Indications for anti IgE other Indications for anti IgE other than asthmathan asthma

Diana DeleanuDiana Deleanu

Univ of Medicine & Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania

deleanudiana@yahoo.comdeleanudiana@yahoo.com

Disclosure

In relation to this presentation, I declare the following, real or perceived conflicts of interest:

• No conflicts of interest to report

A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict with the current presentation. Conflicts of interest do not preclude the delivery of the talk, but should be explicitly declared. These may include financial interests (eg. owning stocks of a related company, having received honoraria, consultancy fees), research interests (research support by grants or otherwise), organisational interests and gifts.

Indications of anti-IgE TherapyIndications of anti-IgE Therapy

Indications (drug company)Indications (drug company)

• is indicated for adults and adolescentsadults and adolescents (12 years of age and above)

• with moderate to severe persistent asthmamoderate to severe persistent asthma • who have a positive skin testa positive skin test or • in vitro reactivity to a perennial aeroallergenreactivity to a perennial aeroallergen • and whose symptoms are inadequately

controlled with inhaled corticosteroids. • Safety and efficacy have not been established in

other allergic conditions!

WikipediaWikipedia

• Omalizumab (trade name Xolair, Genentech/Novartis) is a humanized antibody drug approved for patients with moderate-to-severe or severe allergic asthma, which is caused by hypersensitivity reactions to certain harmless environmental substances. Omalizumab's cost is high Omalizumab's cost is high ($10,000 to $30,000 per year), as compared to other ($10,000 to $30,000 per year), as compared to other drugs used for asthma, and hence omalizumab is drugs used for asthma, and hence omalizumab is mainly prescribed for patients with severe, mainly prescribed for patients with severe, persistent asthma, which cannot be controlled even persistent asthma, which cannot be controlled even with high doses of corticosteroids.with high doses of corticosteroids. Like other protein and antibody drugs, omalizumab causes anaphylaxis  (a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000.

Human mind is allways surching!

New perspective on anti-IgE therapyNew perspective on anti-IgE therapy

Fagaras Mountains

BackgroundBackground

• Anti-IgE was developed for severe allergic asthma therapy

• It blocks binding free IgE to the specific receptor (FcεRI and FcεRII) on basophils and mast cells

• Lower the IgE level

• Downregulation of the IgE receptors on circulating basophils

IgE releaseIgE release

PlasmocytePlasmocyte

B lymphocyteB lymphocyte

-switch-switch

ExacerbationExacerbationof allergy of allergy

Allergic Allergic Inflammation:Inflammation:eosinophile &eosinophile &lymphocytslymphocyts

AllergenAllergen

Mast cellsMast cellsBasophilsBasophils

Allergic Allergic MediatorsMediators

Allergic CascadeAllergic Cascade

Mechanism of inhibition by Mechanism of inhibition by omalizumabomalizumab

Allergy Symptoms

Possible Targets for the action of Anti-IgE Possible Targets for the action of Anti-IgE TherapyTherapy

Allergens

Anti-IgE MoAb

Binds to free IgE, reduce

IgE for binding on mast cells

Reduce high

affinity receptors

ReduceThe release of mediators

Reduce exacerbation And

symptoms

Plasmocyte

B lymphocyte

-switch Mediators

Release of IgE

Mast cellsBasophil

Inflammation:eosinophil and

lymphocyte

Barnes PJ. Int Arch Allergy Immunol. 2000;123:196-204.

Other effects of anti-IgE Other effects of anti-IgE beyond IgEbeyond IgE

• On thrombus formation

• Cardiovascular effect.*

• Steroid-sparing effect**

*Townley RG et al. Expert Opin Biol Ther 2010;10:1595-608**Soler M, et al. Eur Respir J 2001; 18:254-61

Out–off label Anti-IgE therapyOut–off label Anti-IgE therapy

• Respiratory Disease

• Skin Disease

• Anaphylaxis (as disease or a side effect)

• Others

Anti-IgE therapy as off–label Anti-IgE therapy as off–label indicationsindications

