Dal convegno "Novità diagnostico-terapeutiche in Allergologia e Immunologia Clinica" del 10 Novembre 2018, Torino

1. OLIVIERO ROSSI
oliviero.rossi@unifi.it
S.O.D. IMMUNOALLERGOLOGIA
Direttore Prof. F. Almerigogna
AZIENDA OSPEDALIERA UNIVERSITARIA CAREGGI FIRENZE
Omalizumab : utilizzi clinici

2. 1968-2018:
la storia delle IgE
s s
s s s
ss
s
1968
Registration of the new
isotype
2018
The death of who discovered IgE

4. J Allergy Clin Immunol.2018 Sep;142(3):788-789.

5. SIAAIC TOSCANA 2016

6. SIAAIC TOSCANA 2016
FcεRI is expressed on mast cells and basophils

7. 
FcRI
ad alta affinità
Mastociti Cellule dendritiche
Basofili
Eosinofili
Monociti Piastrine
.
M. liscio
Il recettore ad alta affinità per le IgE non è espresso
solo dai mastociti e basofili

8. The low affinity IgE receptor CD23
(FcεRII)
Human CD23 exists as two isoforms (CD23a and CD23b
CD23 is mainly expressed on B-cells, epithelial
cells as well as antigen-presenting cells

9. Immunol Lett. PMC 2012 Dec 30.
IgE : Recettori solubili

10. "Monomeric IgE response" means that mast cells
can be activated by IgE in the absence of its
antigen.
Monomeric IgE increases surface expression of
FcεRI on basophils and mast cells
IgE monomeriche

11. 11
Modificato da Humbert et al JACI Pract 2014
IgE ed i suoi recettori coinvolte nei differenti steps patogenetici dell’asma bronchiale

12. In 1993 a team at Genentech had developed a molecule called
omalizumab, which successfully helped block the IgE
antibodies.
They were very excited about the potential of the first biologic
for allergic asthma, but were unsure what other roles IgE might
play in the body, or what the effects of blocking that antibody
would be.
Omalizumab : 25 years ago

13. Grande interesse ha suscitato l’introduzione
dell’anticorpo monoclonale anti IgE
nella terapia dell’asma bronchiale
Nel 1998 , presso l’Universita’ del Colorado e’ stata sperimentata una
terapia con anticorpi monoclonali anti-IgE. Sono stati esaminati
317 pazienti gia’ in trattamento cortisonico e randomizzati per
placebo o per anticorpi monoclonali anti-IgE a diverso dosaggio.
Henry Milgrom, MD
OMALIZUMAB: 20 YEARS AGO

14. 1999; 341:1966-73
Riduzione della dose di CCS) Sospensione dei CCS

15. Approved indication of anti-IgE therapy:
Add-on treatment in allergic severe asthma
(GINA 2006)
Anti-IgE
treatment
Australia: 2002
US: 2003
EMA: 2005

16. 2014

17. Studi di fase III di Omalizumab in adulti e adolescenti con
asma grave: 10 anni di esperienza in real-life
1. Humbert M, et al. Allergy 2005; 2. Ayres JG, et al. Allergy 2004; 3. Vignola AM, et al. Allergy 2004;
4. Busse W, et al. J Allergy Clin Immunol 2001; 5. Solèr M, et al. Eur Respir J 2001;
6. Holgate ST, et al. Clin Exp Allergy 2004

18. *‘Pre-treatment’ is for 12 months prior to the start of omalizumab treatment. Annualised data are presented for ‘Month 12’ (combining Week 16,
Month 8 and Month 12 time-points) and ‘Month 24’ (combining Month 18 and Month 24 time-points). N=number of evaluable patients at baseline,
Months 12 and 24. Error bars represent SD.
Mean number of clinically significant and severe clinically significant
exacerbations
Meannumberofexacerbations
n=847 n=842 n=686 n=691 n=620 n=625
Clinically significant exacerbations
Severe clinically significant exacerabtions
Significativa riduzione delle riacutizzazioni in real life
(The eXpeRience registry) “real world” 943 pazienti
Braunstahl G-J, et al. Respir Med 2013

