omalizumab in practice use

Omalizumab in practical use

Sadudee Boonmee, MD

Topic outline

• Introduction of anti IgE • Clinical application for

- Asthma- Allergic rhinitis - Immunotherapy- Chronic urticaria

• Dosage• Safety

• Omalizumab is a humanized monoclonal anti-IgE antibody (IgG1), molecular weight 150 kD

• binds to Fc portion of IgE molecule at Cε3 same site where IgE binds to FcεRI

Mechanism o action • primary mechanism of action of omalizumab is the binding of

free IgE in the circulation• secondary mechanism of action down regulation of FcεRI

expression (on Mast cell, Basophil, DC, monocyte) and Low affinity FcεRII (CD23) (B cell )

Journal of Asthma and Allergy 2011:4

• Form trimer of two omalizumab molecule per IgE antibody or form other complex

biologically inert complex do not activate complement and are cleared by the reticular endothelial system Half life = 26 day

Anti-IgE therapyImmunol Allergy Clin N Am 24 (2004) 551– 568

• omalizumab does not bind to receptor-bound IgE does not trigger degranulation by cross-linking IgE located on FceRI receptors of mast cells or basophils

Omalizumab and asthma

Expert Panel Report 3:Guidelines for the Diagnosis and and management of asthma

Omalizumab may be considered at this step for patients who have sensitivity to relevant perennial allergens (e.g., dust mites, cockroach, cat, or dog) (Evidence B)

GINA Guideline 2011

Effectiveness of omalizumab in reducingcorticosteroid burden in patients with moderate to severe persistent allergic asthma

• pooled analysis (N 1,071) of 2 similarly designed, randomized, double-blind, placebo-controlled omalizumab trials and their extension phases

• Pt. aged 12 to 75 years with moderate to severe, persistent, allergic asthma and inadequately controlled with ICSs

J ALLERGY CLIN IMMUNOL AUGUST 2001

Eur Respir J 2001; 18: 254–261

Ann Allergy Asthma Immunol. 2003;91:154–159.

Eur Respir J 2002; 20: 73–78

• Inclusion criteria 1. positive skin prick test result in response to at least 1 perennial allergen (including Dermatophagoides farinae, Dermatophagoides pteronyssinus, cockroach, dog, or cat)2. total serum IgE level of 30 IU/mL through 700 IU/mL3. body weight of 150 kg or less4. 12% or greater increase in forced expiratory volume in 1 second (FEV1) over baseline value within 30 minutes of taking 1 to 2 puffs of albuterol (90 g per puff)5. baseline FEV1 of 40% through 80% of the predicted normal value for the patient6. mean daily total symptom score of 3.0 or higher (range, 0-9) during the 14 days before randomization7. ICS doses equivalent to beclomethasone dipropionate of 420 through 840 g/d (study 1 ) and 500 through 1,200 g/d (study 2 ) for more than 3 months before randomization

Outcome Measures • Corticosteroid burden Median change in ICS from

baseline to the end of steroid – reduction phase and steroid extension phase

Phase Dose of BDP equivalent in Omalizumab group

Dose of BDP equivalent in Placebo group

Steroid stable 669.7 680

Steroid reduction 210.5 338

Extension 263 394

P < 0.001 for each phase

Outcome

• Number of OCS bursts significantly lower for the omalizumab group

Outcome

• Clinical outcome (28 wk core study and 24 wk extension phase)

Adverse events

• Summary • Pt. persistent asthma symptoms at baseline who

received adjunctive omalizumab- able to reduce systemic corticosteroid burden - Maintaining or improving asthma control andlung function- improved clinical outcomes (reduced asthma impairment and a decreased risk of exacerbations)

- Omalizumab effective option for treating moderate to severe persistent allergic asthma, which can minimize the burden of systemic corticosteroids

Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly

controlled (moderate-to-severe) allergic asthma: ETOPA

• randomized, open-label, multicentre, parallel-groupStudy

• 312 pt ( 12 – 75 yr) with poorly control (moderate to severe ) allergic asthma , treat step 3 and 4 of the NHLBI receiving ≥ 400 mcg/day (adolescent) or ≥ 800 mcg/day (adult) inhaled BDP or equivalent were included

