Document

Report
New Approaches to Allergen
Immunotherapy
Harold S. Nelson. MD
Professor of Medicine
National Jewish Heath
University of Colorado School of Medicine
Denver, Colorado, USA
Increased Safety with
Currently Available Extracts
 Delayed absorption:
Aluminum √
Tyrosine adsorption √
Encapsulation (liposomes)
 Reduce levels of IgE
Omalizumab √
 Alternative routes
Nasal
Oral √
Sublingual √
Intralymphatic √
Epicutaneous √
√ Active study or current use
SLIT: What Are the Answered &
Unanswered Questions?
 Answered:
- Efficacy with monotherapy (Yes)
- Optimal duration (3-4 years)
- Prevention of new sensitization and
progression to asthma. (Yes)
- Persistent benefit after stopping (Yes)
- Relative safety in subjects with allergic rhinitis
and controlled asthma. (Yes)
 Unanswered:
- Optimal dosing for allergens other than grass
- Relative efficacy versus subcutaneous
immunotherapy
- Use of mixes of multiple unrelated allergens
- Safety in poorly controlled asthma
SLIT: Efficacy of Grass Tablets
 628 adult subjects with grass SAR.
 Treated with placebo or 100 IR, 300 IR, or
500 IR 5-grass tablets beginning 4 months
before season.
 The two highest doses significantly reduced
symptoms 27% and 24%, the low dose was
ineffective.
Didier JACI 2008
Dose-Response to Grass Pollen
Extract SLIT
N= 628 patients
Placebo
100 IR
300 IR
500 IR
100 IR ~ 8mcg Gp p 5, 300IR ~ 25mcg Gp p 5
Didier et al. JACI 2007;120:
Long-lasting Effects of sublingual
Imunotherapy According to its Duration:
A 15-year Prospective Study
M Marogna, et al. J Allergy Clin Immunol 2010;126:969-75
 78 patients were treated with house dust mite
extract by SLIT at about 30X SCIT dose.
 Initial treatment was for 3, 4 or 5 years.
 When group symptom scores rose above
50% of baseline they were retreated.
 Total duration of observation was 15 years.
A 15-year Prospective Study
 After stopping treatment relapse and
retreatment occurred in 7 years in the 3-year
group and 8 years in the 4-year and 5-year
groups.
 The second course of SLIT produced more
rapid improvement than the first in all three
groups.
 Methacholine sensitivity and nasal
eosinophils paralleled the clinical course.
M Marogna, et al. J Allergy Clin Immunol 2010;126:969-75
Symptom/Medication Scores
400
200
100
**
*
*
** ** *
*
** ** * *
** * ** ***
*
*
2002
2000
1998
SLIT
1996
1994
1992
SLIT
2006
** **
*
2004
*
300
A 3-years
B 4-years
C 5-years
JACI
2010
Monthly Drug Intake Score
SLIT3
SLIT5
SLIT4
CONTROLS
60
*
*
*
40
*
*
*
* *
2004
2002
2000
1998
1996
1994
JACI
2010
126:
96975
1992
20
2006
Drug Intake Score
80
Methacholine PD20
SLIT3
SLIT5
SLIT4
CONTROLS
Methacholine PD20
1000
*
*
*
*
*
600
*
*
*
*
*
*
NS
NS
NS
NS
2006
2004
2002
2000
1998
1996
1994
JACI
2010
126:
969-75
1992
200
Percent of Patients with New Prick
Skin Test Reactions
SLIT3
SLIT5
SLIT4
CONTROLS
%
80
60
40
* Significant from
2006
2004
2002
2000
1996
1994
JACI
2010
126:
969-75
1992
20
1998
this point onward
A 15-year Prospective Study
 SLIT administered for 3 years resulted in
remission persisting for 7 years following
discontinuation.
 SLIT administered for 4 or 5 years resulted in
remission persisting for 8 years after
discontinuation.
 Reinstitution of SLIT following relapse
resulted in accelerated improvement
compared to original response.
M Marogna, et al. J Allergy Clin Immunol 2010;126:969-75
Adverse Reactions to Grass SLIT
Summary of 7 Phase III Studies
Adults
(n=2096)
Children
(n=598)
AIT
Placebo
AIT
Placebo
Oral Pruritus
39%
5%
35%
3%
Throat
Irritation
21%
3%
25%
2%
Ear Pruritus
14%
1%
8%
<1%
Mouth Edema
11%
<1%
8%
<1%
Oral
Paresthesias
8%
1%
Any Drugrelated
70%
23%
62%
27%
Abstract EAACI June 2011
Onset and Duration of Adverse
Reactions to Grass SLIT (Median
Days)
Adults
Children
Onset
Duration
Onset
Duration
Oral Pruritus
1
8
1
5
Throat
Irritation
1
6
1
4
Ear Pruritus
1
3.5
1
6
Oral
Paresthesias
1
10
