anti-ige in severe persistent allergic asthma

Respirology (2007) 12 (Suppl. 3), S22–S28 doi: 10.1111/j.1440-1843.2007.01016.x

© 2007 The AuthorJournal compilation © 2007 Asian Pacific Society of Respirology

Blackwell Publishing AsiaMelbourne, AustraliaRESRespirology1323-7799© 2006 The Author; Journal compilation © 2006 Asian Pacific Society of Respirology200712S12228Original ArticleAnti-IgE in severe persistent allergic asthmaH Fox

Correspondence: Howard Fox, Novartis HorshamResearch Centre, Horsham RH125AB UK. Email: [email protected]

Conflict of interest: Howard Fox is employed byNovartis, who developed and sell Omalizumab.

ORIGINAL ARTICLE

Anti-IgE in severe persistent allergic asthma

Howard FOX

Novartis Horsham Research Centre, Horsham, UK

Anti-IgE in severe persistent allergic asthmaFOX H. Respirology 2007; 12 (Suppl. 3): S22–S28Abstract: Omalizumab is an mAb targeted against IgE. It reduces asthma exacerbations and symp-toms and has low anaphylactic potential. In the placebo-controlled double-blind study, INNOVATE,omalizumab was used in the patient population with the greatest unmet clinical need, who beingthose meeting the Global Initiative for Asthma 2002 step 4 criteria for severe persistent asthma. Whenadded to existing therapy, patients treated with omalizumab had a 26.2% lower rate of clinicallysignificant asthma exacerbations, after an adjustment to take into account an observed pre-studyimbalance in the exacerbation rate (P = 0.042). The Global Initiative for Asthma has recognized therole of anti-IgE therapy in treating patients with severe persistent asthma. Initiation of anti-IgE ther-apy is now recommended for these patients at step 4. Severe asthma has a major impact on health-care resource utilization. To date, treatment options have been limited in this target population.Omalizumab reduces symptoms, exacerbations and emergency visits in patients who are notadequately controlled on inhaled corticosteroids and long-acting beta agonists. It is a valuabletherapeutic option, addressing an unmet need in the area of severe asthma.

Key words: asthma, omalizumab, anti-IgE.

CHARACTERISTICS OF XOL AIR

Omalizumab (Xolair Novartis Pharmaceuticals S.A.S.Huningue, France.) is a humanized mAb that targetsIgE. It works by forming complexes with circulatingIgE, which inhibits the binding of IgE to the high-affinity IgE receptor (Fc∈RI) on the surface of mastcells and basophils. Binding of omalizumab to IgEresults in the formation of small, biologically inertcomplexes. Humanization of the murine anti-IgE wasperformed in order to avoid the clinical problemsassociated with murine antibodies. Humanized anti-IgE was developed by grafting the variable sequenceof a mouse antibody (binds to the Fc3 bindingdomain of IgE) onto the constant IgG1 kappa humanframework. Omalizumab consists of more than 95%IgG1 kappa human framework and less than 5%mouse sequence, which is hidden from the immunesystem when omalizumab binds to IgE.

The dosing table for omalizumab is based on thepatient’s total IgE before treatment and the patient’sbody weight. Omalizumab has low anaphylactogenicpotential and is administered as a subcutaneous

injection. It binds circulating IgE regardless ofspecificity and it forms small, biologically inertomalizumab : IgE complexes, mainly trimers. It doesnot activate complement.

Omalizumab works by binding to the constantregion of the IgE molecule, as illustrated in Figure 1.IgE binds either to the high-affinity FceRI receptor onthe mast cell or to omalizumab, but it cannot bind toboth at the same time.

The allergic inflammatory cascade, including theeffect of omalizumab in patients with IgE-mediatedasthma, is depicted in Figure 2. By binding to free IgEomalizumab inhibits the binding of IgE to the high-affinity IgE receptor on the surface of mast cells andbasophils, hence reduced cell-bound IgE. Reductionin surface-bound IgE on high-affinity receptor-bearing cells limits the degree of release of mediatorsof the allergic response. The resultant effect is toreduce asthma exacerbation and symptoms.