• patients were randomized (2 : 1) to receive BSC (best starndard care ) with or without subcutaneous omalizumab for 12 months

Allergy 2004: 59: 701–708

• dose of omalizumab at least 0.016 mg/kg for every IU/ml of total IgE every 4 weeks according to patient body weight and serum total IgE at screening

Allergy 2004: 59: 701–708

• primary efficacy variable : annualized number of asthma deterioration-related incidents (ADRIs) - those treated with omalizumab experienced 4.84 fewer ADRIs per patient-year compared with BSC alone, a reduction of 49.6% [95%CI : 27.8–64.8%]- omalizumab-treated patients remained ADRI-free during the study compared with BSC alone [36.1% vs 20.2% - prolongation of the time to first ADRI with omalizumab vs. BSC (median time to first ADRI of 126 vs 75 days )

Allergy 2004: 59: 701–708

• Secondary efficacy variables annualized mean number of exacerbations- lower with omalizumab than BSC (1.12 and 2.86 per patient-year ; P < 0.001) = a reduction of 60.8% (95% CI: 46.9–71.0%)- omalizumab remained exacerbation-free during the study compared with BSC alone ( 49.5% and 26.4%; P = 0.001)

• median rescue bronchodilator use 0.60 puffs / day for omalizumab vs 3 puffs per/day for BSC (P < 0.001)

• Patients treated with omalizumab showed a significant improvement in morning FEV1 , difference in absolute FEV1 of 0.2 L (2.48 and 2.28 L ; P = 0.02 )

Allergy 2004: 59: 701–708

• In conclusion : therapy with omalizumab, combined with BSC, is well tolerated and offers the potential to improve disease control and symptoms in patients with poorly controlled (moderate-to-severe) allergic asthma

Allergy 2004: 59: 701–708

Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE• 28 weeks in a double-blind, parallel-group, multicentre study

• 419 pt (12–75 yr ) inadequately controlled with high-dose ICS and LABA with reduced lung function were randomized to receive either omalizumab ( 209 pt) vs placebo ( 210 pt )

• Omalizumab dose of at least 0.016 mg/kg per IU/ml of IgE

subcutaneously (based on the patient’s bodyweight and total serum IgE level ) was administered every 2 or 4 weeks

Allergy 2005: 60: 309–316

- In omalizumab treated group ,clinically significant asthma exacerbation (adjustment for baseline exacerbation rate ) was reduced by 26% as compared with placebo (0.68 vs 0.91, P = 0.042)- Severe exacerbation rate (PEF or FEV1 <60% of personal best, requiring treatment with systemic corticosteroids) was halved in the omalizumab group (0.24 vs 0.48, P = 0.002 )

Allergy 2005: 60: 309–316

• Total emergency visits in the treated-group were reduced by 44% ( 0.24 vs 0.43, P = 0.038 )

• Clinically meaningful improvement asthma quality of life questionnaire (AQLQ) ( > 0.5-point from baseline) was observed in the treated-group as compared to placebo (60.8% vs 47.8%, p =0.008)

• Mean morning PEF sinificant greater for omalizumab than placebo ( P= 0.042)

• FEV1 (% predicted) difference = 2.8% ( P=0.0043 )

Allergy 2005: 60: 309–316

Safety and tolerability : similar in Omalizumab and Placebo

Allergy 2005: 60: 309–316

• conclusion, omalizumab significantly - decreased asthma exacerbation rates in these difficult-to-treat pt with severe persistent asthma who were inadequately controlled despite high-dose ICS and concomitant LABA therapy as recommended according to GINA step 4.

