A UNIQUE SOLUTION FOR SEVERE ASTHMA.

DR TALKER OLGAPULMONARY DEPARTMENT

CASE PRESENTATION, 10.2009 :

48 year old lady, teacher at schoolMarried +7s/p op. d/t scoliosis at age 17No smoking historyFamily history of severe asthmaAllergy to dust mitesSevere asthma with recurrent exacerbations, recurrent prolonged courses of oral steroids, prednisone 30-40 mg.

A CASE, 10.2009 :

BMI- 23Normal CXR, normal ECHO, p-ANCA, c-ANCA- normalHigh eosinophil count-1100Stool examination- no parasitesPFT- obstructive pattern with FEV1- 60%Treatment- Prednisone, Seretide 500, Foradil, Flixonase, Omepradex.

What is to be done?

SEVERE ASTHMA, DEFINITION:

Severe asthma- disease that requires high dose inhaled or near continuous oral glucocorticoid treatment to maintain asthma

control .

TO BE EXCLUDED:

Ongoing exposure to triggersNonadherenceAlternative disorder that mimics asthmaComorbidities

TO BE EXCLUDED:

Ongoing exposure to triggers:allergens, irritants at patient’s home, school, work-laboratory animals, latex, glutaraldehide, toluene diisocyanate, flour, NSAID’s, beta-blockers.

Adherence

TO BE EXCLUDED:Conditions that mimic asthma:

Vocal cord dysfunction( combination of inspiratory flow volume loop and laryngoscopy during symptoms), vocal cord paralysis, vocal cord lesions.

Central airway obstruction- tracheal strictures, tracheal copmpression by goiter, thracheal and proximal bronchial tumors, vascular rings( CT, bronchoscopy)

COPD- greater than 20 p.y. smoking history, family history of emphysema or alpha-1 antitrypsin deficiency, irreversible airflow obstruction and low diffusing capacity .

TO BE EXCLUDED:

Bronchiectasis- copious productive cough, refractory to bronchodilator therapy, HRCT.

ABPA may develop patients with asthma d/t colonization of the airways with aspergillus and typically present with recurrent mucoid impaction and atelectasis, proximal bronchiectasis, skin test positive to aspergillus, elevated IgE (>1000 ng/ml).Hypersensitivity pneumonitis- exposure to allergens- birds, barns, humidifiers, PFT-

mixed obstructive and restrictive pattern, reduced DLCO, fleeting infiltrates .

TO BE EXCLUDED:Eosinophilia and respiratory sypmtoms: filariasis, trichinellosis, strongiloides infection- patients from endemic area, blood eosinophilia, elevated IgE, specific IgG to parasites, improvement with specific treatment .

Paranasal sinus disease, skin lesions, peripheral neuropathy, eosynophilia > 10% is common in Churg-Strauss s-me, p-ANCA positive.Chronic eosinophilic pneumonia- fever, weight loss, night sweats, pulmonary infiltrates.Endobronchial sarcoidosis- hylar adenopathy and interstitial opacities .Cardiac disease- echocardiography .

TO BE EXCLUDED:

Comorbidities:Chronic rhinosinusitis, allergic rhinitisGERDOngoing smokingObesityOSAAnxiety , depression.

A CASE, 01.2010 :

IgE- 80 u/mlStarted Xolair- monoclonal anti-IgE antibody, 225 mg every two weeksPrednisone tapering down

A CASE, 11.2010 :

Receiving Xolair 225 mg every two weeksStopped Seretide No prednisonePFT- FEV1- 75%

Th2-cell

B-cell

Eosinophil

IL-4

IL-13

Mast cell

FceRI

IgE

HistamineLeukotrienesProstaglandinsCytokines

Atopicdisease

IL-5

Antigen-presentingcell

Allergen

THE IGE-MEDIATED INFLAMMATORY RESPONSE:TYPE I HYPERSENSITIVITY REACTION

Holgate ST. QJM 1998

XOLAIR® (OMALIZUMAB) PREVENTS IGE INTERACTING WITH FCERI ON ALL CELL TYPES

Mast cellBasophil

Dendritic cell

IgE

Macrophage/monocyte

Eosinophil

Trimers~(490 kD- 530 kD)

Hexamer~(1000 kD)

Omalizumab )~150 kD(

IgE )~190 kD(

OMALIZUMAB:IGE COMPLEXES

Omalizumab:IgE complexes are either trimers or hexamers, based on Xolair IgE ratio

The complexes are of limited size and are eliminated via the reticuloendothelial system

No specific organ accumulation, no bigger complexes

300mg administered once monthly for 48 weeks topatients with moderate-to-severe asthma

Day 0 = screening )n=93(

Days )not to scale(

REDUCTION IN SERUM FREE IGE FOLLOWING S.C. ADMINISTRATION OF XOLAIR®

Day 1 post-dose

0

300

200

100

0 1 3 7 14 112 168 252 336

Median free IgE )ng/mL(

Source: Extension Study Report 8C

INNOVATE INVESTIGATION OF OMALIZUMAB IN SEVERE ASTHMA TREATMENT

Patients (aged 12–75 years) with allergic asthma

FEV1 40–<80% at randomizationAsthma symptoms in the 4 weeks prior to randomization despite high-dose ICS and LABA

