Anti Immunoglobulin E Therapy

Anti – Immunoglobulin E Therapy

Suda Sibunruang, M.D.

Outline

Immunoglobulin E (IgE) & IgE receptors

Anti – IgE monoclonal Ab (Omalizumab)

• Mechanism of action

• Clinical benefits

• Dosing and administration

• Safety • Issues in clinical use

Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition

Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80 Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition

IgE levels in cord blood are low (<2 kIU/L; < 4.8 mg/L), gradually increase throughout childhood with a peak

at 10 – 15 yrs of age, and then decrease throughout adulthood

From www.hindawi.com, access July 2015

Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition

Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80 Oettgen H. Middleton’s Allergy Principle and Practice. 8th edition, 2014

• Large amount of FcεRI on cell surfaces: - mast cells, basophils • Other cell types: - antigen presenting cells

IgE control level of FcεRI expression - FcεRI not occupied by IgE has a half-life on mast cell surface of 24 hrs in vitro, whereas receptors bound to IgE appear to be expressed for life of cell - Density of human basophil FcεRI expression correlates directly with serum IgE levels, where binding of IgE stabilizes receptor at cell surface

Picture A. from www.frontiersin.org Vichyanond P. Asian Pac J Allergy Immunol 2011;29:209-19

http://www.frontiersin.org/

Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80 Oettgen H. Middleton’s Allergy Principle and Practice. 8th edition, 2014

- Ca-dependent lectin - Consists of a large extracellular domain with lectin head that binds IgE - Like FcεRI receptor, expression of CD23 is upregulated by IgE and IL-4 - CD23 can be shed from membrane into a soluble form, sCD23, by endogenous proteases (a disintegrin and metallopeptidase 10-ADAM10) and exogenous proteases, including dust mite major allergen Der p 1

Oettgen H. Middleton’s Allergy Principle and Practice. 8th edition, 2014

Boyman O., et al. Allergy 2015;70:727–54

Omalizumab

• Humanized, anti-IgE monoclonal antibody • Composed of 5% murine sequences that were engrafted onto a human IgG1κ framework

5% mouse

• Binds to heavy-chain constant CH3 domain of IgE molecule • Same site by which IgE binds to FcεRI

Holgate ST. Q J Med 2004;97:247- 57 Stokes JR. and Casale TB. Middleton’s Allergy 8th edition, 2014, 1480-90

Price D. Primary Care Respiratory Journal 2008;17: 62-72 Stokes JR. and Casale TB. Middleton’s Allergy 8th edition, 2014, 1480-90

Omalizumab - IgE complexes

Soluble, inert immune complexes that are subsequently cleared from circulation via interactions with FcγRs of hepatic sinusoidal

endothelial cells of reticuloendothelial system (half-life 26 days)

Picture from www.what-when-how.com, access July 6, 2015 Owen CE. Pharmacology & Therapeutics 2007;113:121–33

Price D. Primary Care Respiratory Journal 2008;17: 62-72

As IgE upregulates IgE receptors on mast cells, reduction in amount of free IgE in circulation also results in a decrease

in number of IgE receptors on surface of mast cells

Holgate ST. and Polosa R. Nature Reviews Immunology 2008;8:218-30

Holgate S., et. al. J Allergy Clin Immunol 2005;115:459-65

Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36

Owen CE. Pharmacology & Therapeutics 2007;113:121–33 Stokes JR. and Casale TB. Middleton’s Allergy 8th edition, 2014, 1480-90

- 99% reduction in free serum IgE levels has occurred within 2 hrs after omalizumab administration - Omalizumab administration reduces allergen-induced nasal challenge responses and expression of FcεRI on basophils within 7 days - Within 3 months, human basophil responsiveness (i.e., histamine releasability) was reduced by 90%

Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80

Total IgE levels generally increase by up to 5-fold after omalizumab treatment because of increased stability of omalizumab-IgE complexes,

whereas free IgE levels decrease by up to 95%. There is great variability in accuracy of different systems for total IgE measurements in presence of omalizumab