- Omalizumab also significantly reduced the severe asthma exacerbation rate and the need foremergency medical interventions

- Patients QoL was improved,

Allergy 2005: 60: 309–316

The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency

medical visits in patients with severe persistent asthma

• pooled data from 7 studies ,omalizumab was added to current asthma therapy and compared with placebo (in five double-blind studies) or with current asthma therapy alone (in two open-label studies)

• included 4308 patients (2511 treated with omalizumab and 1797 were control ), 93% severe persistent asthma

Allergy 2005: 60: 302–308

Study 1 : INNOVATEStudy 2 : ETOPAStudy 3 : SOLARStudy 4,5 : 2 อั�นแรกStudy 6 : Study 7 : ALTO unpublished

• Asthma exacerbations

Allergy 2005: 60: 302–308

←←←

Reduced asthma exacerbation 38% in omalizumab group

• Emergency visits

Allergy 2005: 60: 302–308

Reduced ER visit 47 % in omalizumab group

Allergy 2005: 60: 302–308

Improvement with omalizumab was seen regardless of age, sex, baseline FEV1, baseline serum IgE, dosind schedule

• Conclusion :Omalizumab should be considered asadd-on treatment for patients with severe persistent asthma who continue to suffer with inadequately controlled asthma despite best available therapy.

Allergy 2005: 60: 302–308

Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma• International, multicenter randomized,

double-blind, placebo-controlled trial

• Children age 6 to <12 years with moderate to severe allergic asthma

• BW 20 -150 kg , SPT + at least 1 perrennial allergen, serum total Ig E 30 -1300 IU/ml

Bob Lanier (J Allergy Clin Immunol 2009;124:1210-6.)

• 1 week of screening phase• 8 week of run-in phase ( adjust ICS dose to

optimized asthma control for first 4 wk )• Pt. were randomized to receive omalizumab or

placebo

• In study group Omalizumab 75 -300 mg 1-2 time q month ( every 2-4 wk )

• Double-blind treatment period - 24-week fixed-steroid phase (constant ICS dose unless adjustment was required for an exacerbation) - 28-week adjustable-steroid phaseBob Lanier (J Allergy Clin Immunol

2009;124:1210-6.)

Primary efficacy end point : rate of clinically significant asthma exacerbation over 24 wk period

Secondary efficacy end point : rate of clinically significant asthma exacerbation over 52 wk period

• Rate of clinically severe exacerbations reduced 44% over a period of 24 weeks (0.10 vs 0.18; RR [95% CI], 0.55 [0.32-0.95]; P=0.031)

• Sustained over a period of 52 weeks (rate, 0.12 vs 0.24) 50% reduction (RR [95% CI], 0.49 [0.30-0.80]; P 0.004)

• Investigator and patient global evaluation of treatment effectiveness (GETE) at 52 weeks favored omalizumab with rate of excellent or good by 79 % and 80% ( physicial and patient respectively )by 56% and 72% respectively in placebo group ( both P < 0.001 )

• Other secondary end point - nocturnal asthma symptom - daily puff of rescue medication - QoL

• Safety

Numerically greater change in omalizumab group but no statistically significant

At least 1 AE; mild or moderate in severity. no statistically significant of AEs in the omalizumab group compared with placebo

Clinical implications: Many children with moderate-to-severeallergic (IgE-mediated) asthma remain inadequately controlleddespite treatment with ICSs. Add-on omalizumab reduces exacerbations in this population and may provide an additional therapeutic option

Randomized Trial of Omalizumab (Anti-IgE)for Asthma in Inner-City Children• randomized, double-blind, placebo-controlled,

parallel-group trial at multiple centers

• 419 inner-city children, adolescents, and young adults (6 to 20 years of age) with persistent allergic asthma

• at least 1 + SPT to perennial allergen, BW 20 – 150 kg, tatol serum IgE 30-1300 IU/mL

William W. Busse, N ENGL J MED 364;11

4 wk run - in Wk 0 Randomized

Omalizumab vs placebo sc injection Omalizumab 75-375 mg every 2-4 wk

Wk 60 Wk 36

Additional visit for evalute and management of care every 3 mo- Adjusted Rx based on symptom that occured during previous 2 wk-adherence to the study regimen- other asthma treatments- FEV1