Respiratory DiseaseRespiratory Disease

Medline searchMedline search

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2001 2003 2005 2007 2009 2011

articles

asthma

rhinitis

Churg-Strauss

ABPA

Respiratory Disease

• Asthma with no positive skin prick tests, but with total IgE >30-700 UI/mL

• Rhinitis

• Nasal polyposis/sinusitis

• ABPA

• Churg-Strauss syndrome

• COPD with high level of IgE

Allergic RhinitisAllergic RhinitisDBPC trial of 536 pts with severe seasonal allergic

rhinitis (Casale Tb et al Clin Exp Allergy 1998; 28: 664-667)• Omalizumab decrease serum-free IgE levels• Clinical benefit (dose-dependent manner)DBPC trial of adults and adolescents with severe

perennial rhinitis (N = 289) (Chervinsky P et al. Ann Allergy Asthma Immunol

2003; 91: 160-167)• Omalizumab decrease daily nasal symptom score

(p < 0.001)• Omalizumab decrease use of rescue antihistamine

(p = 0.005)• Improved quality of life

Allergic RhinitisAllergic Rhinitis

• Daily nasal severity score

Kimihiro Okuda & Toshikazu Nagakura, Allergology International 2008; 57: 205-9

Japanase cedar pollinosisJapanase cedar pollinosis

Kimihiro Okuda & Toshikazu Nagakura, Allergology Internationakl 2008; 57: 205-9

Japanase cedar pollinosisJapanase cedar pollinosis

Kimihiro Okuda & Toshikazu Nagakura, Allergology Internationakl 2008; 57: 205-9

Occupational rhinitisOccupational rhinitis

• Occupational rhinitis is a heterogenous group of chronic inflammatory disease with an allergicallergic, neurologic or toxic mechanism

• Anti-IgE was not evaluated

Nasal PolyposisNasal PolyposisRetrospectively collected on two groups of patients with atopic asthma and NP

• who underwent endoscopic sinus surgery (ESS), including • a control group (n=4) and an anti-IgE treatment group (n=4), who received

the anti-IgE agent, omalizumab, postoperatively. • Preoperatively no differences between the groups with regard to their total

serum IgE levels, sinus CT scores, and endoscopically

RESULTS:• The nasal polyp scores significantly improved in the anti-IgE group, whereas

the control group showed no significant improvement.

CONCLUSION:• This pilot study provides new evidence establishing that (1) endoscopic NP

severity directly correlates to total serum IgE levels and (2) inclusion of anti-IgE therapy in the postpolypectomy management of atopic asthmatic individuals may reduce the severity of NP recurrence.

Penn R, Mikula S, Am J Rhinol 2007

Chronic SinusitisChronic Sinusitis

• Is under evaluation• Since 2008 (Grundmann SA et al, JACI

Jan 121 (1): 257-8)• DBPC trial for chronic rhinosinusitis √ √ improvement in Sino-Nasal Outcome Test at 3, 5, 6 months 9 (vs control, vs

baseline)

√√ no other differences (Pinto JM et al, Rhinology 2010; 48: 318-24)

Allergic broncho-pulmonary Allergic broncho-pulmonary Aspergillosis (ABPA)Aspergillosis (ABPA)

• Treatment of a 12 years old girl with cystic fibrosis colonized with A. fumigatus (with adverse effects of GCS therapy)

Cornelis K van der Ent et al Thorax 2007

Allergic broncho-pulmonary Allergic broncho-pulmonary Aspergillosis (ABPA)Aspergillosis (ABPA)

• The use of anti-IgE therapy in 3 children with CF and ABPA (mean age at start of therapy = 14.2 years) who were steroid-dependent.

• All 3 were already experiencing significant side effects from chronic steroid therapy.

• After the start of omalizumab, these children experienced significant and sustained clinical improvements at the same time that they were discontinued from chronic systemic steroids. 

• Conclusion: “IgE blockade has tremendous potential as a strategy to control this disease in steroid-dependent patients”.

Zirbes and Milla (Pediatr Pulmonol. 2008 Jun;43(6):607-10)

Allergic broncho-pulmonary Allergic broncho-pulmonary Aspergillosis (ABPA)Aspergillosis (ABPA)

• Recent reviews on the management of ABPA (Meza Brítez et al, 2008; Schubert, 2009) did not mention the use of anti-IgE as a therapeutic option !

• Brinkmann F et al: Steroid dependency despite omalizumab treatment of ABPA in cystic fibrosis.

(Allergy 2010; 65: 134-5)

Churg-Strauss Syndrome

• The first Anti-IgE therapy in Churg-Strauss Syndrome• A 46-year-old male patient with CSS followed up for 17

years is described. • anti-IgE was administered. Following omalizumab

administration, asthma symptoms (according to clinical features and lung function tests) and eosinophilia improved.