Clinical benefits

Picture from www.xolair.com, access July 2015

Allergic asthma

Effect on airway inflammation

Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 Djukanovic R, et. al. Am J Respir Crit Care Med 2004;170:583-93

Bronchial biopsy specimens obtained from patients with mild steroid-naive asthma and who received omalizumab show a marked decrease in inflammatory cells (eosinophils, IgE+cells, FceRI+ cells, IL-4-secreting cells, and CD3+ T lymphocytes) within epithelium and submucosa Indicate additional modulatory effects of omalizumab

Effect on remodelling

Hoshino M, et. al. Respiration 2012;83:520-8

Effects of Adding Omalizumab, an Anti-Immunoglobulin E Antibody, on Airway Wall Thickening in Asthma

Obj: To assess effects on airway wall thickness using CT Methods: 30 severe persistent asthma pt were randomized to conventional therapy with (n = 14) or without omalizumab (n = 16) for 16 wks Airway dimensions were assessed at right apical segmental bronchus by CT: - airway wall area corrected for BSA (WA/BSA) - percentage wall area (WA%) - wall thickness (T)/ BSA - luminal area (Ai)/BSA % of eosinophils in induced sputum Pulmonary function Asthma Quality of Life Questionnaire (AQLQ) Results: Significantly decreased WA/BSA, WA%, T/ BSA and increased Ai/BSA, whereas conventional therapy resulted in no change -Decrease % of sputum eosinophils -Improved FEV 1 -Improved AQLQ score

Hoshino M, et. al. Respiration 2012;83:520-8

Effects of Adding Omalizumab, an Anti-Immunoglobulin E Antibody, on Airway Wall Thickening in Asthma

Obj: To assess effects on airway wall thickness using CT Methods: 30 severe persistent asthma pt were randomized to conventional therapy with (n = 14) or without omalizumab (n = 16) for 16 wks Airway dimensions were assessed at right apical segmental bronchus by CT: - airway wall area corrected for BSA (WA/BSA) - percentage wall area (WA%) - wall thickness (T)/ BSA - luminal area (Ai)/BSA % of eosinophils in induced sputum Pulmonary function Asthma Quality of Life Questionnaire (AQLQ) Results: Significantly decreased WA/BSA, WA%, T/ BSA and increased Ai/BSA, whereas conventional therapy resulted in no change -Decrease % of sputum eosinophils -Improved FEV 1 -Improved AQLQ score

Omalizumab reduced airway wall thickness and airway inflammation

Allergic asthma

Clinical efficacy of omalizumab in patients with moderate to-severe and severe allergic asthma

has been well documented in several large-scale clinical trials that involved adults, adolescents,

and children


Humbert M., et. al. Allergy 2005:60:309–16

Double-blind, parallel-group, multicentre study Obj: Determined effect of omalizumab on clinically significant asthma exacerbations (requiring systemic corticosteroids) Participants: Patients (12-75 yrs) with severe persistent asthma who are inadequately controlled despite Global Initiative for Asthma (GINA) 2002 step 4 therapy (high-dose ICS and LABA)

Method: randomized to receive omalizumab or placebo for 28 wks Omalizumab significantly improved asthma-related quality of life, morning PEF and asthma symptom scores

Humbert M., et. al. Allergy 2005:60:309–16

Double-blind, parallel-group, multicentre study Obj: Determined effect of omalizumab on clinically significant asthma exacerbations (requiring systemic corticosteroids) Participants: Patients (12-75 yrs) with severe persistent asthma who are inadequately controlled despite Global Initiative for Asthma (GINA) 2002 step 4 therapy (high-dose ICS and LABA)

Method: randomized to receive omalizumab or placebo for 28 wks Omalizumab significantly improved asthma-related quality of life, morning PEF and asthma symptom scores

Omalizumab significantly reduced rate of clinically significant asthma exacerbations, severe exacerbations and emergency visits