Clinically meaningful exacerbations in the previous year:

Either 2 exacerbations requiring systemic steroids Or a severe exacerbation (PEF or FEV1 <60% personal best) requiring systemic steroids and ER treatment Or hospitalization

Humbert M, et al. Allergy 2005

INNOVATE RESULTS

0.91

0.48 0.43

0.24***0.24**

0.68*

0

0.25

0.5

0.75

1

ExacerbationGeneral

SevereExacerbation

FEV1 < 60

ER visits

Exa

cerb

atio

ns R

ate

*P = 0.04, ** P = 0.002, *** P = 0.038Omalizumab Placebo

26%

50% 44.2%

QOL SIGNIFICANTLY IMPROVED OVERALL AND ACROSS ALL DOMAINS COMPARED WITH PLACEBO

0.46

0.57

0.440.40

0.46

AQLQ score†OmalizumabPlacebo

**p<0.01; ***p<0.001†Change from baseline (least squares mean)

AQLQ = Asthma Quality of Life Questionnaire

0.91***

0.90***

0.95** 0.89

***

0.91***

1.0

0.8

0.6

0.4

0.2

0

ActivitiesEmotionsSymptomsEnvironmentOverall

OMALIZUMAB WAS WELL TOLERATED The percentage of patients who experienced

adverse events (AEs) was similar in both treatment groups omalizumab, 72.2%; placebo, 75.5%

Fewer serious AEs in the omalizumab group omalizumab, 11.8%; placebo, 15.6%

AEs were generally mild or moderate in nature and of short duration

Humbert M, et al. Allergy 2005

GINA 2007 GUIDELINES* ANTI-IGE THERAPY AT STEP 5

*For children older than 5 years, adolescents and adults†Receptor antagonist or synthesis inhibitorICS = inhaled corticosteroid; LABA = long-acting β2-agonist

Step 1 Step 2 Step 3 Step 4 Step 5Asthma education

Environmental controlAs needed rapid-acting β2-agonist

As needed rapid-acting β2-agonist

Controller options

Select one Select one Add one or more Add one or more

Low-dose ICS Low-dose ICS plus LABA

Medium- or

high-dose ICS plus LABA

Oral corticosteroid )lowest dose(

Leukotriene modifier† Medium- or high-dose ICS

Leukotriene modifier

Anti-IgE treatment

Low-dose ICS plus leukotriene

modifierSustained release

theophylline

Low-dose ICS plus sustained

release theophylline

GINA Workshop Report 2007

SUMMARY OF DOSING STRATEGY FOR XOLAIR®

Free IgE target ~25ng/mL (10.4 IU/mL) At least 0.016 mg / kg / IU IgE / month Target Xolair®:IgE ratio greater than 15:1 Dose to be adjusted for individual’s baseline

IgE and body weight Dosing strategy accommodates a wide range

of baseline IgE and body weights

UPDATED DOSING TABLE

PULMONARY OUTPATIENTS CLINIC

OMALIZUMAB IN SEVERE ALLERGIC ASTHMA: REAL LIFE EXPERIENCE MEIR MEDICAL CENTER

54 patients 47 patients fulfilled the selection criteria (at

least 3 months of treatment) Age: 61± 12 years (26-85) Mean Ig E total levels: 281 ± 236 IU/ml

OMALIZUMAB IN SEVERE ALLERGIC ASTHMA: REAL LIFE EXPERIENCEMEIR MEDICAL CENTER

Duration of disease: 25 ±17 years (2-60) Mean monthly Xolair dosage: 401± 241mg(150-1200). Mean time on Xolair: 28± 18 months

REAL LIFE EXPERIENCE: MEIR MEDICAL CENTER: SEX

14 (30%)

33 (70%)

male

female

BASELINE TREATMENT

ICSCOMBINATION THERAPY

SINGULAIR0

10

20

30

40

50

60

70

80

90

9%

88%

6%

ASTHMA EXACERBATION RATE(ONE YEAR)

020406080

33/47 (70.2%)

18/47 (38.3%)

P=0.007

LUNG FUNCTIONS

FEV1 before

FEV1 affter

55.0

56.0

57.0

58.0

59.0

60.0

61.0

62.0

63.0

64.0

63.9±17

58.1±13.9

P=0.002

STEROIDS DOSAGES

Dose before

Dose after

5.6

5.8

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

6.3±6.8

7.3±8.1

P=0.027

STEROIDS REDUCTION 4 (8.5%) stopped steroids. 10 (21%) reduced the dosage.

HOSPITALIZATIONS DURING XOLAIR TX

45%

25%

17%13%

No hospitalizationOne hospitalizationTwo hospitalizations>3 Hospitalizations

SIDE EFFECTS Only 1 patient withdrawn 5 patients with musculoskeletal pains. No cardiovascular side effects. No anaphylaxis. No malignancies.

CONCLUSIONS Omalizumab is effective add-on treatment in

patients with moderate to severe allergic asthma and accompany by an acceptable safety profile.

FUTURE?

POTENTIAL TARGETS FOR SELECTED NOVEL THERAPIES FOR TREATMENT RESISTANT

ASTHMA

MEPOLIZUMAB, A HUMANIZED ANTI-IL-5 MAB, AS A OPTION FOR SEVERE ASTHMA

THANK YOU