CONCLUSIONS:• Anti-IgE improved our patient's asthma and decreased

the eosinophil blood count but did not worsen the outcome of CSS. However, large and long-term studies are necessary before a more widespread utilization of anti-IgE in CSS patients can be implemented.

Giavina-Bianchi P et al, Int Arch Allergy Immunol 2007

Churg-Strauss Syndrome induced by anti-IgE therapy

• Definitive cases – 13

• Probable cases – 4

Wechsler ME et al, Chest, 2009

COPDCOPD

• Under evaluation

Anti-IgE therapy beyond asthmaAnti-IgE therapy beyond asthma

Skin DiseaseSkin Disease

Anti-IgE therapy beyond asthmaSkin Disease

• Atopic dermatitis/eczema

• Chronic idiopatic urticaria/Angioedema

• Autoimmune urticaria

• Mastocytosis

• Bullous Pemphigoid

Atopic DermatitisAtopic Dermatitis

• Efalizumab (anti CD11a) and omalizumabomalizumab are monoclonal antibodies with a possible future role in the treatment of AD, but further studies are needed. (Ricci et al, 2009)

Debating results in off-label Anti-IgE therapy

• No effect on clinical course (DBPC trial by Heil PM et al. J Dtsch Dermatol Ges. 2010; 8: 990-8)

• Atopic dermatitis* (no clinical efficacy)

*Krathen RA, et al. J Am Acad Dermato 2005; 53:338-40

Belloni B, et al. J Allergy Clin Immunol 2007:120: 1223-25

Chronic UrticariaChronic Urticaria(Autoimmune, Idiopathic)(Autoimmune, Idiopathic)

• Newer experimental therapies include intravenous immunoglobulin and anti-IgE. (Fonacier et al ,2010) 

• Anti-IgE MoAb – reduce

√√ The expression of FcεRI

√√ The level of free IgE

Monotherapy with second generation AH1

Maximixe H1- AH therapy (including first, second generation AH1, H2-antagonists and/or doxepin

Anti-inflammatory (hydroxychloroquine, sulfasalazine, colchicine or dapsone)

Immunosupressants (calcineurin inhibitors, mycophenolate, cyclophosphamide…) or biologics (Omalizumabbiologics (Omalizumab, IVGV, TNF-…)

Considerer adding leukotriene modifying agebnt, cyproheptadine or oral albuterol

Other treatments (stanazol, theophylline, ….)

STEP THERAPY STEP THERAPY FOR CHRONIC FOR CHRONIC URTICARIAURTICARIA

Chronic Autoimmune UrticariaChronic Autoimmune Urticaria

Conlusion:

• “This exploratory proof of concept study suggests omalizumab is an effective therapy for CAU resistant to antihistamines.” (Kaplan et al, JACI 2008)

Chronic AngioedemaChronic Angioedema

• 3 pts treated successfully with Omalizumab

Sands MF et al, JACI 2007; 120:979-81

MastocytosisMastocytosis

• Case reports

• Since 2007

• In pts with mastocytosis

• In pts with mastocytosis and anaphylaxis to venom insect treated with SIT

• Well tolerated

• Successful treatment

Bullous PemphigoidBullous Pemphigoid

• A letter to editor

• Reporting one 70 years old women

Fairley JA, et al. JACI 2009; 123: 704-5

Bullous PemphigoidBullous Pemphigoid

• A letter to editor

• Reporting one 70 years old women

Fairley JA, et al. JACI 2009; 123: 704-5

Anti-IgE therapy – clinical utilityAnti-IgE therapy – clinical utility

Allergic DiseaseAllergic Disease

Anti-IgE therapy – clinical utilityAnti-IgE therapy – clinical utilityAllergic DiseaseAllergic Disease

• Immunotherapy (to reduce side effects of immunotherapy)

• Latex allergy

• Food allergy (peanut)

• Drug allergy

Side effects of SIT

• Linda Cox tb

Safety methods for Immunotherapy with allergenic vaccines

Premedication with:

• Antihistamine

• Leukotriene antagonist

• Omalizumab

Omalizumab and ImmunotherapyOmalizumab and Immunotherapyin pts with rhinitis and asthmain pts with rhinitis and asthma

• Improved symptoms load & asthma control when used 2 wks before & during grass season

• Reduced the symptom load by 39% (P=0.0464, Wilcoxon test) over SIT monotherapy.