Bousquet J., et. al. Allergy 2005:60;302–8 Price D. Primary Care Respiratory Journal 2008;17: 62-72

Pooled data from 7 studies to examine effect of omalizumab on exacerbations n = 4,308 (2,511 treated with omalizumab), 93% severe persistent asthma Omalizumab was added to current asthma therapy, duration 24 – 52 wks - compared with placebo (5 double-blind studies) or - with current asthma therapy alone (2 open-label studies)


Hanania NA, et. al. Ann Intern Med 2011;154:573-82

(EXTRA) Prospective, multicenter, randomized, double-blind, placebo-controlled trial 193 sites in USA and 4 sites in Canada Obj: To evaluate efficacy and safety of omalizumab in (850) patients (12-75 yrs) with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy Duration: 48 wks Primary end point: Rate of protocol defined exacerbations Results: Rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (25% reduction), increase time to first asthma exacerbation, improved mean AQLQ(S) scores, reduced mean daily albuterol puffs, decreased mean asthma symptom score. Incidence of adverse events were similar.

Protocol-defined asthma exacerbation was worsening asthma symptoms requiring treatment with systemic corticosteroids for 3 or more days; for patients receiving long-term OCS, an exacerbation was a 20-mg or more increase in average daily dose of oral prednisone

Hanania NA, et. al. Ann Intern Med 2011;154:573-82

(EXTRA) Prospective, multicenter, randomized, double-blind, placebo-controlled trial 193 sites in USA and 4 sites in Canada Obj: To evaluate efficacy and safety of omalizumab in (850) patients (12-75 yrs) with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy Duration: 48 wks Primary end point: Rate of protocol defined exacerbations Results: Rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (25% reduction), increase time to first asthma exacerbation, improved mean AQLQ(S) scores, reduced mean daily albuterol puffs, decreased mean asthma symptom score. Incidence of adverse events were similar.

Protocol-defined asthma exacerbation was worsening asthma symptoms requiring treatment with systemic corticosteroids for 3 or more days; for patients receiving long-term OCS, an exacerbation was a 20-mg or more increase in average daily dose of oral prednisone

Omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and

LABA therapy

Holgate ST, et. al. Clin Exp Allergy 2004;34:632-8

Randomized, double-blind, placebo-controlled trial Obj: Evaluated ability of omalizumab to improve disease control sufficiently to enable ICS reduction in patients with severe allergic asthma Omalizumab improved asthma symptoms and asthma related QoL , and reduced rescue medication requirements compared to placebo

Holgate ST, et. al. Clin Exp Allergy 2004;34:632-8

Randomized, double-blind, placebo-controlled trial Obj: Evaluated ability of omalizumab to improve disease control sufficiently to enable ICS reduction in patients with severe allergic asthma Omalizumab improved asthma symptoms and asthma related QoL , and reduced rescue medication requirements compared to placebo

Omalizumab improves asthma control in severe allergic asthma, reducing ICS requirements without

worsening of symptom control or increase in rescue medication use

Vignola AM, et. al. Allergy 2004;59:709-17

Multicentre, randomized, double-blind, placebo controlled trial Obj: To evaluate efficacy and safety in patients with concomitant moderate-to-severe asthma and persistent allergic rhinitis Method: 405 pts (12–74 yrs) with a stable treatment (400 µg budesonide Turbuhaler) and 2 unscheduled medical visits for asthma during past year or 3 during past 2 years were enrolled to receive omalizumab or placebo for 28 wks Fewer patients experienced asthma exacerbations (20.6%) than placebo-treated patients (30.1%) Clinically significant ( 1.0 point) improvement in both Asthma Quality of Life Questionnaire and Rhinitis Quality of Life Questionnaire occurred in 57.7% of omalizumab compared with 40.6% of placebo Serious adverse events were observed in 1.4% of Omalizumab and 1.5% of placebo