XOL AIR AND ASTHMA RESPONSE

In 1997, Fahy et al. published information looking atclassic allergen exposure and lung function over timein patients receiving omaliaumab1 The significantacute depression in FEV1 during the early asthmaresponse and the prolonged suppression of FEV1

during late asthma response at hours 2–7 in patientstaking placebo is illustrated on the left-hand panel

H Fox S23


of Figure 3. The panel on the right-hand side depictsthe first documented efficacy of omalizumab in mildasthmatics. After 56 days of dosing with omalizumab,the decrease in late asthma response was significant.

At about the same time, MacGlashan et al. pub-lished data showing that omalizumab markedly andsignificantly reduced high-affinity receptor density by97% on basophils in patients with perennial allergicrhinitis (P = 0.0022).2 More recently, Djukanovic et al.published data in asthmatic patients looking at

bronchial biopsies with staining for high-affinityreceptors both before and after treatment.3 Thesedata showed a reduction in high-affinity receptors inasthmatics. In this same study, Djukanovic et al. alsoreported a significant reduction in submucousal eosi-nophils in patients treated with omalizumab(P = 0.033) as well as a reduced level of eosinophils inthe sputum (P = 0.0495).

The level of evidence to support the role of IgE inasthma has developed over time. In a study publishedin 1989, Burrows et al. showed that ‘total’ IgE levelscorrelate with the risk of developing asthma inadults.4 What has been less clearly understood is thatapproximately two-thirds of asthma is estimated tobe allergic5 and more than 50% of patients with severeasthma have allergic asthma.6 The anti-inflammatoryeffects of omalizumab provide proof of concept of theimportance of IgE in allergic respiratory disease.1–3

CLINICAL TRIAL PROGRAMME

To date, seven large phase III controlled trials of oma-lizumab have been completed in adults and adoles-cents with allergic asthma.7–12 These studies consist offive double-blind placebo-controlled studies, includ-ing INNOVATE, and two randomized open-labelstandard therapy controlled studies. Omalizumab wasFigure 1 Xolair blocks IgE binding to mast cells.

Mast cell

IgE molecule

FceRI receptor

Omalizumab Omalizumab

Figure 2 Omalizumab mecha-nism of action in IgE-mediatedasthma.

Asthma exacerbation

PerennialaeroallergensOmalizumab

Binds to free IgE, reducing

cell-bound IgE

Reduces high-affinity receptors

Reducesmediatorrelease

Reduces asthma exacerbations and

symptoms

Plasma cell

B lymphocyte

ε-switchAllergic

mediators

Release of IgE

Mast cellsBasophils

Allergicinflammation:

eosinophils and lymphocytes

Figure 3 Omalizumab affectsboth early- and late-phase asthmaresponse.

Omalizumab Placebo

65

75

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85

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0 1 2 3 4 5 6 7Time (h)Time (h)

0 1 2 3 4 5 6 7

Before treatmentAfter 56 daysof treatment

S24 Anti-IgE in severe persistent allergic asthma


given as add-on therapy to at least inhaled corticos-teroids (ICS) in all studies and in some cases to long-acting beta agonists (LABA), and 93% of the enrolledpatients met the Global Initiative for Asthma (GINA)2002 step 4 criteria for severe persistent asthma.

The end-points and duration of treatment for eachof these seven phase III studies of omalizumab inpatients with allergic asthma are summarized inTable 1.

THE INNOVATE STUDY

The INNOVATE (INvestigatioN of Omalizumab inseVere Asthma TrEatment) study included more than400 patients aged 12–75 years with allergic asthma.7

Patients were skin prick-positive or had asthma con-firmed by the radioallergosorbem (RAS) test. Forstudy entry, patients were required to have inade-quate asthma control despite high-dose ICS andLABA, demonstrated by:• FEV1 ≥40–<80% at randomization• Continued meaningful asthma symptoms, despitemedication• 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 emer-gency room treatment or hospitalization.