• Reduced symptom severity (P=0.0044), while rescue medication use did not change significantly.

• Improved asthma control (Asthma Control Questionnaire, P=0.0295) and quality of life in the case of asthma (Asthma Quality of Life Questionnaire, P=0.0293) and rhinoconjunctivitis (Rhinoconjunctivitis Quality of Life Questionnaire, P=0.0537).

• Numbers of patients with 'excellent or good' treatment efficacy according to ratings of investigators (75.0% vs. 36.9%) or patients (78.5% vs. 46.1%) were markedly higher in the combination group than under SIT alone.

1. Kopp MV et al, JACI 2002; 110: 728-35

Effect of pretreatment with omalizumab on the Effect of pretreatment with omalizumab on the tolerability of specific immunotherapytolerability of specific immunotherapy

in allergic asthma. in allergic asthma.

• 248 randomized pts (126 omalizumab, 122 placebo) - Multicenter, DBPC, parallel-group study treatment with

omalizumab or placebo, after which they received specific immunotherapy to at least 1 of 3 perennial aeroallergens (cat, dog, and house dust mite) according to a 4-week, 18-injection cluster regimen, followed by 7 weeks of maintenance therapy.

- The primary efficacy variable, a systemic allergic reaction after immunotherapy, was analyzed by using the Cochrane-Mantel-Haenszel test.

• Received at least 1 dose of immunotherapy and were evaluated for efficacy.

Massanari M et al, JACI 2010

Omalizumab + SIT in allergic asthmaOmalizumab + SIT in allergic asthma

Anti-IgE + SIT (n=126)

SIT

(n= 122)

P; CI

Side Effects of SIT

17

(13.5%)

31

(26,2%)

P= 0.017

CI = 2.91% to 22.56%

Target Maintenance immunotherapy dose

110

(87.3%)

88 (72.1%),

P = 0.004

Grade 3(respiratory)

6 24

Grade 4 2 2

Massanari M et al. JACI 2010; 125: 383-9

Combination therapy: anti-IgE Combination therapy: anti-IgE and SIT in Rhinitisand SIT in Rhinitis

DBPC trial in children and adolescents with SIT (grass and birch pollen) for allergic rhinitis (N=225) (Kuehr J et al. JACI 2002; 109:274-

80)• Significantly decrease of symptoms/rescue

medication in co-seasonal adm vs SIT alone

DBPC trial in adults with rush SIT for ragweed-induced rhinitis (Casale TB et al JACI 2006;

117:134-40)• Decrease daily symptom score (p = 0.04)

vs SIT alone

Reduce side effects in Omalizumab Reduce side effects in Omalizumab + SIT- rush in Allergic Rhinitis+ SIT- rush in Allergic Rhinitis

• Adult patients with ragweed allergic rhinitis were enrolled in a 3-center, 4-arm, double-blind, parallel-group, placebo-controlled trial.

• Patients received either 9 weeks of omalizumab (0.016 mg/kg/IgE [IU/mL]/mo) or placebo, followed by 1-day rush (maximal dose 1.2-4.0 mug Amb a 1) or placebo immunotherapy, then 12 weeks of omalizumab or placebo plus immunotherapy.

RESULTS:• Of the 159 patients enrolled, 123 completed all treatments. • Ragweed-specific IgG levels increased >11-fold in immunotherapy patients, and • Free IgE levels declined >10-fold in omalizumab patients. • Patients receiving omalizumab plus immunotherapy had fewer adverse events than

those receiving immunotherapy alone. • Post hoc analysis of groups receiving immunotherapy demonstrated that addition of

omalizumab resulted in a 5-fold decrease in risk of anaphylaxis caused by RIT (odds ratio, 0.17; P = .026).

• On an intent-to-treat basis, patients receiving both omalizumab and immunotherapy showed a significant improvement in severity scores during the ragweed season compared with those receiving immunotherapy alone (0.69 vs 0.86; P = .044).

Casale TB, et al, JACI 2006 117:134-40

Reduce side effects in Omalizumab + Reduce side effects in Omalizumab + SIT- rush in Allergic RhinitisSIT- rush in Allergic Rhinitis

CONCLUSION:• Omalizumab pretreatment enhances the

safety of RIT for ragweed allergic rhinitis.• Combined therapy with omalizumab and

AIT may be an effective strategy to permit more rapid and higher doses of AIT to be given more safely and with greater efficacy to patients with allergic diseases.