Tsabouri S. et. al. J Allergy Clin Immunol Pract 2014;2:332-40

Obj: To assess efficacy and safety in poorly controlled AR 11 studies (1997-2010) of 2870 patients were finally included Result: Significant reduction in daily nasal symptom severity score, daily nasal rescue medication score and improvement QoL

Efficacy of omalizumab in reducing DNSSS

Braunstahl GJ, et. al. Respir Med 2013;107:1141-51

The eXpeRience registry: The ‘real-world’ effectiveness of omalizumab in allergic asthma

2-year, single-arm, open-label, observational 943 pts with uncontrolled persistent allergic asthma Evaluate effectiveness variables (physician’s Global Evaluation of Treatment Effectiveness [GETE], change from baseline in exacerbation rate, symptoms, rescue medication use, and oral corticosteroid [OCS] use

69.9% responded after 16 (±1) wks Proportion of patients with no clinically significant exacerbations increased Symptoms and rescue medication use at Month 24 were reduced by >50% from baseline. Maintenance OCS use was lower at Month 24 (14.2%) compared with Month 12 (16.1%) and baseline (28.6%) Acceptable safety profile GETE: overall clinical evaluation of asthma control at 16 weeks, based on all available information: patient interview and physical examination, and review of patient notes and diary

Poachanukoon O.,et. al. J Allergy Clin Immunol 2014;AB2 abstract

METHODS: Multi-center, observational study in severe allergic asthma patients RESULTS: 61 patients were reviewed - ACT score increased from 13.8 baseline to 16.4 at Wk 16 (p=0.201) and increased to 20.6 at Wk 52 (p=0.005) - Proportion of patients with controlled asthma (ACT score >20) increased from 17% baseline to 52.8% and 72.2% at Wk 16 and 52 - Mean annualized rate of asthma exacerbations was reduced - Mean hospitalization rate was reduced - Reduction in ER visits - Mean daily dose of ICS equivalent to fluticasone was reduced slightly - 78.7% patients continued omalizumab for at least 1 year - Of the 9 patients who discontinued omalizumab, 55.5% had relapse within 3 months and needed to restart treatment

Remark

• Limited data are available on efficacy of omalizumab for active smokers and for exsmokers with substantial pack-year histories because these patients often are excluded from clinical trials

• But it is suggested that efficacy is likely to be similar to that in nonsmokers


Global Initiative for Asthma (GINA), 2015 update

Indication in the United States

• Approved in 2003 for treatment of patients

12 yrs with moderate-to severe persistent

allergic asthma despite treatment with ICS


Indication in the European Union

Approved in 2005 as add-on therapy in patients >12 years with severe persistent allergic asthma: • Positive skin test or serum IgE to a perennial

aeroallergen • Reduced lung function (FEV1 <80%) • Frequent daytime symptoms or night-time

awakenings • Multiple documented severe asthma

exacerbations (PEF/FEV1 <60% of patients’ maximum recorded)

despite receiving daily high-dose ICS plus a LABA


‘Multiple severe asthma exacerbations’ is defined as either two or more severe exacerbations of asthma requiring hospital admission within the previous year, or three or more severe exacerbations of asthma within the previous year, at least one of which required admission to hospital

Holgate S., et. al. Respiratory Medicine 2009;103:1098-113

แนวทางการใหยา Omalizumab (asthma) ผปวยตองมเกณฑทกขอดงน • ตองอยในการดแลของแพทยผเชยวชาญดานโรคปอดและภมแพ • ผปวยตองใชยาตามแพทยสงไดถกตองสม าเสมอ • ตองมการสบคนวาผปวยไมมภาวะ/โรคอยางอนทเปนสาเหตท าให ควบคม โรคหดไมได

และหลกเลยงสงกระตน • มระดบ Total lgE 75-1,300 IU/mL • มการตรวจสารกอภมแพ ดวยการตรวจสอบ skin prick test หรอ specific IgE ตอ

สารกอภมแพในอากาศ (aero-allergen) ใหผล บวก • ไดรบการรกษาโรคหดตาม ระดบท 4 มาเปนเวลาอยางนอย 6 เดอนแลว ยงคมอาการ