Wk 12 wash -in

• Allergen skin testing of a panel of 14 extracts: mouse and rat epithelia, dog epithelium, dust mites (Der f and Der p), cat hair, an American–German cockroach mix, German cockroach, molds (Penicillium notatum, aspergillus species, Alternaria tenuis, and Cladosporium herbarum),timothy grass, and a ragweed mix (Greer Laboratories)

• Total serum levels of IgE and allergen-specific IgE levels for dust mites, German cockroach, and A. tenuis were measured

• Dust from the participant’s bed and bedroom floor was collected with validated self-collection procedure and assayed for dust mite (Der p 1 and Der f 1), German cockroach (Bla g 1), cat (Fel d 1), dog (Can f 1), and mouse (Mus m 1) William W. Busse, N ENGL J MED 364;11

• Nasal-secretion samples collected at 4/8 research sites at week 48 and within 7 days after the onset of an asthma exacerbation. Total RNA was extracted and analyzed (PCR)

Primary outcome : days with symptom (No./2wk )

Reduced 24.5%

Primary outcome : Exacerbation (%)

Primary outcome : Lower dose of ICS

Other outcome

←←

• omalizumab’s benefit was greatest in participants who were both sensitized and exposed to cockroach allergen and in those sensitized to dust mites, two major relevant indoor allergens - reduced day of symptom per 2 week interval 48.5% - reduced dose of ICS 32.9% - reduced asthma exacerbation 38.4% , OR 3.7

Subgroup analysis

post hoc analysis of Omalizumab on Seasonal Exacerbations

nearly doubled in the placebo group during the fall and spring as compared with summer(9.0% and 8.1%, respectively, vs. 4.6%; P<0.001).

seasonal spike exacerbations was not observed in the omalizumab group (4.3% in fall and 4.2% in spring vs. 3.3% in summer), and the difference between the placebo and omalizumab groups was significant (P<0.001 )

daily dose of ICS varied little during the year in the omalizumab group whereas in the placebo group, dose adjustmentswere required to achieve asthma control

post hoc analysis of Omalizumab on Seasonal Exacerbations

Safety One or more adverse events were reported in 47.4% of participants in the placebo group and 39.4% of those inthe omalizumab group (P = 0.06)

- Omalizumab group had significantly more GI disorders but significantly fewer hematologic disorders compared with placebo gr. - Seven participants had anaphylaxis: 6 in placebo gr. and 1 in omalizumab gr.

• In summary omalizumab reduces symptomsand exacerbations in children, adolescents, andyoung adults with persistent allergic asthma,providing protection beyond that conferred withguidelines-directed care. Our findings may alsohelp identify those patients most likely to have aresponse to omalizumab and provide insightinto novel mechanisms of asthma exacerbationsthat could lead to improved treatment

Randomized Trial of Omalizumab (Anti-IgE)for Asthma in Inner-City Children

Omalizumab and AR

Effect of Omalizumab on Symptomsof Seasonal Allergic RhinitisA Randomized Controlled Trial• Randomized, double-blind, dose-ranging, placebo-

controlled trial ,25 OPD center in USA

• 536 patients (12 to 75 years) with at least a 2-year Hx of moderate to severe ragweed-induced seasonal allergic rhinitis and a baseline IgE level between 30 and 700 IU/mL.

• randomly assigned to receive omalizumab, 50 m, 150 mg, 300 mg or placebo sc 2 wk prior to ragweed season and repeated during the pollen season every 3-4 wk

JAMA, December 19, 2001—Vol 286, No. 23

Rhinitis-specific quality of life scores were consistently better in pt. who received 300 mg of omalizumabthan in those who received lower dosages or placebo and did not decline during peak season

Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR

• aim : to evaluate the efficacy and safety of omalizumab in patients with moderate-to-severe asthma and persistent AR

• multicentre, randomized, double-blind, parallel-group, placebo controlled trial