Mouth Edema
5
29.5
7.5
16.5
Abstract EAACI June 2011
Anaphylactic Reactions to SLIT
Allergen
BU
or Mnt
Symptoms
Multiple
BU
Latex
BU
Multiple
Mnt
HDM
Mnt3 yrs
6X dose
1st dose
Pruritus, AE,
Allergy
wheezing, dizziness
2006;61:1235
Urt, asthma,
Allergy
“anaphylactic shock”
2006;61:236
AE, chest pain,
Allergy
nausea, abd pain
2007;62:567
Urt, wheezing
Allergy
hypotension, syncope
2008;63:374
Includes hypotension
History of intolerance for SCIT Allergy
2009;64:963-4
Grass (2)
Reference
Clinical Efficacy of Sublingual and Subcutaneous
Birch Pollen Allergen-Specific Immunotherapy: A
Randomized, Placebo-Controlled,Double-Blind,
Double-Dummy Study
MS Khinchi, et al. Allergy 2004;59:45-53
 Subcutaneous maintenance dose contained 3.28
g Bet v 1 once monthly.
 Sublingual maintenance dose contained 49.2 g
Bet v 1 every other day (225 time SC dose).
 5 cases of grade 3 or 4 systemic reactions in the
s.c. group, two treated with adrenalin. No grade 3
or 4 reactions with SLIC
SLIT versus SCIT
Treatment Symptoms Medication*
Placebo
SLIT
SCIT
+ .02
- .36
- .75
+ 1.35
+ .29
No change
SLIT & SCIT significantly better than placebo, no
difference between active treatments.
* Pollen counts higher second year
3
Pollen Count
2000
2
1600
1200
1
800
400
0
1st
Mean daily symptom score
SCIT
SLIT
Placebo
2400
0
1
2
treatment season
3
4
5
6
Week number
7
8
9
Allergy 2004;59:45
10
2400
Pollen Count
2000
8
1600
6
1200
4
800
2
400
0
0
1st
Mean daily medication score
SCIT
SLIT
Placebo
1
2
treatment season
3
4
5
6
Week number
7
8
9
Allergy 2004;59:45
Comparison of Subcutaneous &
Sublingual Immunotherapy
SCIT Has
SLIT Has
Identified effective doses
Greater efficacy
Greater safety and
convenience
Studies with multiple allergen
mixes
But
But
Inconvenient
Optimum dose not defined
except for grass
More systemic reactions
Less effective (first year)
Multiple allergen mixes may
be ineffective.
Grass Transcutaneous
Immunotherapy in Children with
Seasonal Rhnoconjunctivitis
F Agostinis, et al. Allergy 2010;66:410-1
 15 children received grass transcutaneous
immunotherapy and 15 placebo patches from
February to April.
 Patches (grass pollen extract containing 11.25
mcg major allergen, 50% petrolleum jelly and
<3% salicylic acid) were applied weekly for 12
weeks and removed after 24 hours.
Grass Transcutaneous
Immunotherapy in Children with
Seasonal Rhnoconjunctivitis
 There were no local or systemic reactions to
the patches.
 Symptoms during the grass pollen season
favored active treatment for:
- Rhinitis (p = .009)
- Nasal obstruction (p = .003)
- Dyspnea (p = .03)
- Ocular tearing (p < .05)
- Antihistamine use (p < .02)
F Agostinis et al. Allergy 2010;66:410-1
Grass Transcutaneous Immunotherapy
Grass pollen count
1.8
180
1.6
160
1.4
Symptoms
140
1.2
120
1.0
100
0.8
80
0.6
60
0.4
40
0.2
20
0
0
April 28-May 4
May 5-11
May 12-16
May 19-25
180
0.70
0.50
Antihistamines
160
140
120
0.40
100
80
0.30
60
0.20
40
0.10
20
0.00
April 21-27
April 28-May 4
May 5-11
May 12-16
May 19-25
0
Pollen counts (m3)
Mean antihistamine intake per week
April 21-27
0.60
Pollen counts (m3)
Green: Grass
pollen count
Pink: Peak
grass pollen
season.
Red: placebo
Yellow:
active
treatment
Total symptom score
o
Active
Placebo
Agostinis et al
Allergy 2009;
60:L410-1
Epicutaneous Allergen Administration
As a Novel Method of Allergen-Specific
Immunotherapy
G Senti, et al. J Allergy Clin Immunol 2009;124:997-1002
 A double-blind study was conducted in 37 grasssensitive adults in Zurich, Switzerland.
 Prior to and during the 2006 grass pollen season
subjects had 13 weekly patches applied to tapestripped sites (2 in clinic and 11 by patient).
 Patches remained on the skin 48 hours.
 Clinical response was assessed for the grass pollen
seasons of both 2006 and 2007 (without further
treatment)
Symptoms Compared to 2005
2006
2007
G Santi
JACI
2009:124
997-1002
 Outliers
-10
P=
0.005
-5