Patients were randomized to receive either omali-zumab or placebo for 28 weeks. The INNOVATE trialexclusively targeted the patient population with thegreatest unmet clinical need, who being those meetingthe GINA 2002 criteria for severe persistent asthmawho despite step 4 therapy had continuing inadequatecontrol. The clinical features of this difficult-to-treatpatient population are illustrated in Figure 4.

The primary efficacy variable in INNOVATE was therate of clinically significant asthma exacerbations, asdefined by worsening asthma symptoms to the extentthat patients required treatment with systemic corti-costeroids. Additional efficacy variables included thesevere exacerbation rate (as defined by the GINA cri-teria of PEF or FEV1 <60% of personal best, requiringtreatment with systemic corticosteroids) and acomposite emergency visit rate (inclusive of hospitaladmissions, emergency department visits andunscheduled doctor’s visits). Other more classic end-

points were also looked at, including lung functionsymptoms and quality of life.

Patients enrolled in INNOVATE were predomi-nantly women (66%) with a mean age of 43 years.Lung function was markedly reduced to about 60% ofthat predicted despite large doses (on average morethan 2300 µg per day) of beclomethasone dipropi-onate and the universal use of LABAs. About 20% ofpatients were taking daily doses of oral corticoster-oids, 24–30% were taking theophylline and about 35%were taking anti-leucotrienes. Baseline quality of lifewas markedly reduced in this patient population.Two-thirds of patients were at high risk of asthma-related death according to the GINA definition(previous intubation or emergency room visit/hospi-talization in past year) and patients were experienc-ing approximately two clinically significant asthmaexacerbations per year and five unscheduled doctor’svisits. Enrolled patients missed an average of 31school/work days in the previous year.

Omalizumab reduced the clinically significantasthma exacerbation rate, as illustrated in Figure 5.The rate of clinically significant asthma exacerba-tions (after an adjustment to take into account anobserved pre-study imbalance in the exacerbationrate) was 0.68 with omalizumab and 0.91 with pla-cebo, equating to a 26.2% reduction (P = 0.042).Without that adjustment, statistical significance wasnot reached.

To put the INNOVATE study into context; the annu-alized exacerbation rates across all seven studies inthe clinical trial programme are illustrated in Table 2.In addition to the 26.2% reduction in INNOVATE, con-sistent reductions in the asthma exacerbation ratewere seen cross all seven studies. A pooled analysisshowed that omalizumab significant reduced the rateof asthma exacerbations by 38.3% versus controltherapy (P < 0.0001).13

In relation to severe exacerbations, dropping tobelow 60% of personal best, these events were halvedin the INNOVATE study. Similarly, the closely relatedemergency visit rate end-point was also reduced byaround 44%. Both of these were highly statisticallysignificant results (P = 0.002 and P = 0.038,respectively). The emergency visit rate in the pooledpopulation, as published by Bousquet et al., was 47%(P < 0.0001).13 Specifically, hospital admissions werereduced by 51% (P = 0.041), emergency department

Table 1 Omalizumab in allergic asthma

Study No. patients

Treatment

duration (weeks) Efficacy end-point

INNOVATE study7 419 28 Asthma exacerbation rateETOPA study8 312 52 Asthma exacerbation rateSOLAR study9 405 28 Asthma exacerbation incidenceBusse study10 525 52 Asthma exacerbation rateSolèr study11 546 52 Asthma exacerbation rateHolgate study12 341 32 Reduction in inhaled corticosteroid useALTO study 1899 24 Safety study

Summary of phase III studies in adults and adolescents. Ninety-tree per cent of patients met Global Initiative for Asthmacriteria for severe persistent asthma.

H Fox S25


visits by 60% (P = 0.013) and unscheduled doctor’svisits by 43% (P < 0.0003). This is an important result,especially considering that omalizumab was used asan add-on therapy. That is, the results seen were overand above those seen with ICS therapy and LABAs.