(Uncontrolled ตาม GINA) รวมกบประเมน PEF variability > 20% • มอาการก าเรบของ (Exacerbation) อยางรนแรงโดยตองได systemic

corticosteroids มากกวาหรอเทากบ 2 ครงในชวง 1 ปท ผานมา หรอมประวตการใชสเตยรอยดชนดรบประทาน (Prednisolone) มากกวาหรอเทากบ 10 มลลกรมตอวนตดตอกนนานเกนกวา 30 วน

แนวทางการวนจฉยและรกษาโรคหด ในประเทศไทย V.5 ส าหรบผใหญและเดก พ.ศ. 2555/ สมาคมสภาองคกรโรคหดแหงประเทศไทย

การประเมนผปวยหลงไดรบยา Omalizamab หลงไดรบยา Omalizamab เปนเวลา 16 อาทตยแลวประเมนผ ปวย อยในระดบ controlled ตาม GINA ยกเวน ผลการตรวจสมรรถภาพปอด (ในตารางท 3) รวมกบมคา PEF variability < 15% ใหยาตอจนครบ 6 เดอน แลวใหหยดยา แตถาประเมนผ ปวยหลงไดเปนเวลา 16 อาทตย ไมอยในระดบ controlled ใหหยดยาไมใหยาตอ ในกรณทหยดยา หลงท ใหยาครบ 6 เดอนแลวผ ปวยมอาการก าเรบ พจารณาใหยาใหมตามขอ บงชขางตน



Garcia G., et. al. Chest 2013;144:411–9

Urticaria

Chang T.et al. J Allergy Clin Immunol 2014

Casale TB., et. al. J Allergy Clin Immunol Pract 2015 article in press

Maurer M. et. al., J Eur Acad Dermatol Venereol 2015;29:s16-32

Zuberbier T. et al. Allergy 2014; 69: 868–87

แนวทางการใหยา Omalizumab (urticaria)

• ผปวยตองอยในการดแลของแพทยผเชยวชาญดานโรคผวหนง และ/หรอ โรคภมแพ • มอาย 12 ป ขนไป • ไดรบการตรวจวนจฉยเพมเตมวาไมมสาเหตหรอปจจยกระตนอนททาใหเกดโรคลมพษ

- การตรวจทางหองปฏบตการทจ าเปน คอ CBC, UA, ANA

• ไดรบการวนจฉยจากแพทยผเชยวชาญวาเปน chronic spontaneous urticaria และไมตอบสนองตอการรกษาพนฐาน มความรนแรงของโรคระดบปานกลางถงรนแรง

• ผปวยมอาการของโรคมาอยางนอย 3 เดอน แตยงไมตอบสนองตอการรกษา ถงแมจะไดรบการรกษาตามขนตอนการรกษามาตรฐาน (อางองแนวทางการรกษาโรคลมพษ

แหงประเทศไทย 2557 ) จงจะมการพจารณาใหยา omalizumab

Clinical Practice Guideline 2557 แนวทางการดแลรกษาโรคลมพษ/ สมาคมแพทยผวหนงแหงประเทศไทย สมาคมโรคภมแพ โรคหด และวทยาภมคมกนแหงประเทศไทย ชมรมแพทยผวหนงเดกแหงประเทศไทย





Omalizumab beyond asthma/urticaria

Boyman O., et al. Allergy 2015;70:727–54

A number of trials are underway…

• Rhinitis

• Atopic dermatitis

• Hymenoptera allergy

• Mastocytosis

• Idiopathic anaphylaxis

• Ocular allergy

• Eosinophilic gastrointestinal diseases

• Food allergy

• Latex allergy

• Mieniere’s disease

• Churg-Strauss Syndrome

• Hyper IgE syndrome

• Bronchopulmonary aspergillosis

Omalizumab beyond asthma/urticaria

Sanchez J. et. al. Allergol Immunopathol (Madr) 2012;40:306-15

Dosing and administration

75 mg 150 mg

Lyophilized product takes 15 to 20 min to dissolve

From www.xolair.com, access July 2015

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

Subcutaneous injection every 2 or 4 weeks, with dose being based on pretreatment serum total IgE levels and body weight