19. Omalizumab migliora il controllo dell’asma
e la qualità della vita (The eXpeRience registry)
✓ indicates meaningful improvement Mean (SD) change from baseline:
Measure Month 12 Month 24
ACT
Meaningful improvement =
increase of 3 points vs. baseline
6.1 ✓ 6.2 ✓
ACQ
Clinically relevant improvement = decrease of
0.5 points vs. baseline
0.83 ✓ 0.80 ✓
AQLQ
Clinically relevant improvement = increase of
0.5 points vs. baseline
0.97 ✓ 0.75 ✓
Mini-AQLQ
Clinically relevant improvement = increase of
0.5 points vs. baseline
1.3 ✓ 1.62 ✓
Misurazioni validate mostrano un miglioramento nel controllo dell’asma e della
qualità di vita nei 24 mesi
QoL = Quality of Life; SD = Standard Deviation; ACT = Asthma Control Test; ACQ = Asthma Control Questionnaire;
AQLQ = Asthma Quality-of-Life Questionnaire
Braunstahl G-J, et al. Respir Med 2013

20. Since its initial licensing for use in adults and adolescents 12 years of age and
older, the clinical efficacy, safety, and tolerability of omalizumab have been
demonstrated in several published clinical trials in children aged 6 to less than
12 years with moderate-to-severe AA
These studies supported the approval of the pediatric indication (use in
children aged >_6 years) by the European Medicines Agency in 2009 and the US
Food and Drug Administration in 2016.
(J Allergy Clin Immunol 2017;139:1431-44.)
Omalizumab in children

21. • Nei pazienti pediatrici in trattamento
da 2 anni si osserva una riduzione quasi
completa delle riacutizzazioni rispetto al
basale e al primo anno di terapia
• Non si sono verificate ospedalizzazioni
per riacutizzazioni nel secondo anno di
trattamento
• Nel 63% dei pazienti si è più che
dimezzata la dose di steroide inalatorio
(fluticasone equivalente) rispetto a
basale e rispetto al primo anno di
terapia.
Notevole riduzione delle riacutizzazioni e delle
ospedalizzazioni nei bambini con asma grave allergico
Real-life long term omalizumab therapy in children with severe allergic asthma
Deschildre et al., Eur Respir J 2013

22. E’ da poco iniziato uno studio di fase II (Studio PARK, Preventing Asthma in High Risk K
bambini in età pre-scolare (2-4 anni) che siano ad alto rischio di sviluppare l’asma e ven
preventiva con omalizumab (per due anni) per vedere se questo impedirà la progressio
Omalizumab in children < 6 aa

23. OMALIZUMAB
The first “biologic” approved for allergic asthma was omalizumab, a mAb (monoclonal
antibody) binding free IgE, inhibiting activation of mast cells, basophils, and DCs.
•Omalizumab è un anticorpo monoclonale
umanizzato (PM ~150 kDalton). I residui
murinici, inferiori al 5%, sono localizzati nella
regione variabile;
•Omalizumab, legandosi alle IgE circolanti
attraverso il binding con il dominio C3,
previene il legame delle IgE a recettori ad alta
e bassa affinità;
•Forma complessi con le IgE piccoli e
biologicamente inerti
•Non fissa il complemento
•Non causa anafilassi

24. Mechanism of action of omalizumab
Tabatabaian F Journal of Asthma and Allergy 2018

25. Bloccare le IgE: NON è un
singolo effetto (effetto
MULTI-TARGHET)!
25
Modificato da Humbert et al JACI Pract 2014
Peripheral, sputum
and sub-mucosal
eosinophilia1
Impact on
T-lymphocytes
and
B-lymphocytes5
IL-2, IL-4,
IL-5, IL-13
and GM-CSF1–4
Binds free IgE and down-
regulates IgE receptors
(FcRI) on mast cells,
basophils and DCs
Bloccare le IgE : effetti sul network immunologico di asma
bronchiale ed orticaria cronica
Asma bronchiale

26. Maggi L, EJI 2018

27. Receptor bound-IgE
FcRI expression
IgE detachment:
new mechanism
IgE neutralization:
established mechanism
FcεRI
Omalizumab
IgE
Allergen
Omalizumab in allergic asthma
Maggi L, EJI 2018

