
63
70
77
84
Axis Title
doxy
0
7
14
21
28
35
42
49
56
Placebo
63
70
77
84
Days
doxy
MMP-9
2.000
MMP-9 (pg/ml) in nasal secretions (
ECP (µg/l)
1.000
0
-2.000
p=0.4
-4.000
-6.000
p=0,02
p=0,02
-8.000
0
7
Placebo group: n=18
Methylprednisolone group: n=14
p=0,08
p=0.007
14
21
28
35
42
Placebo
49
56
63
70
77
84
Days
doxy
Upper Airways Research Laboratory
Gevaert P, Van Zele T (in preparation)
Department of Otorhinolaryngology
Doxycycline
First double blind placebo controlled trial with antibiotics in nasal
polyps that shows:
a significant effect of doxycycline on nasal polyp size
Doxycycline reduces local inflammation in terms of ECP and MPO
effect on eosinophilic inflammation
effect on neutrophilic (may be related to the effect on S. aureus)
Doxycycline has a sigificant effect on remodeling (MMP-9)
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Gevaert P, Van Zele T (in preparation)
Practical management of Nasal Polyposis
•
•
Nasal douche with saline
Nasal corticosteroids
• GCS sprays: 2x/d, symptoms↓, no resolution of NP
• GCS drops:
symptoms↓, surgery↓↓
•
Oral corticoids: effective but fast recurrence
• Antibiotics:
• Antibiotic ointment
• Long-term antibiotics: macrolides 500mg/d ged 3m
doxycycline 100 mg/d ged 1m
Combinations?
•
Endoscopic sinus surgery: only chance for cure!!
in NP: recurrences
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Treatment of nasal polyposis following EP³OS
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Advanced medical treatments in
recurrent nasal polyposis
Eotaxin
IgE
Corticosteroids
Anti-IL-5
IL-5
ECP
Antibiotics
Upper Airways Research Laboratory
Department of Otorhinolaryngology
IL-5 and eosinophils in nasal polyposis
Migration
Homing
IL5 + Eotaxin



 IL-5
  IL-5
 IL-5
Maturation
Differentiation
Recruitement
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Survival
Activation
 ECP
Anti-interleukin 5 in nasal polyposis
Migration
Homing
IL5 + Eotaxin

x

 IL-5
x
 IL-5
Maturation
Differentiation
Recruitement
Upper Airways Research Laboratory
Department of Otorhinolaryngology

x
  IL-5
Survival
Activation
 ECP
Objective and study design
To asses the therapeutic potential of
two injections of 750 mg IV mepolizumab (28days)
• endoscopic score
• symptom scores
• CT scan
Two-arm, randomized, double blind, placebo controlled, trial
20 Subjects
MEPO 750mg IV
Placebo
30 Subjects
Severe nasal polyps
10 Subjects
endpoint
* Primary
Dosing
Follow up
Weeks
Upper Airways Research Laboratory
Department of Otorhinolaryngology
0 1 4 8 12 24 36 48
*
Endpoints
Primary endpoint
• Endoscopic Nasal polyp score 8
weeks post 1st dosing
Secondary endpoints
• CT scan assessment (blinded)
0
1
2
3
Difference <10% or 10-30% or 3050% or >50%
•
•
•
4
Symptom score
Peak nasal inspiratory flow
nasal (merocel) and systemic
Inflammatory mediators
Score
0
Upper Airways Research Laboratory
Department of Otorhinolaryngology
1
2
3
4
Endoscopic Nasal polyp score
and improvement
13/20
12/20
10/20
intranasal steroids permitted
*
*
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Need for surgery - Number of exclusions
(= sytemic steroids or AB or surgery)
p=0.03
*
*
Upper Airways Research Laboratory
Department of Otorhinolaryngology
CT scores improvement from
baseline at week 8
Upper Airways Research Laboratory
Department of Otorhinolaryngology
CT SCAN
Baseline
Upper Airways Research Laboratory
Department of Otorhinolaryngology
8 weeks post 1st Mepo dose
Symptoms
intranasal steroids permitted
intranasal steroids permitted
Upper Airways Research Laboratory
Department of Otorhinolaryngology
intranasal steroids permitted
intranasal steroids permitted
Peak nasal inspiratory flow
(change from baseline)
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Anti IgE in nasal polyposis
24 patients:
16 got anti-IgE
8 got placebo
4 (evt 8) Injections over 3 months
? Local Anti-IgE
x
Concentration?
 IgE
x
 IgE
Improvement in total nasal polyp score
Omalizumab (n=15) versus placebo (n=8)
1
80
0.5
70
0
60
-0.5
50
-1
-1.5
placebo
40
omalizumab
30
-2
20
-2.5
10
-3
placebo
omalizumab
0
BL W2 W4 W6 W8 W10W12W14W16W18
W2
W4
W6
W8 W10 W12 W14 W16 W18
Improvement in symptoms
Omalizumab (n=15) versus placebo (n=8)
UPSIT smell test
CT-scans before and after Anti-IgE
Upper Airways Research Laboratory
Department of Otorhinolaryngology
CT-scans before and after Anti-IgE
Upper Airways Research Laboratory
Department of Otorhinolaryngology
CT-scans before and after Anti-IgE
mean percentage improvement
30
25
20
15
placebo
omalizumab
10
5
0
- 5
better obsA
-10
Upper Airways Research Laboratory
Department of Otorhinolaryngology
better obsB
Allergic versus non allergic patients
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Future therapeutic options in nasal polyposis
Anti-IgE
Eotaxin
First DBPC
finished in
24 NP patients
In Ghent
IgE
Anti-IL-5
IL-5
Corticosteroids
ECP
Antibiotics
Vaccination
New multicenter
trial started with
120 NP patients
Practical management of Nasal Polyposis
•
•
•
•
•
Nasal douche with saline
Nasal corticosteroids
• GCS sprays: 2x/d, symptoms↓, no resolution of NP
• GCS drops:
symptoms↓, surgery↓↓
Oral corticoids: effective but fast recurrence
Antibiotics:
• Antibiotic ointment
• Long-term antibiotics: macrolides 500mg/d ged 3m
doxycycline 100 mg/d ged 1m
Future:
• Omalizumab (antiIgE) allergic 85% vs non allergic NP 55%
• Mepolizumab (anti-IL5): 2 injections in 65% better
Upper Airways Research Laboratory
Department of Otorhinolaryngology
Upper Airways Research Laboratory 2009
Upper Airways Research Laboratory
Department of Otorhinolaryngology