New Approaches to Allergen Immunotherapy

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New Approaches to Allergen Immunotherapy

• Harold S. Nelson. MD
• Professor of Medicine
• National Jewish Heath
• University of Colorado School of Medicine
• Denver, Colorado, USA

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Increased Safety with Currently Available Extracts

• Delayed absorption Aluminum v Tyrosine
  adsorption v Encapsulation (liposomes)
• Reduce levels of IgE Omalizumab v
• Alternative routes Nasal Oral v Sublingual v
  Intralymphatic v Epicutaneous v
• v Active study or current use

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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

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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
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Dose-Response to Grass Pollen Extract SLIT
Didier et al. JACI 2007120
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Long-lasting Effects of sublingual Imunotherapy
According to its Duration A 15-year Prospective
Study
M Marogna, et al. J Allergy Clin Immunol
2010126969-75

• 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.

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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
2010126969-75
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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
2010126969-75
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Adverse Reactions to Grass SLITSummary of 7
Phase III Studies
Adults (n2096) Children (n598)
AIT Placebo AIT Placebo
Oral Pruritus 39 5 35 3
Throat Irritation 21 3 25 2
Ear Pruritus 14 1 8 lt1
Mouth Edema 11 lt1 8 lt1
Oral Paresthesias 8 1
Any Drug-related 70 23 62 27

Abstract EAACI June 2011
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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
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Anaphylactic Reactions to SLIT

• Allergen BU Symptoms Reference or
  Mnt
• Multiple BU Pruritus, AE, Allergy
  wheezing,
  dizziness 2006611235
• Latex BU Urt, asthma,
  Allergy
  anaphylactic shock
  200661236
• Multiple Mnt AE, chest pain, Allergy
  nausea, abd pain 200762567
• HDM Mnt3 yrs Urt, wheezing Allergy
• 6X dose hypotension, syncope 200863374
• Grass (2) 1st dose Includes hypotension
  History of
  intolerance for SCIT Allergy
  200964963-4

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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 20045945-53

• 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

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SLIT versus SCIT

• Treatment Symptoms Medication
• Placebo .02 1.35
• SLIT - .36 .29
• SCIT - .75 No change
• SLIT SCIT significantly better than placebo, no
  difference between active treatments.
• Pollen counts higher second year

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Allergy 20045945
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1st treatment season
Allergy 20045945
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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.
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Grass Transcutaneous Immunotherapy in Children
with Seasonal Rhnoconjunctivitis
F Agostinis, et al. Allergy 201066410-1

• 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 lt3
  salicylic acid) were applied weekly for 12 weeks
  and removed after 24 hours.

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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 lt .05)- Antihistamine
  use (p lt .02)

F Agostinis et al. Allergy 201066410-1
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Grass Transcutaneous Immunotherapy
ActivePlacebo
Grass pollen count
Green Grass pollen countPink Peak grass pollen
season.Red placeboYellow active treatment
Symptoms
Anti-histamines
Agostinis et alAllergy 200960L410-1
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Epicutaneous Allergen Administration As a Novel
Method of Allergen-Specific Immunotherapy
G Senti, et al. J Allergy Clin Immunol
2009124997-1002

• A double-blind study was conducted in 37
  grass-sensitive adults in Zurich, Switzerland.
• Prior to and during the 2006 grass pollen season
  subjects had 13 weekly patches applied to
  tape-stripped 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)

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Symptoms Compared to 2005
Act Pla Act Pla
P 0.02
P 0.005
G SantiJACI2009124997-1002
? Outliers
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Intralymphatic Allergen Administration Renders
Specific Immunotherapy Faster and Safer A
Randomized Controlled Trial
G Senti et al. Proc Nat Acad Sci 200810517908-12

• 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.

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Intralymphatic vs. Subcutaneous
G SentiPNAS200810517908-17
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Nasal Challenge IL versus SC
Max. tolerated allergen conc. (log10)
G SentiPNAS200810517908-17
0
12
24
36
Months
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Symptom Scores IL versus SC
PNAS 200810517908-12
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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

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Enhanced Safety and Efficacy with Modified
Allergens

• Chemical Treatment of Allergens- Allergoids v
• Recombinant Technology- Unmodified allergens v
  - Site-directed mutagensis and deletion v -
  peptides v - Fusion proteins.
• Combined with Immune Stimulation- ISS-ODN (CpG)
  v - Monophosphoryl Lipid A (MPL) v vActive
  study or current use

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Development and Preliminary Clinical evaluation
of a Peptide Immunotherapy Vaccine for Cat Allergy
M Worm---AB Kay, M Larche. J Allergy Clin
Immunol 201112789-97

• 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.

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Current Status of Peptide Allergen Extracts
Google for Circassia Ltd January 2011

• Cat (November 2009) Phase II, n121,
  cat-exposure 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, n50, 4 doses over
  several weeks decreased skin and ocular challenge
  response by 32-87.
• Grass Results of Phase II study due in 2011.

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Tyrosine Adsorbed Grass Allergoid with MPL
Ragweed MATA MPL
D1
D7
D14
D21
D35
August
December
October
September
21 randomisation
n661
300 SU 2000 SU
700 SU 6000 SU
Screening
n332
Placebo(2 L-tyrosine depot vehicle, no MPL)
Treatment period
Follow-up/monitoring
Daily symptom and medication scores during
pollen season
MATA, modified allergen tyrosine
adsorbed International multi-centre 76 centers
in the US and Canada 3 weeks before start of
season
Quality of life questionnaire and immunoglobulin
measurement
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Median CSMS during the 3 peak weeks by treatment
group
12
- 12p 0.048
10
Median CSM score
8
6
4
2
0
300 SU set
700 SU set
2000 SU set
6000 SU set
Total placebo
N 249
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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.

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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.