AntiAnti --IgE Treatment In Severe AsthmaIgE Treatment In Severe Asthma

Thomas B. Casale, MDProfessor of Medicine

Chief, Allergy/ImmunologyCreighton University

Omaha, NE

Relevant DisclosuresRelevant Disclosures

•Financial Relationship/Consulting Fees:

Value< $10,000: MedImmune,

• Research: All grants to Creighton University: Amgen, Novartis, Genentech, NIH, State Of Nebraska

• Legal Consult/Expert Witness: None

• Organizational: EVP of AAAAI and BOD WAO• Gifts: None

• Other: N/A

Objectives

� To explain the rationale behind IgE blockade

� To consider which patients benefit

� To address how to assess response to treatment

The First Question

• What is severe asthma?

• Answer: –Depends upon who is asking and why

WHO Definition Of Severe AsthmaWHO Definition Of Severe Asthma

• Defined by the level of current clinical control an d risks which can result in frequent severe exacerbations and/or adverse reactions to medications and/or chronic morbidity.

• 3 groups, each carrying different public health messages and challenges. – Untreated severe asthma– Difficult to treat asthma– Treatment resistant severe asthma

• Controlled on high dose medication • Not controlled on high dose medication

Bousquet et al, JACI 2010

2009 ATS/ERS Task Force On Severe Asthma Definition

• Asthma which requires treatment with high dose ICS (fluticasone > 1000 mcg/d or equivalent) plus a 2 nd controller (and/or systemic CS) to prevent a patient from becoming “uncontrolled” or which, despite high dose therapy, remains “uncontrolled“.

Uncontrolled Asthma– Any one of the following:

• Poor symptom control: ACQ consistently >1.5 (or “not well controlled” by NAEPP guidelines)

• Frequent exacerbations: 2 or more bursts of systemic CSs (>3 days each) in previous year

• Severe exacerbations: at least 1 hospitalization, ICU stay or mechanical ventilation in previous yr

• Persistent airflow limitation: pre-short and long acting bronchodilator FEV1< 80% predicted (in the face of reduced FEV1/FVC)

2009 ATS/ERS Task Force On Severe Asthma Definition

Second Question

What Is the Role of IgE in Severe Asthma?

Secretion and

Epithelial Permeability

AllergensBacteria

Histamine,

LTC4

and

PGD2

IgE

Immune-cell

Recruitment

and

activation

Neutrophil

Mast Cell

Histamine,

LTC4,

Chymase, and

heparin

Histamine, PGD2,

and proteases

Epithelium

TNF TGFβ and FGF

Fibroblasts

Wound healing

and fibrosis

ILs-3,4, 5,6,8,9,11,13TNF-αααα, MIP1, MCP

Blood flow

coagulation

and vascular

permeability Blood vessel

endothelium

Eosinophil B-cell T-reg Cell

Nerve cellSmooth

Muscle

Cell

Immune cell

activation and recruitment

Neuroimmune interactions,

Peristalsis bronchoconstriction

and pain

IgEIgEIgEIgEIgEIgEIgEIgE-------- Mediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic Reactions

Adapted from Bischoff, Nature Immunol, ‘07

Prevalence of Asthma Related to Serum Prevalence of Asthma Related to Serum IgE Level Standardized for Age and GenderIgE Level Standardized for Age and Gender

Age 6 to <35 years

Age 35 to <55 years

Age 55+ years

< -1.5 -1.5 to <-0.5 -0.5 to <0.5 0.5 to <1.5 ≥≥≥≥1.5

Ranges of serum IgE Z score

0

10

20

30

40

Pre

vale

nce

of A

sthm

a (%

)

Burrows B, et al. N Engl J Med 1989; 320: 271-7.

Longitudinal Association Between IgE & Lung Function in Adult Asthmatic Non-Smokers

Sherrill DL, et al. Am J Respir Crit Care Med 1995;152:98-102.