*
P = 0.02
Act

Pla


0
5
Hay fever Improvement
Act
Pla
10
Intralymphatic Allergen Administration
Renders Specific Immunotherapy Faster
and Safer: A Randomized Controlled Trial
G Senti et al. Proc Nat Acad Sci 2008;105:17908-12
 Randomized, open label comparison of 3 years of
subcutaneous injections (cumulative dose 4 X 106 SQ
-U) or 3 intralymphatic injections at 4-week intervals
(cumulative dose 3,000 SQ-U)
 Nasal tolerance was faster with IL injections (4
months versus 1 year) and persisted at 3 years.
 Reactions were fewer with IL injections.
 Other outcomes at three years were similar for the 2
approaches.
Intralymphatic vs. Subcutaneous
Allergen (SQ-U)
Cum. dose = 4’031’540 SQ-U
100,000
10,000
1,000
10
0
10
1
0
8
16
24
32
40
140
148 156
Allergen (SQ-U)
100,000
Cum. dose = 3’000 SQ-U
10,000
1,000
10
0
10
1
0
8
16
24
Pollen
season
baseline
40
140
Sept
Oct
Jan
Feb
148 156
Pollen
season
2+3
Pollen
season
1
baseline 4 months
Evaluation
visits
32
1 year
3 years
Sept
Oct
Sept
Oct
G Senti
PNAS
2008:105:
17908-17
Max. tolerated
allergen conc. (log10)
Nasal Challenge: IL versus SC
6.0
5.5
5.0
IL
G Senti
PNAS
2008;105:
17908-17
SC
4.5
0
12
24
Months
36
Symptom Scores: IL versus SC
Symptom score (VAS)
10
hayfever
nasal
congestion
8
nasal itching
sneezing
asthma
dry cough
6
4
IL
2
SC
0
10
red eyes
ocular itching
8
6
4
2
0
0
1
3
0
1
3
Years
0
1
3
0
1
PNAS 2008;105:17908-12
3
Increased Safety with
Currently Available Extracts
 Delayed absorption:
Allows more rapid escalation of dose
 Reduce levels of IgE
Omalizumab - Reduces asthmatic reactions
to immunotherapy by improving asthma control
 Alternative routes
Oral - Investigated in food allergy
Sublingual - Established efficacy and safety
Epicutaneous - Promising in initial studies with
long-lasting effect.
Intralymphatic - 3-year response with 3
injections
Enhanced Safety and Efficacy
with Modified Allergens
 Chemical Treatment of Allergens:
- Allergoids √
 Recombinant Technology
- Unmodified allergens √
- Site-directed mutagensis and deletion √
- peptides √
- Fusion proteins.
 Combined with Immune Stimulation
- ISS-ODN (CpG) √
- Monophosphoryl Lipid A (MPL) √
√Active study or current use
Development and Preliminary Clinical
evaluation of a Peptide Immunotherapy
Vaccine for Cat Allergy
M Worm---AB Kay, M Larche’. J Allergy Clin Immunol 2011;127:89-97
 Determined binding affinities of Fel d 1
peptides for 10 commonly expressed HLA-DR
molecules.
 Functional immunodominant peptides were
identified by means of peptide induced
proliferation and cytokine secretion from PBMC
of allergic donors.
 Histamine releasing activity was assessed to
rule out reactivity with IgE.
Current Status of Peptide Allergen Extracts
Google for Circassia Ltd January 2011
 Cat: (November 2009) Phase II, n=121, catexposure chamber, optimal dose decreased
symptoms 67%.
(September 2010) Phase II, n-200, ongoing.
 Ragweed: (February 2010) Phase II, early skin
response reduced 47%.
(September 2010) Phase II, n-275, ongoing
 House dust mites: Phase II, n=50, 4 doses over
several weeks decreased skin and ocular
challenge response by 32-87%.
 Grass: Results of Phase II study due in 2011.
Tyrosine Adsorbed Grass Allergoid
with MPL
Ragweed MATA MPL
D1 D7 D14 D21**
D35
August
September
October December
2:1
randomisation
n=661
300 SU 2000 SU
700 SU 6000 SU
Screening
n=332
Placebo
(2% L-tyrosine
depot vehicle, no
MPL)
MATA, modified allergen tyrosine adsorbed
*International multi-centre: 76 centers in the US and
**≥3 weeks before start of season
Treatment period
Follow-up/monitoring
Daily symptom and medication
scores during pollen season
Quality of life questionnaire
Canada and immunoglobulin measurement
Median CSMS during the 3
peak weeks by treatment group
12
- 12%
p = 0.048
10
Median CSM score
8
6
4
2
0
Total
placebo
300 SU set
700 SU set
2000 SU set
6000 SU set
N = 249
Enhanced Safety and Efficacy with
Modified Allergens
 Chemical Treatment of Allergens:
- Allergoids - May reduce immunogenicity as well
as allergenicity.
 Recombinant Technology
- Unmodified allergens - No enhanced safety or
efficacy.
- Site-directed mutagensis and deletion - Results
to date disappointing.
- peptides – Preliminary data encouraging
- fusion proteins - no human studies
 Combined with Immune Stimulation
- ISS-ODN (CpG) & Monophosphoryl Lipid A
(MPL) - Results in large trials have been
disappointing.
Conclusions
 Only subcutaneous and sublingual
immunotherapy may be considered
established.
 Omalizumab increases safety but is cost
prohibitive for routine use.
 Intralymphatic and transcutaneous
administration and peptide therapy show
early promise.

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