28. Lommatzsch M Allergo J Int. 2016; 25: 11–17.
BIOLOGICS IN ASTHMA 2018
Journal of Allergy and Clinical
Immunology 2017 139, 1411-142

29. OMALIZUMAB
OMALIZUMAB COME IMMUNOMODULATORE ?!

30. (J Allergy Clin Immunol 2008;122:671-82.)
Ruolo degli Interferoni nelle riacutizzazioni asmatiche virali
Nei soggetti asmatici è dimostrato un difetto di risposta
con interferone nelle infezioni da rinovirus e da altri virus
E’ dimostrata una
ridotta produzione di
INF-alfa da parte dei
PBMCs e dei macrofagi
dei soggetti asmatici.
L’epitelio bronchiale dei
soggetti asmatici
dimostra un difetto di
produzione di IFN-beta
in risposta alle infezioni
da rinovirus

31. (J Allergy Clin Immunol 2015;136:1476-85.)
OMALIZUMAB COME IMMUNOMODULATORE ?!
L’Interferone  è il principale attore dell’immunità innata (difesa vs
infezioni virali)
Nei soggetti asmatici le IgE sono correlate in modo inverso ai livelli di
IFN-
Omalizumab, sequestrando le IgE, riduce le riacutizzazioni da
infezioni virali

32. (J Allergy Clin Immunol 2018;141:1735-43
Treatment with omalizumab restores ex vivo IFN-a responses to
rhinovirus and influenza virus
Stretta correlazione tra ridotta espressione dell’ FcεRIα sulle pDC ed incrementata
produzione di IFNα nei pazienti trattati con Omalizumab e riduzione delle riacutizzazioni
asmatiche.

33. Panettieri et al. J Allergy Clin Immunol 121:607-13, 2008
Airway Remodeling
33
OMALIZUMAB COME IMMUNOMODULATORE ?!

34. ✓ 16 settimane di trattamento con omalizumab
riducono lo spessore della parete delle vie
aeree
✓ La variazione dello spessore della parete è
associata ad una marcata riduzione degli
eosinofili nell’espettorato, a miglioramenti
della funzionalità polmonare e della QoL
Hoshino. Respiration 2012
Data are expressed as median (range). Ai = airway luminal area; BSA = body surface area
NS = non significant; T = wall thickness; WA = airway wall area; WA% = percentage of wall area
*p<0.05; **p<0.01: within-group comparisons
Omalizumab riduce l’infiammazione e
l’ispessimento della parete bronchiale
OMALIZUMAB COME IMMUNOMODULATORE ?!

35. Riccio et al. Int J Immunol Pharmacol 2012
Omalizumab modula lo spessore della membrana
basale e riduce l’infiltrazione eosinofilica

36. AQLQ FEV1 EXACERBATIONS

37. OMALIZUMAB COME IMMUNOMODULATORE ?!
Evaluating the Xolair Persistency Of Response After
Long-Term Therapy (XPORT) was a randomized, double-blind,
placebo-controlled withdrawal study
5 + 1 Year
(J Allergy Clin Immunol 2017)

38. Studio XPORT- benefici dell’uso a lungo termine di omalizumab
• La continuazione del trattamento con omalizumab porta ad un numero significativamente maggiore di pazienti nel
gruppo con omalizumab (67%) rispetto al placebo (47.7%) che non ha avuto esacerbazioni gravi
• Il controllo dei sintomi è significativamente maggiore nel gruppo di pazienti trattati con omalizumab rispetto al
gruppo placebo, come dimostra la variazione del punteggio dal basale alla settimana 52 nei questionari ACT e ACQ
• Anche dopo l’interruzione della terapia con omalizumab potrebbero esserci dei benefici persistenti in alcuni
pazienti (47.7% dei pazienti nel braccio placebo è senza esacerbazioni), tuttavia i soggetti che proseguono la terapia
hanno maggiori benefici
(J Allergy Clin Immunol 2017)

39. 45
pazienti
23-121
mesi
Media
60.7 +/-
30.9
mesi
10 anni
Riduzione dei ricoveri dovuti all’asma Riduzione dell’utilizzo dei ccs

