biological therapy with anti-IgE monoclonal antibodies

1. Indications for anti IgE otherIndications for anti IgE other
than asthmathan asthma
Diana DeleanuDiana Deleanu
Univ of Medicine & Pharmacy Iuliu Hatieganu,
Cluj-Napoca, Romania
deleanudiana@yahoo.comdeleanudiana@yahoo.com

2. 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.

3. Indications of anti-IgE TherapyIndications of anti-IgE Therapy

4. 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!

5. 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 highOmalizumab'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 isdrugs 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 evenpersistent 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.

6. Human mind is allways
surching!

7. New perspective on anti-IgENew perspective on anti-IgE
therapytherapy
Fagaras Mountains

8. 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

9. IgE releaseIgE release
PlasmocytePlasmocyte
B lymphocyteB lymphocyte
εε-switch-switch
ExacerbationExacerbation
of allergyof allergy
AllergicAllergic
Inflammation:Inflammation:
eosinophile &eosinophile &
lymphocytslymphocyts
AllergenAllergen
Mast cellsMast cells
BasophilsBasophils
AllergicAllergic
MediatorsMediators
Allergic CascadeAllergic Cascade

10. Mechanism of inhibition byMechanism of inhibition by
omalizumabomalizumab

11. Allergy Symptoms
Possible Targets for the action of Anti-IgEPossible 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
Reduce
The release
of mediators
Reduce exacerbation
And
symptoms
Plasmocyte
B lymphocyte
ε-switch Mediators
Release
of IgE
Mast cells
Basophil
Inflammation:
eosinophil and
lymphocyte
Barnes PJ. Int Arch Allergy Immunol. 2000;123:196-204.

12. Other effects of anti-IgEOther 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

13. Out–off label Anti-IgE therapyOut–off label Anti-IgE therapy
• Respiratory Disease
• Skin Disease
• Anaphylaxis (as disease or a side effect)
• Others

14. Anti-IgE therapy as off–labelAnti-IgE therapy as off–label
indicationsindications
Respiratory DiseaseRespiratory Disease

15. Medline searchMedline search
0
10
20
30
40
50
60
70
80
90
100
2001 2003 2005 2007 2009 2011
articles
asthma
rhinitis
Churg-Strauss
ABPA

16. 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

17. Allergic RhinitisAllergic Rhinitis
DBPC 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

18. Allergic RhinitisAllergic Rhinitis
• Daily nasal severity score
Kimihiro Okuda & Toshikazu Nagakura, Allergology International 2008; 57: 205-9

19. Japanase cedar pollinosisJapanase cedar pollinosis
Kimihiro Okuda & Toshikazu Nagakura, Allergology Internationakl 2008; 57: 205-9

20. Japanase cedar pollinosisJapanase cedar pollinosis
Kimihiro Okuda & Toshikazu Nagakura, Allergology Internationakl 2008; 57: 205-9

21. 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

22. Nasal PolyposisNasal Polyposis
Retrospectively 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

23. 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)

24. Allergic broncho-pulmonaryAllergic 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

25. Allergic broncho-pulmonaryAllergic 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)

26. Allergic broncho-pulmonaryAllergic 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)

27. 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

28. Churg-Strauss Syndrome induced
by anti-IgE therapy
• Definitive cases – 13
• Probable cases – 4
Wechsler ME et al, Chest, 2009

29. COPDCOPD
• Under evaluation

30. Anti-IgE therapy beyond asthmaAnti-IgE therapy beyond asthma
Skin DiseaseSkin Disease

31. Anti-IgE therapy beyond asthma
Skin Disease
• Atopic dermatitis/eczema
• Chronic idiopatic urticaria/Angioedema
• Autoimmune urticaria
• Mastocytosis
• Bullous Pemphigoid

32. 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)

33. 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

34. 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

35. 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-α…)
Considerer adding leukotriene modifying
agebnt, cyproheptadine or oral albuterol
Other treatments (stanazol,
theophylline, ….)
STEP THERAPYSTEP THERAPY
FOR CHRONICFOR CHRONIC
URTICARIAURTICARIA

37. 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)

38. Chronic AngioedemaChronic Angioedema
• 3 pts treated successfully with
Omalizumab
Sands MF et al, JACI 2007; 120:979-81

39. 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

40. Bullous PemphigoidBullous Pemphigoid
• A letter to editor
• Reporting one 70 years old women
Fairley JA, et al. JACI 2009; 123: 704-5

41. Bullous PemphigoidBullous Pemphigoid
• A letter to editor
• Reporting one 70 years old women
Fairley JA, et al. JACI 2009; 123: 704-5

42. Anti-IgE therapy – clinical utilityAnti-IgE therapy – clinical utility
Allergic DiseaseAllergic Disease

43. Anti-IgE therapy – clinical utilityAnti-IgE therapy – clinical utility
Allergic DiseaseAllergic Disease
• Immunotherapy (to reduce side effects of
immunotherapy)
• Latex allergy
• Food allergy (peanut)
• Drug allergy

44. Side effects of SIT
• Linda Cox tb

45. Safety methods for Immunotherapy
with allergenic vaccines
Premedication with:
• Antihistamine
• Leukotriene antagonist
• Omalizumab

46. Omalizumab and ImmunotherapyOmalizumab and Immunotherapy
in 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

47. Effect of pretreatment with omalizumab on theEffect 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

48. 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

49. Combination therapy: anti-IgECombination 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

50. Reduce side effects in OmalizumabReduce 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

51. 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

52. Reduce side effects of SITReduce side effects of SIT
Hymenoptera AllergyHymenoptera Allergy
Beginning of Treatment with Omalizumab
Week 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 Omalizumb
Week 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

53. Reduce side effects of SITReduce side effects of SIT
Hymenoptera 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

56. 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.

57. 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

58. Anti-IgE therapy in other
Non-allergic diseases

59. Anti-IgE therapy in other
non-allergic diseases
• Hyper IgE syndrome (Job’s Syndrome)
• Eosinophilic gastrointestinal disease
• Idiopathic anaphylaxis
• Interstitial cystitis/Bladder Pain Syndrome

60. Therapeutic options for EosinophilicTherapeutic 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)

61. Eosinophilic EsophagitisEosinophilic Esophagitis
• Clinical trials on EoE with Omalizumab are
ongoing

62. Anti-IgE therapy off-labelAnti-IgE therapy off-label
indicationsindications
• Age: 6-76 years old
• Pregnancy

63. 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

64. 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

65. 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)

66. Peles CastlePeles Castle

67. Black SeeBlack See
CasinoCasino

68. Thank youThank you
deleanudiana@yahoo.com

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