A consistent reduction in exacerbations was seen inpatients who received omalizumab, regardless of theuse of oral corticosteroids. A similar reduction inexacerbations was demonstrated in the patient sub-populations who received oral corticosteroids and inthose who did not. These data show that the effect of

omalizumab persists even when it is added on top oforal corticosteroid therapy.

Other end-points were also looked at in the INNO-VATE study. These included asthma symptoms, whichwere recorded in patient diaries over the 28-weekduration of the study, as well as PEF. Significantbenefits were seen with omalizumab, although asnoted in all studies undertaken to date with omali-zumab, the effect was gradual. Maximal benefits inthe day-to-day control of asthma symptoms were notseen until after 12–16 weeks of omalizumab therapy.This can be largely explained by the fact that cells arealready primed with IgE and mast cell turnover isrequired before the full effect of omalizumab can berealized. It is important to be aware of time to maxi-mal effect when determining whether a patient isresponding to omalizumab or not.

QUALITY OF LIFE

Another important end-point looked at in the INNO-VATE study was quality of life. Quality of life wasimproved following omalizumab therapy in patientsenrolled in the INNOVATE study. A significantimprovement in overall quality of life was demon-strated, with a change in the Asthma Quality of LifeQuestionnaire baseline score for omalizumab of 0.91compared with 0.46 for placebo patients (P < 0.001).This questionnaire was chosen, as it was the mostfully validated questionnaire for patients with

Figure 4 INNOVATE targeted greatest unmet need population. Target population according to Global Initiative for Asthma.BDP, beclomethasone dipropionate; LABA, long-acting beta agonists.

Intermittent

Mild persistent

Step 4>1000 μg BDP + LABA ± other

Step 3200–1000 μg BDP + LABA

Step 2 <500 μg BDP

Step 1No controller

Current treatment step

Severe persistent

Severe persistent

Severe persistent

Step 4 Symptoms dailyFrequent nocturnal symptomsFEV1 <60% predicted

Severe persistent

Severe persistent

Moderate persistent

Step 3Symptoms dailyNocturnal symptoms ≥1 x week FEV1 60–80% predicted

Severe persistent

Severe persistent

Step 2Symptoms >1 x week Nocturnal symptoms <1 x weekLung function normal between episodes

Severe persistent

Moderate persistent

Mild persistent

Step 1Symptoms <1 x weekNocturnal symptoms ≤2 x monthLung function normal between episodes

Clinical features

Moderate persistent

Patients included in the INNOVATE study

Severe persistent

Severe persistent

Figure 5 INNOVATE. Omalizumab reduces significantasthma exacerbations. *Adjustment was necessary becauseof a pre-study imbalance in exacerbation rate −19.2%(P = 0.156) reduction unadjusted.

Omalizumab(n = 209)

Placebo(n = 210)

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1.0

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0.6

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asthma. Significant improvements were also notedfor each domain of the questionnaire, includingactivities, emotions, symptoms and environment (seeFig. 6). A change from baseline of ≥0.5 is consideredclinically meaningful and detectable. Across allsix studies where quality of life was investigated, asignificantly higher proportion of patients treatedwith omalizumab experienced clinically meaningfulimprovements in quality of life.7–12

PHYSICIAN’S OVERALL ASSESSMENT

Physician’s overall assessment was also documentedin five of the seven studies. Measured at the end of thestudy, the doctor was asked whether the patient hadachieved complete control or a marked improvementin control (a responder), or discernible but limitedcontrol, no appreciable change or a worsening of con-trol (a non-responder). The data from the five studieswhere this evaluation was included are shown inFigure 7. In each case, there were significantly morepatients in the omalizumab group than in the placeboor control arm who responded to therapy. Theproportion of patients who were judged as beingresponders was relatively consistent, especially con-sidering the fact that each of the studies had a slightlydifferent design. Around 60% of patients in each studywere judged as having marked or complete control ofsymptoms. From a negative perspective, this meantthat around a third of patients did not appear toexperience marked benefit from this therapy.