• 405 patients (12–74 years) with a stable asthma treatment

• Omalizumab (≥ 0.016 mg/kg/IgE [IU/ml] per 4 weeks) or placebo for 28 weeks Allergy 2004: 59: 709–717

• patients treated with omalizumab fewer experienced asthma exacerbations (20.6% vs 30.1%, P = 0.02 )

• Clinically significant (≥ 1.0 point) improvement in AQLQ and RQLQ occurred in 57.7% of omalizumab pt vs 40.6% placebo pt . (P < 0.001)

Allergy 2004: 59: 709–717

Change from baseline in total asthma symptom score

P < 0.05

Change from baseline in total rhinitis symptom score

P< 0.001 Change from baseline in total combined symptom score

P< 0.001

Allergy 2004: 59: 709–717

In conclusion, this study of patients with concomitant asthma and PAR found that omalizumab is significantly more efficacious than placebo in preventing asthma exacerbations and in improving disease-related QoL when added to standard asthma and rhinitis therapies.

Omalizumab and IT

Omalizumab pretreatment decreases acutereactions after rush immunotherapy forragweed-induced seasonal allergic rhinitis

• randomized, double-blind, placebo-controlled study

• 159 pt. were randomized to the 4 treatment arms

• Pretreatment with omalizumab vs placebo

• One-day RIT completed at least 3 weeks before the start of ragweed season

• After RIT, pt. had 12 weekly visits to receive IT and omalizumab injections (weeks 0-12) ,3 additional follow-up visits (weeks 13, 19, and 31)

(J Allergy Clin Immunol 2006;117:134-40.)

• primary efficacy endpoint : comparison of the average daily allergy severity scores between Pt. receiving omalizumab + IT vs IT alone

statistically significant improvement in severity scoresfor patients treated with omalizumab and IT vs IT alone (P = 0.02)

Casale et al JACI 2006;117:134-40

intent-to-treat basis, the benefit of omalizumab + IT was significantImprove in severity scores 0.69 vs 0.86 (P < 0 .044).

• secondary endpoint : comparison of the incidence of AE (examine of omalizumab on the safety of IT)

Omalizumab + immunotherapy vs immunotherapy only demonstrated that the addition of omalizumabresulted in a significant, 5-fold decrease in risk ofanaphylaxis caused by RIT (OR, 0.17; P = 0.026 )

• Summary : - Omalizumab pretreatment enhances the safety of RIT for ragweed allergic rhinitis- combined therapy (omalizumab + IT): effective strategy to permit more rapid and higher doses of allergen IT : given more safely and greater efficacy to patients with allergic diseases

• Randomized, double-blind, parallel-group, 26 wk study

• 275 adult pt. with at least moderate persistent allergic asthma inadequately controlled with ICS

• SPT positive to at least 1 of 3 perennial aeroallergens• Specific immunotherapy (SIT) began after 12 wk of

omalizumab or placebo• Antihistamine could also be administered prior to

each SIT dose • Systemic allegic reaction were evaluated

J Allergy Clin Immunol 2010;125:383-9

3 wk overlap omalizumab/placebo +SIT

SIT to HDM and cat 4 wk, 18 injection cluster regimen

followed by 7 wk of weekly maintenance therapy

RandomizedN=275

Efficacy population n=248

• primary efficacy variable was a SAR within 1 hr after injection of SIT

• SAR within 1st hr occurred in 49 pt. (19.8%)

• 32 (26.2%) in placebo gr. vs 17 (13.5%) in omalizumab gr , the difference was significant (P < 0.006)

less proportion of pt. who had their 1st SAR after injection in omalizumab group than placebo

Day 98 Placebo = 13 pt

Omalizumab =3 pt

Secondary efficacy variables

1. Severity of the first SAR to SIT

P = 0.192

2. Decreased in propotion of pt. receiving recue medication during SIT

Treatment with omalizumab decreased the proportion ofpatients receiving at least 1 rescue medication during SIT(10.3% for omalizumab vs 24.6% for placebo).