Log IgE = 0.8Log IgE = 1.75

55

65

70

75

80

85

35 75

Age (yrs)Age (yrs)

FE

V1/

FV

C (

%)

The Relationship between IgE and FcεεεεRI Expression

Fractional increase over Day 21

0

3.0

0

Incubation time (days)

2.5

2.0

1.5

1.0

0.5 Log fluorescence

Cou

nt

IgE (500 ng/mL)

IgE absence

1 2 3 4 5 6 7

MacGlashan D, et al. Blood 1998;91:1633-43.

Atopicasthmatics

Non-atopicasthmatics

Atopiccontrols

Non-atopiccontrols

180

160

140

120

100

80

60

40

20

0

Fc εε εε

RI+

(22

E7)

cel

ls/m

m2

p=0.001p=0.006

p=0.0006

p=0.02

170

160

30

20

10

0

Asthma Patients

Controls

Saline Allergen Saline Allergen

Fc εε εε

RI αα αα

mR

NA

+ ce

lls (

x 10

6ce

lls)

FcFcεεεεεεεεRI Expression Upregulated in AsthmaRI Expression Upregulated in Asthma

Rajakulasingam K, et al. Am J Respir Crit Care Med 1998;158:233-40.Humbert M, et al. Am J Respir Crit Care Med 1996;153:1931-7.

Expression of High-Affinity IgE ReceptorIncreased in Fatal Asthma

302328

Fatal Asthma(n=10)

Non-Pulmonary Deaths(n=9)

Fc εε εε

RI r

ecep

tor

expr

essi

on in

la

min

a pr

opria

(+

cells

/mm

2 )

Mild Intermittent Asthma †

(n=16)

1200

1000

800

600

400

200

0

1085*

*P<0.05 vs other groups.†Biopsy

Fregonese L, et al. Am J Respir Crit Care Med. 2004;169:A297.

Mechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of Omalizumab

���� airway eosinophils, mast cells,

basophils, T + B lymphocytes

���� IgE+, FcεεεεRI+, IL-4+cells in

bronchial epithelium

���� response to allergen skin test

���� eNO

Lung Ag Challenge

���� free IgE, IgE bound toFceRI, and FceRI expressionon mast cells, basophils,dendritic cells,monocytes

Omalizumab Down-Regulates Fc εεεεRI Expression on Dendritic Cells in SAR

Omalizumab Placebo

0

>100

0 7 2814Study day

25

50

75

42

0 7 2814 420

150300450

>600FcεεεεRIαααα (MFI)

0 7 2814Study day

42

0 7 2814 42

0

>100

25

50

75

0150300450

>600

pDC1

pDC2

*

*****

***

* ***

*

*p<0.05; **p<0.01; ***p<0.001 vs Day 0

FcεεεεRIαααα (MFI)

Prussin C, et al. J Allergy Clin Immunol 2003;112:1147-54.

Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation In Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic Asthmatics

� 5555----center, double blind , placebocenter, double blind , placebocenter, double blind , placebocenter, double blind , placebo----controlled, parallelcontrolled, parallelcontrolled, parallelcontrolled, parallel----group, 16group, 16group, 16group, 16----week study (n=44) :week study (n=44) :week study (n=44) :week study (n=44) :

•Reduction in submucosal eos: 8.0 to 1.5Reduction in submucosal eos: 8.0 to 1.5Reduction in submucosal eos: 8.0 to 1.5Reduction in submucosal eos: 8.0 to 1.5

•10101010----fold reduction in IgE+cellsfold reduction in IgE+cellsfold reduction in IgE+cellsfold reduction in IgE+cells---- Decreases in FCDecreases in FCDecreases in FCDecreases in FCεεεεRI cellsRI cellsRI cellsRI cells

•Decreases in B cells, and CD3+, CD4+, and Decreases in B cells, and CD3+, CD4+, and Decreases in B cells, and CD3+, CD4+, and Decreases in B cells, and CD3+, CD4+, and CD8+ cells CD8+ cells CD8+ cells CD8+ cells ……………………