Casale TB, et al, JACI 2006

Reduce side effects of SITReduce side effects of SITHymenoptera AllergyHymenoptera Allergy

Beginning of Treatment with OmalizumabWeek 0: 1 sc inj of Omalizumab 150 mg

Week 2: 1 sc inj of Omalizumab 150 mg

Week 4: 1 sc inj of Omalizumab 150 mg

Initiation of VIT Combined with OmalizumbWeek 5: rush VIT 1 + 5 + 10 μg bee venom (well tolarated)

Week 6: 1 sc inj of Omalizumab 150 mg

Week 7: VIT 30 + 50 μg bee venom (well tolerated)

Week 8: 1 sc inj of Omalizumab 150 mg ….

Galera C et al, J Investig Allergol Clin Immunol 2009; 19: 225-229

Reduce side effects of SITReduce side effects of SITHymenoptera AllergyHymenoptera Allergy

Maintenance Phase : VIT + Combined with Omalizumab Monthly

Month 4: 1 sc inj of Omalizumab 150 mg + after 15 min VIT 200 μg bee venom (well tolerated)

Continuation of the Protocol

Galera C et al, J Investig Allergol Clin Immunol 2009; 19: 225-229

Food allergyFood allergy

• A phase II clinical trial of omalizumab was recently initiated in subjects with peanut allergy, but was stopped as a result of safety concerns after severe reactions occurred during initial oral challenges. 

Food AllergyFood Allergy

• Anti-IgE Ab (TNX-901) –increase the threshold peanut protein dose for oral food challenge (178 to 2805 mg) – Phase I trial

• Clinical trials are in progress: anti-IgE monotherapy and omalizumab + oral immunotherapy (Milk Allergy, Peanut)

Scurlock AM, et al, Curr Opin Aller Clin Immunol, 2010

Anti-IgE therapy in other

Non-allergic diseases

Anti-IgE therapy in other non-allergic diseases

• Hyper IgE syndrome (Job’s Syndrome)

• Eosinophilic gastrointestinal disease

• Idiopathic anaphylaxis

• Interstitial cystitis/Bladder Pain Syndrome

Therapeutic options for Eosinophilic Therapeutic options for Eosinophilic EsophagitisEsophagitis

DietsDiets

•Elemental Diet

•Elimination Diet (individually, allergy-testing based)

•Six-Food Eliminatiobn Diet

MedicationsMedications• Corticosteroids systemically• Corticosteroids topically (Budesonide, Fluticasone)• Leukotriene-Antagosnists (Montelukast)• CRTH2-Blocker (OC)))459)• Biologicals (anti-IL-5, anti-TNF, anti-IgE (Omalizumab),anti-IgE (Omalizumab), anti-IL-13 (QAX576)• Immunosuppressants (Azathioprine, 6-Mercaptopurine)

Endoscopic ProceduresEndoscopic Procedures

• Dilatation (Ballon, Savary)

Eosinophilic EsophagitisEosinophilic Esophagitis

• Clinical trials on EoE with Omalizumab are ongoing

Anti-IgE therapy off-label Anti-IgE therapy off-label indicationsindications

• Age: 6-76 years old

• Pregnancy

Take Home MessageTake Home Message

• Double-blind, placebo-controlled clinical trials in moderate to severe asthma, allergic rhinitis, combined therapy with SIT

• Case series in urticaria, atopic dermatitis

• Case reports on ABPA, Churg-Strauss syndrome, eosinophilic gastroenteritis, mastocytosis

CONCLUSIONSCONCLUSIONS

• Anti-IgE therapy is highly effective in children and adults with allergic rhinitis

• Anti-IgE therapy combined with SIT was demonstrated in DBPC trials superior to SIT alone in reducing side effects and improving symptoms

CONCLUSIONS (2)CONCLUSIONS (2)

• Promising data for anti-IgE therapy in various allergic condition (food allergy, urticaria, ABPA, AD)

• There is a need of more studies ! (28 studies are recruting pts – http://www.clinicaltrials.gov)

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deleanudiana@yahoo.com

. A potential mechanism of omalizumab's effect on thrombus formation and cardiovascular effect is postulated.