Response rate is also important when consideringwhether a patient should discontinue therapy after

say a 16-week period. The data obtained from thephysician’s overall evaluation show the type ofresponse that can be expected in patients who dorespond. The extent of the response in patientsjudged as responders by the physician was quiteconsiderable. In responders, omalizumab provided aconsistently enhanced benefit. The annualized clini-cally significant exacerbation rate was 0.6 in respond-ers compared with 2.6 in non-responders. In relationto the annualized severe exacerbation rate, this was0.2 for responders compared with 1.4 for non-responders. Annualized emergency visit rates were1.5 per year in non-responders versus 0.20 per year inresponders.

SAFETY OF OMALIZUMAB

The INNOVATE study also provides a substantialamount of safety data for omalizumab. INNOVATEforms part of a large safety package of over 7500patients, more than 5000 of who have been treatedwith omalizumab. The incidence of adverse eventsseen in the placebo-controlled asthma studies wassimilar irrespective of whether patients receivedomalizumab or placebo. To date, more than 35 000patients have been treated with omalizumab as it wasfirst approved in the USA. Some of these patients havebeen treated for 2 years or longer in normal practice.In addition, a post-marketing surveillance study of7500 patients for 5 years has already enrolled morethan 4000 patients. This study will provide additionalvaluable safety information for this biologicaltherapy. The post-launch data for omalizumab to

Table 2 Consistent reduction in asthma exacerbation rates across all seven studies

Annual exacerbation rate treatment difference Per cent reduction P-value

INNOVATE study7 0.49 26.2 0.0420ETOPA study8 1.49 60.4 <0.0010SOLAR study9 0.29 37.5 0.0270Busse study10 0.40 40.3 <0.0010Solèr study11 0.70 57.6 <0.0010Holgate study12 0.42 26.5 0.1650ALTO study 0.18 15.3 0.0770Pooled13 0.56 38.3 <0.0001

Figure 6 INNOVATE. Omali-zumab improves quality of life.AQLQ, Asthma Quality of LifeQuestionnaire; LSM, least squaresmean.

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Control

INNOVATE SOLAR Busse Soler Holgate

80

60

40

20

0

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42.8

60.2**

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33.3

66.2**

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H Fox S27


date have been reassuring. The data are consistentwith those seen in the clinical trial programme, andhypersensitivity reactions remain uncommon.Although anaphylactoid type events have beenreported, it has been difficult to determine whetherthese are events that would have occurred in analready atopic population or whether they are directlyrelated to administration of omalizumab. The rate ofanaphylactoid type reactions of about one in 1000 issimilar to that seen in the clinical trial programmewith patients taking placebo.

CONCLUSION

Omalizumab has a clearly defined positive benefit:risk assessment. It addresses an unmet need in thearea of severe asthma. As demonstrated in the INNO-VATE study, omalizumab is effective in reducing therate of clinically significant asthma exacerbations in apatient population at high risk of asthma-relatedmortality. GINA has now recognized the role ofanti-IgE therapy and initiation of anti-IgE therapyis recommended at step 4.

Additional work is required in order to better iden-tify patients who are likely to respond to omalizumabtherapy. Great care has been taken to date to identifyresponders both before and after starting treatment.So far at an individual patient level no robust predic-tor of treatment response has been identified. This issomething that is still being looked at. The other thingthat is still required is further development of the con-cept of a 16-week trial of therapy and the establish-ment of what measures of response should define aresponse. In Europe, the physician’s overall assess-ment of response is being used. Broad measures ofcontrol such as quality of life or overall assessmentseem to correlate better with exacerbations than domarkers of disease such as lung function. The safetyof omalizumab has demonstrated in a large popula-tion, and the ongoing pharmacovigilance programmewill provide additional data. Restricting therapy toonly those patients who are responding to therapywill help to minimize risk.