•implies that IgE plays an important role in implies that IgE plays an important role in implies that IgE plays an important role in implies that IgE plays an important role in airway inflammation in asthmaairway inflammation in asthmaairway inflammation in asthmaairway inflammation in asthma

R Djukanovic, et al, AJRCCM,170:583,2004R Djukanovic, et al, AJRCCM,170:583,2004R Djukanovic, et al, AJRCCM,170:583,2004R Djukanovic, et al, AJRCCM,170:583,2004

Omalizumab Decreases Fc εεεεRI in Bronchial Biopsies

PrePre--OmalizumabOmalizumab PostPost --OmalizumabOmalizumab

Djukanović R, et al. Am J Respir Crit Care Med 2004;170-583-93.

Omalizumab Significantly Reduces Submucosal Eosinophils

Eos

inop

hils

(ce

lls/m

m2 )

Baseline Post-treatment0

20

60

8080

60

20

0

4040

Baseline Post-treatment

8.01.5

6.3 6.4

Placebo (n=14)Omalizumab (n=14)

p<0.001

p=0.81p=0.033

Djukanović R, et al. Am J Respir Crit Care Med 2004;170-583-93.

Clinical Effects Of Omalizumab:Clinical Effects Of Omalizumab:Pooled data from 7 trialsPooled data from 7 trials

� In patients on ICS alone, or in combination with ot her agents, addition of omalizumab:�Reduced number of exacerbations

�Reduced symptom scores

�Reduced need for inhaled corticosteroids

�Reduced use of rescue medication

� Improved asthma-related quality of life

� Consider using in patients with poor control despit e optimal care

11Busse W et al. Busse W et al. J Allergy CLin ImmunolJ Allergy CLin Immunol 2001;108:1842001;108:184 --90.90.22Soler M et al. Soler M et al. Eur Respir J Eur Respir J 2001;18:2542001;18:254 --61.61.33Humbert M, et al. Humbert M, et al. AllergyAllergy 2005;60:3092005;60:309 --16.16.

Effects Of Omalizumab On Exacerbations

G Rodrigo et al, Chest, 2010

Effects Of Omalizumab on Secondary Endpoints

G Rodrigo et al, Chest, 2010

Omalizumab effect was independent of:Omalizumab effect was independent of:

� Duration of treatment� Age� Severity of asthma

Omalizumab In Children 6 - 11

Lanier et al. JACI.2009;124:1210-6

Avg FP dose 515 mcg2/3 on LABA1/3 on LTRA

Effects Of Omalizumab In Elderly

All on high dose ICS & 50% on OCS

S Korn et al, Ann Allergy Asthma Immunol. 2010;105:313–319.

Steps of Therapy: Age Steps of Therapy: Age ≥≥12 Years12 Years

Steps of Therapy: Age Steps of Therapy: Age ≥≥12 Years12 Years

Interm ittentAsthm a

Persistent Asthm a: Daily M edicationConsult w ith asthma specialist if step 4 care or hi gher is required.

Consider consultation at s tep 3.

Step 1Preferred:

SABA PRN

Step 2Preferred:

Low-dose ICS

Alternative:

Cromolyn, LTRA,Nedocrom il, or Theophylline

Step 3Preferred:

Low-doseICS + LABA

OR

Medium-dose ICS

Alternative:

Low-dose ICS + either LTRA, Theophylline, or Zileuton

Step 5Preferred:

High-dose

ICS + LABA

AND

Consider

Omalizumab for

patients who have

allergies

Step 6Preferred:

High-dose

ICS + LABA + oral

corticosteroid

AND

Consider

Omalizumab for

patients who have

allergies

Step up if

needed

(first, check

adherence,

environmental

control, and

comorbid

conditions)

Step down if

possible

(and asthma is

well controlled

at least

3 months)

Step 4Preferred:

Medium-dose ICS

+ LABA

Alternative:

Medium-dose ICS

+ either LTRA,

Theophylline, or

Zileuton

Assess

control

Quick-Relief Medication for All Patients

• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute intervals

as needed. Short course of oral systemic corticosteroids may be needed.

• Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step

up treatment.

Each step: Patient education, environmental control, and management of comorbidities.

Steps 2−4: Consider subcutaneous allergen imm unotherapy for patients who have allergic asthma (see notes).

Dosing Table:Dosing Table:0.016 mg/kg/IU/mL every 4 weeks0.016 mg/kg/IU/mL every 4 weeks

>> 100100--200200 450450

>> 200200--300300 450450 450450 450450 600600

>> 300300--400400 450450 450450 600600 600600

>> 400400--500500 600600 600600 750750 750750

>> 500500--600600 600600 750750

>> 600600--700700 750750

Body Weight (kg)

Mon

thly

Dos

ing

Biw

eekl

y D

osin

g

Omalizumab Onset Of Action In AsthmaOmalizumab Onset Of Action In AsthmaOmalizumab Onset Of Action In AsthmaOmalizumab Onset Of Action In Asthma

Asthma trials suggest that 8 to 16 weeks of treatment might be a reasonable therapeutic trial:

� While the onset of response was measurable at 4 weeks, the proportion of responders continued to increase throughout the 16 week period:

4 wks: 61%8 wks: 78%12 wks: 87%

Factors Predictive of Response to Factors Predictive of Response to OmalizumabOmalizumab

Bousquet J, et al. Chest. 2004;125:1378-1386.

1.87*(0.88 – 3.99)°

N = 120

2.25(1.02 – 4.97)

N = 103

3.54(1.69 – 7.43)

N = 124

1.15(0.54 – 2.44)

N = 114

1.60(0.75 – 3.42)

N = 119

3.38(1.32 – 8.66)

N = 77

4.20

(1.69 – 10.45)

N = 85

BDP dose ≥≥≥≥ 800 µg/day

History of emergencyasthma treatment in past year

FEV1 ≤≤≤≤65% predicted

*Relative Rate(Confidence Interval)

Dose (mg/kg/IgE (IU/mL)) Dose (mg)

**

**p<0.002 vs placebo

Adequate IgE Suppression is NeededAdequate IgE Suppression is Neededto Demonstrate Clinical Responseto Demonstrate Clinical Response

25ng/mLtarget

Serum free IgE (ng/mL)

50mg150mg300mg

0

400

300

200

100

0.001 0.01 0.1

Placebo

0 50 150 300

Average nasal severity scores

1.1

1.0

0.9

0.8

0.7

Casale, JAMA “01

Factors Predictive Of Clinical Response

• Reasons for omalizumab being ineffective for some (~40%) patients are unknown.

• Improvements correlate with IgE reductions, BUT

free IgE levels in nonresponders are similar to those found in responders1

• Possible reasons:2

(1) Relationship between free IgE levels and FcεR1 expression

(2) Ratio of specific IgE to total IgE

(3) Intrinsic cellular sensitivity.

1. Slavin, et al. JACI . 2009;123:1072. MacGlashan. JACI 2009;23: 114

Do the Effects Of Omalizumab Continue After Treatment Is Stopped?

• Conflicting data, but may depend upon duration of treatment

• 2 different studies with 2 different answers:1. INvestigation of Omalizumab in seVere Asthma TrEatment (INNOVATE) study2. Nopp et al, 2010 Allergy

28-week Omalizumab Treatment And 16-week Follow-up

N=476,Dark=Omal, Light=Pl

Slavin, et al. JACI . 2009;123:107

Effects Of Omalizumab On Asthma Control 3 Years After 6 Years Treatment

A Nopp et al, Allergy 2010

Omalizumab and Asthma Summary• Omalizumab is effective in children and adults

in reducing exacerbations and steroid requirements– Also positive effects on SABA use, QOL, Sxs

and PFTs (minor)• Omalizumab has anti-inflammatory effects• If not effective by 4-6 months, probably will not

be effective– Predictors of who will respond are unclear

• Whether omalizumab can be stopped with sustained clinical efficacy is unclear– May depend on duration of treatment