Vichyanond P. Asian Pac J Allergy Immunol 2011;29:209-19 Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36

Patients whose baseline IgE levels or BW are outside limits of dosing table should not

receive omalizumab

Dosage & body weight

• Doses should be adjusted for significant changes in body weight

• Calculate from total body weight, not ideal body weight

เอกสารก ากบยา Ledford DK, et. al. Expert Opin Biol Ther 2009;9:933-43

Dosage & IgE level • Total IgE levels are elevated during treatment and

remain elevated for up to 1 yr after discontinuation

• Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination

• Interruptions lasting < 1 yr: Dose based on serum IgE levels obtained at the initial dose determination

• Interruptions lasting ≥ 1 yr : Re-test total serum IgE levels for dose determination

เอกสารก ากบยา

Use solution for sc administration within 8 hrs following reconstitution when stored in the vial at 2 - 8°C, or within 4 hrs of reconstitution when stored at room temperature. Reconstituted Xolair vials should be protected from direct sunlight

From www.xolair.com, access July 2015

Other concerns (1)

Xolair has not been studied or inadequately studied:

• Patients < 6 yrs or > 65 yrs

• Patients with autoimmune diseases

• Patients with pre-existing renal or hepatic impairment


Other concerns (2)

• One 150 mg Xolair powder vial and solvent for solution dose contains 108 mg of sucrose

• Not indicated for relief of acute bronchospasm or status asthmaticus

• No formal drug interaction studies have been performed with Xolair



Other concerns (3)

• Maximum tolerated dose of Xolair has not been determined.

• Single IV doses of up to 4,000 mg have been administered to patients without evidence of dose limiting toxicities

• Highest cumulative dose administered to patients was 44,000 mg/20 wk period


Safety

Corren J, et. al. Clin Exp Allergy 2009;39:788-97

Safety and tolerability of omalizumab Analyzed safety using data from clinical studies involving > 7,500 patients as well as post-marketing data in 2003 – 2006 (57,300 patients)

Overall incidence of adverse events with omalizumab similar to that in placebo or control groups

Most common systemic adverse events

Adults

• Nasopharyngitis

• Headache

• Upper respiratory tract infection

• Sinusitis

Children

• Nasopharyngitis

• Upper respiratory tract infection

• Headache

• Sinusitis


Cox L, et. al. J Allergy Clin Immunol 2007;120:1373-7

Summary of recommendations • Informed consent • Anaphylaxis education • Epinephrine autoinjector - 24 hrs after administration

• Preinjection health assessment - V/S, lung functions

• Wait period after injection - 2 hrs for first 3 injections and

30 min for subsequent injections (captured 75% of anaphylactic reactions)

Obj: reviewing data on anaphylaxis and anaphylactoid reactions Duration: 2003 – 2005 Results: 35 patients had 41 episodes from 39,510 patients ( 0.09%)

Cox L, et. al. J Allergy Clin Immunol 2011;128:210-12

Duration: 2006 – 2008

Lieberman P, et. al. Ann Allergy Asthma Immunol 2010;105:493-5

Omalizumab Omalizumab antibody Excipients: - Sucrose - L-histidine - Polysorbate 20

Obj: to examine whether omalizumab skin testing is safe and to establish an appropriate nonirritating concentration for prick and intradermal testing Participants: no prior exposure to omalizumab or other biologic therapies Positive reaction: 3-mm wheal or larger and/or 10-mm or larger erythema over negative control Antiomalizumab IgG was analyzed 10 weeks after skin testing

Lieberman P, et. al. Ann Allergy Asthma Immunol 2010;105:493-5

Intradermal Test in Healthy Volunteers (First Cohort, n=30) and Allergic Asthma Patients (Second Cohort, n=30)