3. More pt. achieved target maintenance SIT dose in the omalizumab treatment group

Placebo Omalizumab 0.00%

10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%

100.00%87.3%

72.1%,

Post hoc : subgroup analysis was conducted to determinewhether antihistamine pretreatment to SIT affected the rate of SARs

Placebo Omalizumab0.00%

10.00%

15.00%

20.00%

25.00%

30.00% Antihistamine pre RxNonantihistamine preRx

Loacal reaction Omalizumab = 53.2%Placebo :49.2% P = 0.52

0.8Total Asthma Symptom

Score (mean)

Asthma symptom score

placebo

No. of puff of rescue beta agonist

Daily puffs of rescue beta agonist(mean)0.72

Post hoc : Lower total asthma symptom scores and lower daily puffs of rescue beta agonist – 1 week prior to cluster SIT

Score > 0 Score = 0

10.00%

15.00%

20.00%

25.00%

30.00%

placebo Omalizumab

No. of puff > 0

No. of puff

25%23%

Total asthma symptom score (mean)

Daily puffs of rescue β agonist(mean )

Post hoc: Level of asthma control on the rate of respiratory (grade 3) SAR

• In summary : omalizumab pre treatment + SIT - Improved asthma symptom- Reduced recue use of β- agonist- Significant reducing the proportion of pt. who experienced SAR to SIT- Enable more pt. to achieve the target maintenance dose of immunotherapy.

Omalizumab and urticaria

• evaluate the efficacy and safety of omalizumab in patients with CIU who remain symptomatic despite H1-antihistamine therapy

• phase II, prospective, double-blind, placebo controlled, dose-ranging study investigated omalizumab in - pt. 12 to 75 years in USA- pt. 18 to 75 years in Germany

(UAS over 7 days (UAS7) of 12 or greater despite antihistamine Rx)

• randomized to receive a single SC dose of 75, 300, or 600 mg of omalizumab or placebo added to a stable dose of H1-antihistamine

90 patients

• 300 mg omalizumab group (-19.9 vs- 6.9, P < .001) 600-mg omalizumab group (- 14.6 vs - 6.9, P < 0.047) greater improvement versus the placebo in UAS

• Summary : fixed dose of 300 or 600 mg of omalizumab provides rapid and effective treatment of CIU in patients who are symptomatic despite treatment with H1-antihistamines

Indication for omalizumab in asthma

• FDA approved omalizumab (Xolair ) - adults and adolescents ( ≥ 12 years ) - moderate to severe persistent asthma - test positive for reactivity to a perennial aero allergen- whose symptoms are inadequately controlled with inhaled corticosteroids

http://www.xolairhcp.com/xolairhcp/dosing-and-administration.html

The 2007 NHLBI Guidelines state that signs of lack of control• >2 exacerbations per year requiring oral corticosteroid

bursts• Symptoms >2 days per week• Reliever medication required >2 days per week• Nighttime awakenings 1 to 3 times per week• FEV1 or peak flow at 60% to 80% predicted/personal best• Limited participation in normal activities• Needing urgent medical care, including hospitalization

http://www.xolairhcp.com/xolairhcp/dosing-and-administration.html

Recommendation by TAC

• การให้�ยา Omalizumzb (Anti-IgE) ผู้�ป่�วยต้�องมี�เกณฑ์�ทุ�กข้�อดั�งนี้��• 1. ต้�อังอัยู่��ในการดู�แลขอังแพทยู่�ผู้��เชี่��ยู่วชี่าญดู�านโรคปอัดูและภู�มิ"แพ�• 2. ผู้��ป#วยู่ต้�อังใชี่�ยู่าต้ามิแพทยู่�สั่��งไดู�ถู�กต้�อังสั่มิ'�าเสั่มิอั• 3. ต้�อังมิ�การสั่(บค�นว�าผู้��ป#วยู่ไมิ�มิ�ภูาวะ/โรคอัยู่�างอั(�นท��เป*นสั่าเหต้,

