Dal convegno "Novità diagnostico-terapeutiche in Allergologia e Immunologia Clinica" dell'11 Novembre 2017, Torino

1. 1
IMMUNOTERAPIA CON NPP E DISEASE MODIFYING
Cristoforo Incorvaia
ASST Pini-CTO, Milano

2. L’immunoterapia specifica: definizione
▪ L’immunoterapia specifica si basa sulla
somministrazione in fase iniziale dell’allergene
responsabile a dosi progressivamente crescenti e
in seguito con una dose di mantenimento per 3-5
anni.
▪ Il trattamento induce modificazioni della risposta
immunologica all’allergene somministrato che si
associano a tolleranza clinica.
2

3. The AIT evolution
3
J Allergy Clin Immunol 2010;127:3-7. © 2012 PROGETTO LIBRA • www.progetto-aria.it •

4. Paul Ehrlich Inst Bundesamt Sera Impstoffe Frank AM. 2003;(94):7-14.
Kroon AM. The EAMG position on the regulation of existing products for
treatment with special reference to named patient products (NPPs)
Allergen products have a long history in both diagnosis and management of
allergic disease. It is emphasized that the availability of named patient products
presents a valuable and indispensable option for the effective and safe treatment
of patients suffering from IgE-mediated allergic diseases. A regulatory climate
should be achieved in which these products can survive until a safe and effective
alternative is borne out. Within the context of the paper the following definition is
used: A named patient product or NPP is an allergen product, prepared with a
specific reference number in accordance with a prescription for an individual
patient, identified by the name of this patient and the reference number, and
delivered after control of consistency with previous treatments. It is stressed that
the standards of quality that hold for registered products are also applicable for
named patient preparations which, for various reasons, can not be filed for
registration. The paper frequently refers to a Position Paper that has recently
been adopted by the European Allergen Manufacturers Group, the EAMG. The
presentation breaks a lance for a concerted approach of the NPP-concept by
striving at harmonization of legal, regulatory, manufacturing, and distribution
conditions.

5. Calderon M. Cochrane Database Syst Rev 2007; (1):CD001936.
Symptom scores 15 studies n = 1063 SMD -0.73

6. Calderon M. Cochrane Database Syst Rev 2007; (1):CD001936.
Medication scores 13 studies n = 963 SMD -0.57

7. Allergen immunotherapy for asthma
88 studi controllati, numero totale 3792 pazienti
SMD C.I. P
Sintomi -0.59 -0.83 -0.35 0.001
ITS SOTTOCUTANEA - ASMA
Efficacia
M.J. Abramson – Cochrane Datab Syst Rev - 2010

8. Symptom scores 8 studies n = 304 SMD -0.78
Abramson MJ. The Cochrane Library 2010, Issue 8
Allergen injection immunotherapy for asthma
Abramson MJ, Puy RM, Weiner JM.

10. Wilson D et al. Allergy 2005; 60: 4-12.
Symptom scores 21 studies n = 959 SMD -0.42
The first meta-analysis on SLIT

11. Calamita et al. Allergy 2006; 61: 1162-72.
Meta-analysis of SLIT in asthma

12. Ann Allergy Asthma Immunol 2006; 97:141-48

13. Penagos M et al. Ann Allergy Asthma Immunol 2006; 97:141-48
Symptom scores
Symptom scores 10 studies n = 491 SMD -0.56

14. Chest 2007;

15. Symptom scores
Symptom scores 9 studies n = 441 SMD -1.14

16. Studi
( ITS – Malattia )
Efficacia sui sintomi
( SMD; 95% CI )
Abramson et al. 2003
(SCIT – Asma)
- 0.72 (-0.99, -0.44); P < .001
Calamita et al. 2006
(SLIT – Asma)
- 0.38 (-0.79, -0.003); P < .07
Penagos ed al. 2008
(SLIT – Asma)
- 1.42 (-2.25, -0.59); P < .02
Olaguibel et al. 2005
(SLIT – Asma/Rinite)
- 1.42 (-0.99, -0.34); P < .01
Calderon et al 2007
(SCIT – Rinite)
- 0.73 (-0.97, -0.50); P < .001
Penagos et al. 2006
(SLIT – Rinite)
- 0.56 (-1.01, -0.10); P < .02
Wilson et al. 2005
(SLIT – Rinite)
- 0.42 (-0.69, -0.15); P < .002
-2 +2-1 +10
a favore ITS a favore placebo
SMD ( 95% Cl )
Specific immunotherapy for respiratory allergy:
state of the art according to current meta-analyses
Compalati et al. Ann Allergy Asthma Immunol - 2009