1:10,000 contains 12.5 g/mL of protein SPT with all concentrations diluted with NSS did not elicit any nonspecific reactions No detectable IgG ab to omalizumab

Shankara T. and Petrov A. Curr Opin Allergy Clin Immunol 2013;13:19–24

Malignancy

Analysis of pooled data from omalizumab phase I to III clinical studies showed a numerical imbalance in incidence

of malignancy between placebo (0.18%) and omalizumab (0.5%)


Busse W., et. al. J Allergy Clin Immunol 2012;129:983-9

Obj: Examine incidence of malignancy using pooled data from clinical trials

No cluster of histologies was identified

Busse W., et. al. J Allergy Clin Immunol 2012;129:983-9

A causal relationship between omalizumab therapy and malignancy is unlikely

Long A. et. al. J Allergy Clin Immunol 2014;134:560-7

Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS)

- Request of FDA

- 5-year observational cohort study conducted in patients 12 yrs

with moderate-to-severe asthma (approximately 5,000 pts treated with omalizumab and 2800 control)

- Obj: Evaluate long-term safety of omalizumab, primarily risk of malignancy

Time to first study-emergent primary malignancy

- Crude malignancy rates were similar (16 & 19/1000 patient-years) - Time to study-emergent primary malignancy were similar - Hazard ratio (omalizumab vs nonomalizumab) of 1.09 for all malignancies and 1.15 for all malignancies excluding NMSC - Overall frequency and frequency of individual cancer are consistent with expectations for general population



- Pooled clinical trial data in 2003 showed malignancies in 0.5% of omalizumab- treated patients compared with 0.2% of control


with moderate-to-severe asthma - Obj: Evaluate long-term safety of omalizumab, primarily risk of malignancy


- Crude malignancy rates were similar (16 & 19/1000 patient-years) - Time to first confirmed study-emergent primary malignancy were similar - Hazard ratio (omalizumab vs nonomalizumab) of 1.09 for all malignancies and 1.15 for all malignancies excluding NMSC



- Pooled clinical trial data in 2003 showed malignancies in 0.5% of omalizumab- treated patients compared with 0.2% of control


with moderate-to-severe asthma - Obj: Evaluate long-term safety of omalizumab, primarily risk of malignancy


- Crude malignancy rates were similar (16 & 19/1000 patient-years) - Time to first confirmed study-emergent primary malignancy were similar - Hazard ratio (omalizumab vs nonomalizumab) of 1.09 for all malignancies and 1.15 for all malignancies excluding NMSC

Omalizumab is not associated with an increased risk of malignancy

Namazy J., et. al. J Allergy Clin Immunol 2015;135:407-12

Prospective, observational study of pregnant women exposed to ≥1 dose of omalizumab within 8 wks prior to conception or at any time during pregnancy

Namazy J., et. al. J Allergy Clin Immunol 2015;135:407-12

Do not increase risk of preterm birth or SGA infants and prevalence of major congenital defects in general population with asthma

Omalizumab is classified as a Pregnancy Category B medication

Nursing mother • In monkeys, milk levels of omalizumab were measured

at 0.15% of the maternal serum concentration • It is not known whether Xolair is present in human

breast milk; however, IgG is present in human milk in small amounts

• Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Xolair and any potential adverse effects on breastfed child from Xolair or from underlying maternal condition

• Exercise caution when administering Xolair to a nursing woman


Parasitic (Helminth) Infection

• Monitor patients at high risk of geohelminth infection while on Xolair therapy

• Insufficient data are available to determine length of monitoring required for geohelminth infections after stopping Xolair treatment

• 53% (36/68) of Xolair-treated patients experienced an infection, as diagnosed by standard stool examination, compared to 42% (29/69) of placebo, odds ratio for infection was 1.96

• Response to appropriate anti-geohelminth treatment of infection as measured by stool egg counts was not different


Other adverse events


• None of omalizumab recipients developed measurable antiomalizumab antibodies

• Although thrombocytopenia was noted in preclinical studies, a decrease in platelet counts of 100 x 10⁹/L was seen in only 3.4% of omalizumab and 2.3% of controls

Issues in clinical use

Predictors of response

Not all patients respond to omalizumab !