40. AIRWAY INFLAMMATION AND INFLAMMATORY BIOMARKERS
Semin Respir Crit Care Med 2018; 39(01): 056-063

41. Am J Respir Crit Care Med 2013
BIOMARKERS PER OMALIZUMAB
Omalizumab riduce le esacerbazioni in pazienti con
alti livelli di biomarker- studio EXTRA

42. L’efficacia di omalizumab non è condizionata dal numero degli eosinofili

43. L’efficacia di omalizumab non è condizionata dal numero degli eosinofili

44. Of 806 enrollees, 801 (99.4%) received omalizumab and 622
(77.2%) completed the study. : Omalizumab initiation in patients
with asthma resulted in improved exacerbation rates, reduced
hospitalizations, and improved ACT scores compared with
pretreatment values, regardless of biomarker status
J ALLERGY CLIN IMMUNOL PRACT MONTH 2018

46. Omalizumab is an anti-immunoglobulin E (IgE)
monoclonal antibody (mAb) currently approved as
an add-on treatment for CSU in patients with
inadequate response to H1-antihistamines in more
than 50 countries with a strong evidence base
(clinical trials and case-reports) supporting its
use
Efficacia clinica di omalizumab nell’orticaria cronica

47. ORTICARIA : CLASSIFICAZIONE
chronic idiopathic urticaria (CIU), also
called chronic spontaneous urticaria (CSU)
Efficacia clinica di omalizumab nell’orticaria cronica
spontanea

49. Allergy. 2018;73:1393–1414.
ORTICARIA CRONICA SPONTANEA (CSU)

50. Allergy. 2018;73:1393–1414.
DIAGNOSI ORTICARIA CRONICA : QUALE
RUOLO CLINICO ?

51. > 800 pazienti
Omalizumab: efficacia e sicurezza d’impiego nel paziente con orticaria cronica

52. • This is the first systematic review of omalizumab in chronic idiopathic
urticarial reported in the literature.
• Of 1117 patients obtained, 831 received at least one dose of
omalizumab in randomized controlled clinical trials with placebo.
• Therefore no meta-analysis of the review was conducted
Dose ottimale
The different doses used in the studies show a clear
benefit of using omalizumab 300 mg compared with
placebo in the treatment of the disease

53. ORTICARIA CRONICA : COMPLESSI MECCANISMI PATOGENETICI

55. Its mode of action in CU is not entirely understood.
It might reduce mast cell releasability, by reducing
high affinity receptors for IgE (FcεRI) and IgE, as
well as IgE against autoantigens
It seems to decrease in vitro coagulation abnormalities
that mirror disease activity
Mechanism of action of omalizumab
Journal of Allergy and Clinical Immunology 2017 139, 1411-142

56. Omalizumab sequesters monomeric IgE to
reduce its priming effect on mast cells.

58. Receptor bound-IgE
FcRI expression
IgE detachment:
new mechanism
IgE neutralization:
established mechanism
FcεRI
Omalizumab
IgE
Allergen
Omalizumab in allergic asthma
Maggi L, EJI 2018

59. ANTI-H1 standard dose
OMALIZUMAB
THE ONLY THERAPIES
WITH REGULATORY
APPROVAL
FOR TREATMENT OF
CHRONIC IDIOPHATIC
URTICARIA
NUOVE FRONTIERE ORTICARIA CRONICA

61. Omalizumab nella poliposi nasale
JACI 2013

62. Rivero A, Liang J - Ann Otol Rhinol Laryngol 2017
Omalizumab nella poliposi nasale

63. Omalizumab in ABPA

64. ALLERGEN IMMUNOTHERAPY AND
OMALIZUMAB : SINERGIA D’AZIONE ?!

65. Cochrane Database of Systematic Reviews
2012, Issue 10. Art. No.: CD008838.
Authors' conclusions
• The treatment carries a small but significant risk of systemic adverse
reaction.
• VIT may often be associated with immediate anaphylaxis which can lead
to treatment withdrawal.
• Several cases published in recent years suggest that omalizumab, used as add-on
therapy may be able to prevent anaphylaxis during VIT.

