Role of IgE in Inflammation and Asthma

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Thomas B. Casale, MD
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Observations on the clinical potential of
anti-IgE as a preventive therapy for systemic
atopic disease. What patient types would be
expected to benefit most from anti-IgE treatment
if it were not limited to asthma..
Thomas B. Casale, MD Professor of Medicine Chief,
Allergy/Immunology Creighton University Omaha, NE
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Outline

• Review Diseases that IgE likely plays an
  important role in..other than asthma
• Discuss rationale behind using omalizumab in
  these diseases
• Examine the effects of omalizumab on these
  allergic diseases

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ConsiderReferral Omalizumab
STEP 4 SEVERE PERSISTENT
Step downwhen controlled

• CONTROLLER
• daily multiple medications
• High dose inhaled steroid
• Long-acting bronchodilator
• Oral steroid

To improve control or reduce steroid use

• RELIEVER
• Inhaled ß2-agonist p.r.n.

Avoid or control triggers
STEP 3 MODERATE PERSISTENT
Patient education essential at every step Reduce
therapy if controlled for at least 3
months Continue monitoring

• CONTROLLER
• daily medications
• Low to Med.nods ICS and LABA
• Low to Mod dose ICS plus anti-leukotriene

• RELIEVER
• Inhaled ß2-agonist p.r.n.

Avoid or control triggers
STEP 2 MILD PERSISTENT

• CONTROLLER
• daily medications
• Low dose Inhaled steroid
• Or cromone, oral theophylline or anti-leukotriene

• RELIEVER
• Inhaled ß2-agonist p.r.n.

Avoid or control triggers
STEP 1 INTERMITTENT
Step upif not controlled (after check on inhaler
technique and compliance)

• RELIEVER
• Inhaled ß2-agonist p.r.n.

CONTROLLER none
GINA NIH/NHLBI, 1998 publication number
96-3659B.
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Omalizumab Mechanism Of Action
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Investigators Ecstatic About Anti-Inflammatory
Effects Of Omalizumab
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Omalizumab could be a relatively cost-effective
treatment for SAR?

• Yes
• No
• Both A and B

8
Potential Clinical Uses of Omalizumab

• SAR and PAR- w/ or w/o asthma

9

Effects of Omalizumab on Symptoms During
Ragweed Pollen Season
Casale, et al, JAMA, 01
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Adequate IgE Suppression is Needed to
Demonstrate Clinical Response
Serum free IgE (ng/mL)
Average nasal severity scores
50mg 150mg 300mg
400
1.1
Placebo
300
1.0
plt0.002 vs placebo
200
0.9
0.8
100

25ng/mLtarget
0
0.7
0.001
0.01
0.1
0
50
150
300
Dose (mg/kg/IgE (IU/mL))
Dose (mg)
Casale, JAMA 01
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Effects Of Omalizumab In PAR
Chervinsky, et al, Ann Allergy Asthma Immunol,
2003
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Key Omalizumab Efficacy Points From 52-Week SOLAR
Study

• Symptomatic patients with asthma and rhinitis on
  IHCs and INCs had improvement in asthma and
  rhinitis symptoms
• Less exacerbations (0.25 vs. 0.40) vs. placebo

Vignola et al,Allergy, 07/04
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Effects Of Omalizumab On FCeRI Expression And
Immediate Allergic Responses
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Summary of FACS Studies

• Omalizumab caused significant reduction in Fc?RI
• expression at all time points
• - Basophils (73)
• - pDC1 cells (52)
• - pDC2 cells (83)
• Drops in Fc?RI expression correlated with
  declines in serum
• IgE levels
• 10 fold declines in IgE resulted in 42 62
  reduction in Fc?RI
• Declines in Fc?RI expression were highly
  correlated between
• basophils, pDC1 and pDC2 cells.
• Down Regulation of Fc?RI could affect both the
  sensitization
• and effector phases of allergic responses.

Lin et al, JACI,
04 and Prussin et al, JACI, 03
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Association Between FACS and Clinical Data

• Omalizumab- induced maximal inhibitory
  responses
• - IgE 1 day
• - Fc?RI 14 days
• - Nasal Challenges 14 days
• Kinetics of inhibition of Fc?RI expression and
  nasal
• allergen challenge responses paralleled one
  another.
• Data suggest that down regulation of Fc?R1
  expression
• on effector cells is required for clinical
  inhibition of
• allergic responses.
• It could be a useful agent to quickly control
  allergic
• respiratory symptoms.

Lin et al,
JACI2004
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Extension Study Can You Retreat Without
Problems?