ท'าให�ควบค,มิ โรคห(ดูไมิ�ไดู�และหล�กเล��ยู่งสั่"�งกระต้,�น• 4. มิ�ระดู�บ Total lgE อัยู่��ระหว�าง 75-1,300 IU/mL • 5. มิ�การต้รวจสั่ารก�อัภู�มิ"แพ� ดู�วยู่การต้รวจสั่อับ skin prick test หร(อั

specific IgE ต้�อัสั่ารก�อัภู�มิ"แพ�ในอัากาศ (aero-allergen) ให�ผู้ล บวก• 6. ไดู�ร�บการร�กษาโรคห(ดูต้ามิ ระดู�บท�� 4 มิาเป*นเวลาอัยู่�างน�อัยู่ 6

เดู(อันแล�ว ยู่�งค,มิอัาการ (Uncontrolled ต้ามิ GINA) ร�วมิก�บประเมิ"นPEFvariability > 20%*

Recommendation by TAC

• 7. มิ�อัาการก'าเร"บขอัง (Exacerbation) อัยู่�าง ร,นแรงโดูยู่ต้�อังไดู� systemic corticosteroids มิากกว�าหร(อัเท�าก�บ 2 คร�0งในชี่�วง 1 ป1ท�� ผู้�านมิา

หร(อัมิ�ประว�ต้"การใชี่�สั่เต้�ยู่รอัยู่ดู�ชี่น"ดูร�บประทาน(Prednisolone) มิากกว�าหร(อัเท�าก�บ 10 มิ"ลล"กร�มิ

ต้�อัว�นต้"ดูต้�อัก�นนานเก"นกว�า 30 ว�น

GINA ( ≥ 5 years) and TAC

- Pt. age > 6 yr. with moderate to severe asthma with uncontrolled by GINA step 4 - Sensitization to aeroallergen - High Ig E level

Recommended dose• Dosing base on body weight and total serum IgE

• Recommended dose 0.016 mg/kg//IU of IgE /4 wk, administered SC every 2-4 wk interval (150 to 375 mg)

• 150 mg lyophilized powder+sterile water = 5 ml/vial

After recommended dose serum free IgE declines rapidly and reach < 50 ng/ml

Omalizumab 150 mg >> 18100 บาทุ

Asian Pac J Allergy Immunol 2011;29:209-19

Slowly absorb peak level 7-8 daysHalf-life 26 days

Predicting response to omalizumab

• patients who had a response to omalizumab- ratio of observed to expected forced expiratory volume in one second (FEV1) < 65 %- taking doses of inhaled corticosteroids equivalent to more than 800 μg of beclomethasone dipropionate per day- at least one visit to the emergency department in thepast year

• Patients requiring daily oral corticosteroids to control their asthma less likely to have a response to omalizumab

Chest 2004;125;1378-1386

• การป่ระเมี�นี้ผู้�ป่�วยห้ลั�งไดั�ร�บยา Omalizamab

ห้ลั�งไดั�ร�บยา Omalizamab เป่"นี้เวลัา 16 อาทุ�ต้ย�แล�วประเมิ"นผู้��ป#วยู่ อย#ในี้ระดั�บ controlled ต้ามิGINA ยู่กเว�น ผู้ลการต้รวจสั่มิรรถูภูาพปอัดู ร�วมิ

ก�บมิ�ค�า PEF variability < 15% ให�ยู่าต้�อั จนี้ครบ 6 เดั&อนี้ แลั�วให้�ห้ย�ดัยา แต้�ถู�าประเมิ"นผู้��ป#วยู่หล�งไดู�

เป*นเวลา 16 อัาท"ต้ยู่� ไมิ�อัยู่��ในระดู�บ controlled ให� หยู่,ดูยู่าไมิ�ให�ยู่าต้�อั ในกรณี�ท��หยู่,ดูยู่า หล�งท�� ให�ยู่าค

รบ 6 เดู(อันแล�วผู้��ป#วยู่มิ�อัาการก'าเร"บ พ"จารณีาให� ยู่าใหมิ�ต้ามิข�อั บ�งชี่�0ข�างต้�น