17. Studi che hanno individuato
la dose efficace nella SCIT
Fonte Allergene maggiore Autore, anno Dose in g
Polline di Amb a 1 van Metre, 1980 4-47
ambrosia Creticos, 1996 10
Polline di Phl p 5 Osterballe, 1980 25-41
graminacee
Pelo di gatto Fel d 1 Taylor, 1978 16
Ohman, 1984 8-16
Alvarez, 1994 13
Acari della polvere Der p 1 Bousquet, 1987 5
Wahn, 1988 0.5-11.5
Haugaard, 1993 7

18. Dose dipendenza della SLIT
Sublingual/swallow IT
Efficacy of high allergen dose sublingual/ swallow
IT (at least 50 to 100 times the cumulative dose of
subcutaneous IT) has been documented in double-
blind placebo-controlled studies.
Lower doses are not effective.
Bousquet et al, 2001

19. Sublingual immunotherapy:
World Allergy Organization Position Paper 2009.
Allergy 2009;64 (suppl 91):1-59.
 Dose mensile raccomandata
nella SLIT con polline di
graminacee: 600 mcg di
allergene maggiore Phl p 5
 Tale dose equivale a quella
somministrata con le recenti
preparazioni in compresse per
SLIT

20. Evidenza meta-analitica
di dose-dipendenza della SLIT
126:558-66

21. Pauli G et al, J Allergy Clin Immunol 2008;122(5):951-60
No significant difference in
efficacy between natural product
and ricombinant product

22. Number
of
studies
Number
of
patients
Kind of treatment
of seasonal
rhinitis
Number of
symptoms
evaluated
Duration of
the
evaluation
% improvement
vs
placebo
Meta-analysis
Benninger
38 12 926 Anti-H1 5 15 days  9 %
Nasal CS 4 15 days  26 %
Meta-analysis
Wilson
11 3 924 Anti-H1 5 15 days  7 %
Nasal CS 4 15 days  17 %
Antileukotrienes 4 15 Days  5 %
Registred grass
pollen tablets
Clinical studies
3 1 500 Immunotherapy
6
(all symptoms)
 30 days
(pollen season)
 30 %
 40%
for severe patients
Antileucotrieni Antistaminici Steroidi nasali SLIT Tablets
registrate
Modesto ?
Number
of
studies
Number
of
patients
Kind of treatment
of seasonal
rhinitis
Number of
symptoms
evaluated
Duration of
the
evaluation
% improvement
vs
placebo
Meta-analysis
Benninger
38 12 926 Anti-H1 5 15 days  9 %
Nasal CS 4 15 days  26 %
Meta-analysis
Wilson
11 3 924 Anti-H1 5 15 days  7 %
Nasal CS 4 15 days  17 %
Antileukotrienes 4 15 Days  5 %
Registred grass
pollen tablets
Clinical studies
3 1 500 Immunotherapy
6
(all symptoms)
 30 days
(pollen season)
 30 %
 40%
for severe patients
Antileucotrieni Antistaminici Steroidi nasali ITS
Am J Med 2004;116:338-44
Confronto tra le terapie sintomatiche e
l’ITS nella rinite allergica stagionale