Predictors of response


• It was difficult to reliably predict by using pretreatment characteristics

• Physician’s GETE at 16 wks was the most meaningful measurement of treatment response and the best discriminator of treatment outcomes


1. Overall physician assessment



1. Overall physician assessment

2. Composite measure of asthma control

AQLQ: Asthma related quality of life

UK responder algorithm

Holgate S., et. al. Respiratory Medicine 2009;103:1098-113


Baseline levels of fraction of exhaled nitric oxide (FeNO), peripheral blood eosinophils, and serum periostin

Reduction in asthma exacerbations over 48 wks with omalizumab versus placebo was significantly greater in patients with high versus low baseline levels of all 3 biomarkers


Baseline levels of fraction of exhaled nitric oxide (FeNO), peripheral blood eosinophils, and serum periostin

Reduction in asthma exacerbations over 48 wks with omalizumab versus placebo was significantly greater in patients with high versus low baseline levels of all 3 biomarkers

Stratified approach to treatment, and to determine value of these biomarkers for guiding decisions on initiation of omalizumab

which may potentially enhance cost- effectiveness

Duration of therapy

Optimal duration has yet to be determined

Nopp A, et. al. Allergy 2010;65:56-60

Obj: Report clinical and immunological state of patients 3 yrs after a 6-year period of Xolair treatment for severe allergic asthma Participants: 18 cat allergen sensitivity pt with asthma Results: 12/18 patients reported improved or unchanged asthma compared with ongoing Xolair treatment -Most patients were in stable clinical condition -16/18 had not increased nightly asthma attacks -14/18 little or no increase in medication -CD-sens to cat was still significantly lower than untreated patients with allergic asthma and lower than expected from their serum IgE antibody levels -Considerable, downregulation of basophil allergen sensitivity



Most patients had good asthma control for up to 3 yrs after omalizumab withdrawal



Pro: Most patients had good asthma control for up to 3 yrs after omalizumab withdrawal

Con: Slavin et. al. found that reducing dose of omalizumab at 6 months led to a recurrence of asthma symptoms in patients assessed as responders by physician evaluation at 16 wks

Pharmacokinetic-pharmacodynamic modelling


• IgE production decreases with duration of treatment by approximately 54%/yr, reaching a new equilibrium after 5 years of treatment

• After withdrawal, IgE production is predicted to increase slowly, potentially taking 15 years to return to baseline, which suggests that patients may not need to continue omalizumab indefinitely

• Further research into appropriate duration of treatment is required

Access from www.clinicaltrials.gov/ct2/show/NCT01125748, July 9, 2015

-Study of patients who received omalizumab continuously for up to 5 or more years and who were randomized to either continue or discontinue omalizumab, with follow up for a further year -Results will help to clarify effects of omalizumab withdrawal after successful long term therapy

Monitoring requirements

Monitoring requirements


• Anaphylactic reactions

sometimes occurs for the first time after multiple

administrations

• Assessment of responses at 16 wks by

using GETE

Cost: a major obstacle

ธนะวฒน วงศพน/การศกษาความคมคาทางเศรษฐศาสตรและขอเสนอเพ อปรบราคายา Omalizumab ทเหมาะสมส าหรบผปวยหอบหดในประเทศไทย/2556




Take home messages

• Omalizumab is humanized anti-IgE mAb

• Important treatment option for patients with moderate-to-severe or severe allergic asthma who remain uncontrolled despite current standard therapies

• A number of trials are underway that are investigating efficacy, safety and roles in conditions other than asthma and urticaria

Thank you for your attention

Health & Medicine

Anti Immunoglobulin E Therapy