Severe asthma is a major contributor to health-careresource utilization and the morbidity and mortalityassociated with the condition are significant. Cur-

rently there have been limited treatment options,apart from increasing doses of ICS and LABAs.Omalizumab is effective in this highly targetedpatient population, significantly reducing emergencyvisits, symptoms and asthma exacerbations whileimproving quality of life. The drug is also well-tolerated. Omalizumab is a valuable treatmentoption, addressing an area of unmet need in patientswith severe asthma.

REFERENCES

1 Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, et al.The effect of an anti-IgE monoclonal antibody on theearly- and late-phase responses to allergen inhalation inasthmatic subjects. Am. J. Respir. Crit. Care Med. 1997;155: 1828–34.

2 MacGlashan DW Jr, Bochner BS, Adelman DC, JardieuPM, Togias A, et al. Down-regulation of Fc(epsilon)RIexpression on human basophils during in vivo treatmentof atopic patients with anti-IgE antibody. J. Immunol.1997; 158: 1438–45.

3 Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M,et al. Effects of treatment with anti-immunoglobulinE antibody omalizumab on airway inflammation inallergic asthma. Am. J. Respir. Crit. Care Med. 2004; 170:583–93.

4 Burrows B, Martinez FD, Halonen M, Barbee R, ClineMG. Association of asthma with serum IgE levels andskin-test reactivity to allergens. N. Engl. J. Med. 1989;320: 271–7.

5 Novak N, Bieber T. Allergic and nonallergic forms ofatopic diseases. J. Allergy Clin. Immunol. 2003; 112: 252–62.

6 European Network for Understanding Mechanisms ofSevere Asthma. The ENFUMOSA cross-sectional Euro-pean multicentre study of the clinical phenotype ofchronic severe asthma. Eur. Respir. J. 2003; 22: 470–7.

7 Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, et al.Benefits of omalizumab as add-on therapy in patientswith severe persistent asthma who are inadequatelycontrolled despite best available therapy (GINA 2002step 4 treatment): INNOVATE. Allergy 2005; 60: 309–16.

8 Ayres JG, Higgins B, Chilvers ER, Ayre G, Blogg M, et al.Efficacy and tolerability of anti-immunoglobulin Etherapy with omalizumab in patients with poorly

Figure 7 Physician overall as-sessment shows a consistentlygreater proportion of omalizumabpatients achieve marked im-provement. *P < 0.01, **P < 0.001;†as assessed by physician’s globalevaluation of treatmenteffectiveness.

Mar

ked

impr

ovem

ent o

r co

mpl

ete

cont

rol†

(% p

atie

nts)

Omalizumab

Control

INNOVATE SOLAR Busse Soler Holgate

80

60

40

20

0

60.5**

42.8

60.2**

42.0

53.1**

33.3

66.2**

34.7

68.5*

44.2



controlled (moderate-to-severe) allergic asthma. Allergy2004; 59: 701–8.

9 Vignola AM, Humbert M, Bousquet J, Boulet LP,Hedgecock S, et al. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in pa-tients with concomitant allergic asthma and persistentallergic rhinitis: SOLAR. Allergy 2004; 59: 709–17.

10 Busse W, Corren J, Lanier BQ, McAlary M, Fowler-TaylorA, et al. Omalizumab, anti-IgE recombinant humanizedmonoclonal antibody, for the treatment of severe allergicasthma. J. Allergy Clin. Immunol. 2001; 108: 184–90.

11 Solèr M, Matz J, Townley R, Buhl R, O’Brien J, et al. Theanti-IgE antibody omalizumab reduces exacerbations

and steroid requirement in allergic asthmatics. Eur.Respir. J. 2001; 18: 254–61. Erratum in: Eur. Respir. J. 2001;18 : 739–40.

12 Holgate ST, Chuchalin AG, Hebert J, Lotvall J, PerssonGB, et al. on behalf of the Omalizumab 011 InternationalStudy Group. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severeallergic asthma. Clin. Exp. Allergy 2004; 34: 632–8.

13 Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S,et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergencymedical visits in patients with severe persistent asthma.Allergy 2005; 60: 302–8.

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