Other Potential Clinical Uses of Omalizumab In Asthma

• SAR and PAR +/- Asthma

• Non-allergic Asthma

•ABPA

• Adjuvant to Traditional Immunotherapy:

•Increased Efficacy As Add On in SAR

•Improved Safety As Pretreatment:

• 80% Decr In RIT Assoc Anaphylaxis in SAR

• 50% Decr In Cluster Assoc AEs in Asthma

Omalizumab Cluster IT

Placebo

Maintenance IT

Maintenance ITCluster IT

Screening

Period 1 Period 2 Period 3 Period 4

3 wk overlap

Omalizumab and Immunotherapy:Omalizumab and Immunotherapy:Study DesignStudy Design

150 Patients per arm, Randomized 1:1

Visit 0 Visit 1 Visit 5 Visit 11 Visit 14 Visit 19

-2wks 0 13wks 16 wks 17 wks 24 wks

Persistent perennial allergic asthmatics requiring ICS & FEV1 > 75%

26.2%

13.5%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

Placebo OmalizumabN=122 N=126

P= 0.017

N = 17N = 32

Proportion of Patients Who Experienced AProportion of Patients Who Experienced ASystemic Allergic Reaction: Primary EndpointSystemic Allergic Reaction: Primary Endpoint

M Massanari et al, JACI, 2010

6

0

24

2

7

26

2

0

5

10

15

20

25

30

Grade 1 (Skin) Grade 2 (GI) Grade 3(Resp)

Grade 4 (CV)

Num

ber

of P

atie

nts

Placebo (n=32) Omalizumab (n=17)

Severity of First Systemic Severity of First Systemic Allergic ReactionAllergic Reaction

M Massanari et al, JACI, 2010

Omalizumab and IT Conclusions

• Pretreatment with omalizumab:• Added Efficacy to SCIT•Added Safety to SCIT•Allowed more patients to reach maintenance

• 87 vs. 72% (p<0.01)

• Unanswered questions:•How long do you need to treat with both?•Can you stop the omalizumab after reaching maintenance IT?

Omalizumab Safety Issues

�Anaphylaxis�Cancer�Cardiovascular�Other?

Major Unanswered Question

� If Anti-IgE Prevents Anaphylaxis By Decreasing Circulating and Bound IgE…..

� And IgE is essential for development of anaphylaxis…… ..

How does it cause anaphylaxis?????- Incidence ~0.1 to 0.2%

ConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusions

� Since IgE plays an important role in a number of Since IgE plays an important role in a number of Since IgE plays an important role in a number of Since IgE plays an important role in a number of diseases, strategies aimed at blocking the effects of diseases, strategies aimed at blocking the effects of diseases, strategies aimed at blocking the effects of diseases, strategies aimed at blocking the effects of it will likely prove importantit will likely prove importantit will likely prove importantit will likely prove important…………........• Not just for asthma and rhinitisNot just for asthma and rhinitisNot just for asthma and rhinitisNot just for asthma and rhinitis

� Omalizumab has many potential therapeutic Omalizumab has many potential therapeutic Omalizumab has many potential therapeutic Omalizumab has many potential therapeutic applicationsapplicationsapplicationsapplications• On going safety issues need to be monitoredOn going safety issues need to be monitoredOn going safety issues need to be monitoredOn going safety issues need to be monitored

� Small, easy to make and deliver antagonists should Small, easy to make and deliver antagonists should Small, easy to make and deliver antagonists should Small, easy to make and deliver antagonists should be pursued, especially those thatbe pursued, especially those thatbe pursued, especially those thatbe pursued, especially those that…………....• Induce toleranceInduce toleranceInduce toleranceInduce tolerance