Side effect of omalizumab • most common adverse

reactions (>1% more frequent in XOLAIR-treated patients) - arthralgia (8%)- pain (general) (7%)- leg pain (4%)- fatigue (3%)- dizziness (3%)- fracture (2%)- arm pain (2%)- pruritus (2%)- dermatitis (2%)- earache (2%)

• adverse events needed clinical intervention - injection site reaction (45%)- viral infections (23%)- URI (20%)- sinusitis (16%)- headache (15%)- pharyngitis (11%)

(Omalizumab = control)

Omalizumab safety

• In 2007 Omalizumab Joint Task Force (OJTF)report anaphlaxis rate 0.1% of 39,510 pt. (incidence approximately 0.2% )

• five-step recommendations 1.obtaining informed consent2.delivery of anaphylaxis education3.availability epinephrine autoinjector4. pre-injection health assessment 5. waiting period of 30 minutes after each injection (with an extended waiting period after the first 3 injections to 2 hours) J Allergy Clin Immunol

2007;120:1373-7

Anaphylaxis to omalizumab

• It lacks complement fixing activity• the molecule is so extensively humanized that

antibodies to the remaining mouse epitopes are unlikely but merit further study

• Polysorbate, an additive used to promote the rapid solubilization of pharmaceuticals in aqueous solutions, has been reported to cause hypersensitivity reactions

• Possible mechanisms - antiallotypic or anti-idiotypic antibodies (IgE or IgG) against this reagent that were either pre-existing before drug administration or had developed after initial exposures or a response to the aggregated preparations of omalizumab

• Another possible mechanism is that an unrelated event happened to occur near the time of omalizumab administration (eg, accidental food allergen ingestion

• Previous pooled data (2003) malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%) warranting further investigation

• This pooled analysis primary assessed the incidence of primary malignancy in 32 randomized, doubleblind, placebo-controlled (RDBPC) trials

• 11,459 unique patients in all clinical trials • The primary analysis identified malignancies in 25 patients

(RDBPC trials): - 14 in 4,254 omalizumab-treated patients - 11 in 3,178 placebo-treated patients

J Allergy Clin Immunol 2012;129:983-9.)

• Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 and 4.45, respectively

• no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials

• The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely

J Allergy Clin Immunol 2012;129:983-9.)

Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS)• observational study • 5000 Xolair treated patients and 2500 non-Xolair

treated patients(control group)• primary objective

- to assess the long-term safety profile of Xolair in patients followed for 5 years

• Interim data may suggest a risk of cardiovascular and cerebrovascular adverse event

• EXCELS study is ongoing and final results are not expected until 2013Early Communication about an Ongoing Safety Review of Omalizumab ,FDA , 7/16/2009

IgE level mornitoring

• Monitoring of total serum IgE levels during the course of therapy with omalizumab is not indicated,(these levels will be elevated as a result of the presence of circulating IgE–anti-IgE complexes)

Nat Biotechnol 2000; 18:157-62.

Omalizumab mechanism of action • Decreased free serum IgE• Decreased expression of FcεRI (on mast cell, basophil,

dendritic cell, and monocyte)• Decreased FeNO• Decreased eosinophil (serum, sputum, bronchial

biopsy)• Decreased circulating IL 13• Decreased B lymphocyte• Decreased Ag-induced mediator release from basophil

and mast cells• Decreased airway inflamation

Omalizumab effects on asthma• Decreased exacerbation• Decreased ICS dose• Decreased asthma symptoms• Decreased recue medication use • Increased quality of life• Deceased ER visit• Decreased hospitalization• Improved pulmonary function (small effect)

Omalizumab on AR

• Decreased daily symptom• Decreased recue medication usage• Improved quality of life• Decreased nasal allergen challenge response• Decreased missed school and work days

Thank you

Pharmacoeconomis

• Cost-effectiveness• QALY = Quality Adjusted Life Year• Best day in your life = 100• What is your score today?• If your score today = 80• And this condition continues for 5 years• So you lost 1 QALY

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