66. Omalizumab facilitates rapid oral
desensitization for peanut allergy
March 2017 139, 3, 873–881.e8
Conclusion
Omalizumab allows subjects with peanut allergy to be rapidly
desensitized over as little as 8 weeks of peanut oral immunotherapy.
Results: The median peanut dose tolerated on the initial desensitization day was 250
mg for omalizumab-treated subjects versus 22.5 mg for placebo-treated subject.
Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of
peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving
placebo (P < .01). Twenty-three subjects receiving omalizumab versus 1 subject
receiving placebo passed the 4000-mg food challenge.

67. CONCLUSIONS:
In this first randomized, double-blind, placebo-controlled trial
of omalizumab in combination with food OIT, we found significant
improvements in measurements of safety but not in outcomes of
efficacy (desensitization and SU).
With or without omalizumab, most subjects could be desensitized to a
high dose (10 g) of milk protein over a 24-month period, but half had
increased reactivity after an 8-week period of avoidance
(J Allergy Clin Immunol 2016;137:1103-10.)

68. © Global Initiative for Asthma
Stepwise approach to control asthma symptoms
and reduce risk
GINA 2017, Box 3-5 (1/8)
Symptoms
Exacerbations
Side-effects
Patient satisfaction
Lung function
Other
controller
options
RELIEVER
REMEMBER
TO...
• Provide guided self-management education (self-monitoring + written action plan + regular review)
• Treat modifiable risk factors and comorbidities, e.g. smoking, obesity, anxiety
• Advise about non-pharmacological therapies and strategies, e.g. physical activity, weight loss, avoidance of
sensitizers where appropriate
• Consider stepping up if … uncontrolled symptoms, exacerbations or risks, but check diagnosis, inhaler
technique and adherence first
• Consider adding SLIT in adult HDM-sensitive patients with allergic rhinitis who have exacerbations despite
ICS treatment, provided FEV1 is >70% predicted
• Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations.
Ceasing ICS is not advised.
STEP 1 STEP 2
STEP 3
STEP 4
STEP 5
Low dose ICS
Consider low
dose ICS
Leukotriene receptor antagonists (LTRA)
Low dose theophylline*
Med/high dose ICS
Low dose ICS+LTRA
(or + theoph*)
As-needed short-acting beta2-agonist (SABA) As-needed SABA or
low dose ICS/formoterol#
Low dose
ICS/LABA**
Med/high
ICS/LABA
Diagnosis
Symptom control & risk factors
(including lung function)
Inhaler technique & adherence
Patient preference
Asthma medications
Non-pharmacological strategies
Treat modifiable risk factors
PREFERRED
CONTROLLER
CHOICE
Add tiotropium*
High dose ICS
+ LTRA
(or + theoph*)
Add low dose
OCS
Refer for add-
on treatment
e.g.
tiotropium,*
anti-IgE,
anti-IL5*
SLIT added as
an option
ASMA BRONCHIALE : APPROCCIO TERAPEUTICO IDEALE
GINA 2017 : LA SLIT ANCHE NEL PAZIENTE ASMATICO

69. Severe or uncontrolled asthma is the most important and independent risk factor for
both nonfatal and fatal adverse reactions to AIT .
In general, the frequency and the duration of therapy and the potential for systemic
allergic reactions have limited its use, especially in patients with symptomatic persistent
asthma who are at greater risk for severe reactions
AIT could be an effective treatment in order to optimize the disease control,
omalizumab could be used in order to minimize the risk of adverse event related to AIT
administration or, on top of other treatments, to further ameliorate the disease control.

70. Anti IgE Tomorrow
The only FDA-approved anti-IgE drug is Omalizumab, a humanized
anti-IgE mAb that blocks free IgE, and which is approved for the
treatment of moderate to severe persistent allergic asthma, and
chronic spontaneous urticaria (CSU).

71. PAZIENTI IN TRATTAMENTO CON OMALIZUMAB
(04/2017 >07/2018)
ITALIA
Aprile 2017 : Pazienti totali 5274
di cui ,con asma allergico severo
4.404 (313 pediatrici)
…..e 870 con CSU
Luglio 2018 : Pazienti totali 6960
di cui ,con asma allergico severo
5.575 (395 pediatrici )
…..e 1385 con CSU
2005 2018

72. SIAAIC TOSCANA 2016