23. Hellings PW et al. Allergy 2013; 68: 1-7
© 204 PROGETTO LIBRA •
www.progetto-aria.it •

25. Novembre E. J Allergy Clin Immunol 2004; 114: 851-7.
0%
20%
40%
60%
80%
100%
SLIT Control
%ofpatients
w asthma
w/o asthma
Odds ratio 3.80 (1.5-10.0)
80
%
60%
n=8
20% 40%
n=18
Coseasonal SLIT reduces the development of
asthma in children with allergic rhinitis.
79 children
Allergic rhinitis
Follow-up: 3 yrs

26. 26

27. 0
10
20
30
40
50
60
70
80
90
100
Controllo ITS
Controls SIT

29. ITS con veleno di Imenotteri:
dimostrazione di efficacia con studi controllati
Efficacia completa in circa il 95% dei pazienti

30. Passalacqua G. Ann Allergy Asthma Immunol.
2011;107:401– 406.
ITS: effetto carry-over
© 2012 PROGETTO LIBRA • www.progetto-
aria.it •

31. Several different criteria have been proposed to select patients to stop
treatment based on immunologic and clinical factors. Specific high-risk
factors have been reported from these published reports. There have been
very few reports of the outcome more than 5 years after stopping VIT and
virtually none on patients who had discontinued treatment for more than
10 years.
2010;10:337-341.•

34. Studi
( ITS – Malattia )
Efficacia sui sintomi
( SMD; 95% CI )
Abramson et al. 2003
(SCIT – Asma)
- 0.72 (-0.99, -0.44); P < .001
Calamita et al. 2006
(SLIT – Asma)
- 0.38 (-0.79, -0.003); P < .07
Penagos ed al. 2008
(SLIT – Asma)
- 1.42 (-2.25, -0.59); P < .02
Olaguibel et al. 2005
(SLIT – Asma/Rinite)
- 1.42 (-0.99, -0.34); P < .01
Calderon et al 2007
(SCIT – Rinite)
- 0.73 (-0.97, -0.50); P < .001
Penagos et al. 2006
(SLIT – Rinite)
- 0.56 (-1.01, -0.10); P < .02
Wilson et al. 2005
(SLIT – Rinite)
- 0.42 (-0.69, -0.15); P < .002
-2 +2-1 +10
a favore ITS a favore placebo
SMD ( 95% Cl )
Specific immunotherapy for respiratory allergy:
state of the art according to current meta-analyses
Compalati et al. Ann Allergy Asthma Immunol - 2009

35. Wilson D et al. Allergy 2005; 60: 4-12.
Symptom scores 21 studies n = 959 SMD -0.42
The first meta-analysis on SLIT

38. Situazione degli allergeni in Italia
Due tipi di prodotti:
I prodotti pre-’92 (NPP)
I nuovi prodotti con AIC

39. NPP - regolamentazione degli
allergeni in Italia
Gli allergeni sono
Named Patient Products
NPP
Art 5 nel Dlvo 219
……………….e in fase di regolamentazione in AIFA
LEGGE
DI BELLA
In Italia gli allergeni pre-’92 sono autorizzati per il decreto 1991

40. La direttiva Europea prevede gli NPP
Busto Arsizio, 23 ottobre 2012
Direttiva Europea 2001/83/EC 6 Novembre 2001
Da usare su singolo paziente sotto la responsabilità del medico

41. Situazione NPP in Europa:
Germania, Francia e Italia
Francia:
Registrazione dei bulk. Solo NPP.
Germania:
registrazione per gli allergeni principali. Gli altri restano NPP
Italia:
Modulo 3 (qualità) del CTD per tutti gli
allergeni in commercio

42. • La variabile qualità dei NPP ha rappresentato un importante
fattore di discrepanza tra l’efficacia dimostrata nei trial e quella
rilevata nella pratica clinica
• La disponibilità dei prodotti in compresse di qualità
farmaceutica ha la potenzialità di annullare il divario, ma i costi
elevati non consentono di prevedere la loro produzione per
tutti gli allergeni di rilievo clinico
• E’ prevedibile che il processo attualmente in corso di
regolamentazione degli estratti allergenici possa garantire
adeguati standard qualitativi anche ai NPP
Conclusioni

43. 43
Grazie dell’attenzione
cristoforo.incorvaia@gmail.com