• Evaluate safety and tolerability of omalizumab
  re-treatment during second ragweed SAR season
• No efficacy assessments were made
• No significant AEs identified----including
  allergic reactions

Nayak et al, Allergy Asthma Proc, 2003
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Omalizumab could be a relatively cost-effective
treatment for SAR?

• Yes
• No
• Both A and B

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Potential Clinical Uses of Omalizumab, Contd

• SAR and PAR
• Atopic Dermatitis

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Omalizumab and Atopic Dermatitis

• Two 3-patient case reports J Am Acad Dermatol
• 1 negative (adults, IgE 5440 to 24,000)
• 1 positive (10-13 y/o, IgE 1990 to 6120)
• 300-450 mg qowk for 4-6 mos (3-60 rec dose)
• Third, larger study underway

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Omalizumab has been shown to be an effective
treatment for food allergy?

• True
• False

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Potential Clinical Uses of Omalizumab, Contd

• SAR and PAR
• Atopic Dermatitis
• Food Allergy

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Mean Threshold Dose (95 CI) to Peanut
4400
3900
Double-blind, placebo-controlled,
randomized dose-escalation study (N82)
3400
2900
2400
1900
Threshold Dose (mg)
1400
900
400
-100
Placebo
150 mg
300 mg
450 mg
Dose Group
Leung, Sampson, et al. NEJM 2003348986.
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Clinical Implications

• Average accidental peanut exposure believed to be
  1-2 peanuts or fewer (325-650 mg of peanut)

• Thresholds achieved in 450 mg dose group, 2805
  mg, (8 peanuts), should protect most patients
  25 could ingest 8 gm 25 were no better

• Should be effective for other (any) foods
• Not a cure, but could provide a safety net (!)

• Omalizumab Xolair approved for treating
  moderate severe asthma, is NOT the same drug

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Which of the following urticarial conditions
would most likely respond favorably to omalizumab?

• Aspirin-induced
• Urticaria pigmentosa
• Cholinergic urticaria
• Chronic urticaria with autoantibodies

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Potential Clinical Uses of Omalizumab, Contd

• SAR and PAR
• Atopic Dermatitis
• Food Allergy
• Insect Allergy
• Chronic Urticaria with Autoantbodies

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Functional Autoantibodies of CIU
M. Greaves, JACI, 2000
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Potential Clinical Uses of Omalizumab, Contd

• SAR and PAR
• Atopic Dermatitis
• Food Allergy
• Insect Allergy
• Chronic Urticaria with Autoantbodies
• Adjuvant to Traditional Immunotherapy

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Immunotherapy

• Effective (although not completely so) for both
  allergic asthma and allergic rhinitis
• Has many immunomodulatory effects
• Use is somewhat limited by potential to induce
  anaphylaxis

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Immunotherapy Limitations Associated With
Allergic Reactions

• Inadequate dosing
• Brittle/ Moderate to severe asthma
• Venom
• Food

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Based on current available data, how long should
a patient with severe asthma be treated with
omalizumab before starting immunotherapy?

• 1 day
• gt 1 day lt 2 weeks
• 2 to 8 weeks
• gt 8 weeks

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What About Immunotherapy Plus Omalizumab?
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Study Design 6 17 y/o
SIT (birch) placebo
n 54
Randomization
SIT (birch) omalizumab
n 55
Prescreening
SIT (grass) omalizumab
n 59
SIT (grass) placebo
n 53
SIT Titration
SIT Maintenance study drug
Week 36
Week 0
Week 12
NO SIT dose reduction planned for allergen
season
Kuehr, et al, JACI, 02/02
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SYMPTOM SEVERITY SCORE(entire pollen season)
P0.01
P0.011
? 35
0,5
0.46
? 45
0,4
0.38
0.30
0,3
Symptom severity score (median)
0.21
0,2
0,1
0
Kuehr, et al, JACI, 02/02
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OF DAYS WITH INTAKE OFRESCUE MEDICATION
(entire pollen season)
Wilcoxon test (2-sided)
20
P0.002
17.36
14.1
15
of days of pollen season (median)
10
? 81
? 71
5.13
5
2.74
0
n54
n55
n59
n53
SIT grass Placebo
SIT birch Omalizumab
SIT birch Placebo
SIT grass Omalizumab
Kuehr, et al, JACI, 02/02
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What About Omalizumab Preceding Immunotherapy?
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Omalizumab Preceding IT Should

• Provide Greater Safety for IT
• Reduce Serum IgE FC?RI
• Different Mode of Ag Presentation
• Allow More Rapid Ag Administration
• Allow Use of Greater Amounts of Ag
• Provide Greater Efficacy and Immune Tolerance

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Protocol ITN019AD Efficacy and Safety Evaluation
of Allergen Immunotherapy Co-Administered with
Omalizumab

• Principal Investigator Thomas B. Casale, MD
• Sites
• Creighton U
• U of Iowa Joel Kline and Zuhair Ballas
• U of Wisconsin William Busse
• Sponsors NIAID/ITN
• Genentech Novartis
• Omalizumab and placebo
• Free IgE measures
• Funding for year 2

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Immunotherapy And Omalizumab Mechanism of Action
Immunotherapy
B lymphocyte
Allergic inflammationeosinophils and
lymphocytes
?-switch
Allergic mediators
Favors IgG Switch
Plasma cell
Release of IgE
Block Anaphylaxis
Allergens
Reduces asthma/ rhinitis sxs
Mast cells Basophils
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ITN Grant Hypothesis

• Omalizumab IT will result in enhanced clinical
  efficacy and safety vs. IT alone.
• Omalizumab should prime recipients of IT and
  enhance the immune tolerance postulated to occur
  with IT.

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Study Design
Casale, et al,JACI, 06
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Average Allergy Severity Scores Over the Primary
Ragweed Season for the PP Sample
P0.020
Casale, et al,JACI, 06
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Effects Of Treatments On IgE and Ragweed -
Specific IgG
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Effects Of Treatments On Ragweed-Specific Ig
Levels
gt Omalizumab induced expected effects on IgE gt
Immunotherapy induced 15- to 25-fold increase in
IgG
Casale, et al,JACI, 01/06
44
Did Omalizumab Improve The Safety Of
Immunotherapy?
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Rush Immunotherapy Schedule

• 10 of first 17 patients had an allergic-type
  reaction

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Weekly Ragweed IT Treatment Schedule
Placebo ITHistamine _at_ 1.25mg/mL
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Protective Effects of Omalizumab On RIT and IT

• Omalizumab had a protective effect on
  allergic-type reactions due to both RIT and IT
• Reduced SAEs
• Reduced anaphylactic reactions
• Reduced use of epinephrine and prednisone to
  treat reactions

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Adverse Events W/I 0 - 7 Hours of RIT Patients
CV Events
Nausea/Abdominal Pain
Wheezing
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Anaphylaxis Within 0-7 Hours of RIT
P0.026
of Patients
OmalIT
OmalPl
PlIT
PlPl
Post-Hoc Analysis
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RIT Time-And Dose-Dependent Allergic Reactions
Hours
Casale, et al,JACI, 01/06
51
Key Points From This Study

• Omalizumab pretreatment added safety to RIT and
  IT
• Protective effects of fexofenadine were not
  marked
• Omalizumab pretreatment may be an effective
  strategy to permit
• More rapid and higher doses of allergen IT to be
  used
• Use in wider variety of patients and diseases
• Further analyses of the data will likely provide
  important information on how best to use these
  therapies to create a new paradigm for treating
  allergic diseases
• Exact dosing and timing warrants further study

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How Long Should Omalizumab Pretreatment Be For
Asthma Trials?

• Data to date
• Nasal challenges 2 wks
• FCeRI expression 2 wks
• Skin challenges 8-10 wks
• Asthma improvement 12-16 wks
• Rush immunotherapy 9 wks
• Data suggest that to achieve a safer IT regimen
  --- should treat for gt12 weeks.

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Unanswered Questions

• How long do you need to treat with both?
• Can you stop the omalizumab after reaching
  maintenance IT?
• What are the immunologic and clinical endpoints
  of interest, and when do you measure them?
• Will this approach work for moderate/severe
  asthma?
• Other??

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Potential Clinical Uses of Omalizumab

• SAR and PAR- w/ or w/o asthma
• Atopic Dermatitis
• Food Allergy
• Insect Allergy
• Chronic Urticaria with Autoantbodies
• Adjuvant to Traditional Immunotherapy
• Other IgE-Dependent Diseases

55
Effects Of Omalizumab On Latex-Induced Allergy
Conjunctival Challenge
Leynadier, et al,JACI, 2004
56
Additional Potential Uses Of Anti-IgE

• ABPA
• Chronic hyperplastic sinusitis
• Non-allergic asthma
• Others
• Awaiting new formulations!

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Conclusions

• Since IgE plays an important role in a number of
  diseases, strategies aimed at blocking the
  effects of it will likely prove important..
• Not just for asthma
• Small, easy to make and deliver antagonists
  should be pursued, especially those that.
• Induce tolerance

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Slogans To Avoid When Doing A Clinical Trial
Better Living Through Reckless Experimentation