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

1. Un altro farmaco
biologico «in coming»:
Benralizumab
Dott.ssa Mariaelisabetta Conte
SSD Immunologia ed Allergologia
Ospedale di Pordenone

2. Ilmarinen P et al, JACI Pract 2018 in press

3. Schleich F, et al. Resp Med 2014; 108: 1723 - 1732
Caratteristiche demografiche:
✓ Sesso femminile 57%
✓ Atopia 70%
✓ Late-onset ( ≥ 40 a) 31%

4. Ilmarinen P et al, JACI Pract 2018 in press
2% pts elegible for anti-IL-5 treatment if:
✓ Daily use of medium to high ICS + LABA
✓ Blood eosinophil count ≥ 300 c/mL
✓ FeNO ≥ 50 ppb
✓ ≥ 2 exhacerbations /previous year

5. Ilmarinen P et al, JACI Pract 2018 in press

6. Allergic
Asthma
Intrinsic
Asthma
Elisabeth H Bel, Chest; December 2017
Eosinophilic airway
inflammation is
considered the
most treatable trait
of chronic airway
diseases

7. Varricchi G et al, Curr Opin Allergy Clin Immunol 2016
Eosinofilo espone un ampio spettro
di recettori di superficie molto
importanti per la sua funzione
pleiotrofica

8. Varricchi G et al, Curr Opin Allergy Clin Immunol 2016
E a sua volta modula la funzione di
una moltitudine di cellule della
risposta immune innata ed adattativa

9. Varricchi G et al, Curr Opin Allergy Clin Immunol 2016
IL-5 gioca un ruolo fondamentale
sulla proliferazione, sulla
maturazione a livello del midollo
osseo, sul reclutamento e
l’attivazione dell’eosinofilo nel sito di
infiammazione
Nel tessuto bronchiale:
Iperproduzione di muco
Remodelling delle vie aeree

10. Elisabeth H Bel, Chest; December 2017
Sempre maggiore definizione di singoli target d’azione

11. Humanized
IgG1k anti-IL-5Ra chain
BENRALIZUMAB
Afucosylate: > affinity to FcgRIIIa
FcgRIIIa

12. Pelaia C et al, Bio Med Res Int 2018
Afucosylate: > affinity to FcgRIIIa
Humanized
IgG1k anti-IL-5Ra chain
On cortesy of Prof. A. Matucci
BENRALIZUMAB

13. FcgRIIIa
BENRALIZUMAB
Il grado di fucosilazione della catena
CH2 del frammento Fc delle
Immunoglobuline ne modifica
l’immunogenicità e la capacità di
legame al recettore Fc𝜸RIIIa espresso
su macrofagi, neutrofili ed NK
Afucosilazione:
❖ Aumenta da 5 a 50 volte l’affinità di
legame al recettore
❖ Amplifica di 1000 volte il
meccanismo di ADCC
On cortesy of Prof. A. Matucci

14. BENRALIZUMAB: IgG1k anti-IL-5Ra chain
NK cell
FcgRIIIa
Mechanisms of action:
▪ Neutralizing activity of IL-5 by blocking IL-5-receptor
▪ Eosinophils apoptosis (ADCC) not inducing degranulation
Cytotoxic mediators
Benralizumab
IL-5-receptor: A KEY TARGET
On cortesy of Prof. A. Matucci

15. L’apoptosi dell’eosinofilo mediata da Benralizumab non è associata al rilascio di mediatori tossici
Respiratory Medicine 111 (2016)
Nel paziente asmatico il
livello di EDN ha una
stretta correlazione con
l’eosinofilia periferica
v

16. Kolbeck R et al, Allergy Clin Immunol ,, June 2010

17. Lavoiette M et al, JACI 132 (2013), November
Studio Fase I
Blood eosinophilia
decreases within 6-24
hours after benralizumab

18. Lavoiette M et al, JACI 132 (2013), November
Studio Fase I
Bone marrow
eosinophilis and
eosinophil precursors
Induced sputum eosinophils
- 95,1%
EOS NEUT

19. Lavoiette M et al, JACI 132 (2013), November
Studio Fase I
Airway mucosal eosinophil counts
(green)

20. L’eosinofilo residente a livello
bronchiale pare avere un grado di
maturazione maggiore che lo rende
meno sensibile all’azione di IL-5 e
pertanto meno responsivo all’azione
di mAB anti-IL-5 e IL-5R

21. CALIMA2
Efficacy and safety study of
benralizumab in adults and
adolescents with asthma
inadequately controlled on
medium- to high-dosage
ICS/LABA
SIROCCO4
Efficacy and safety study of
benralizumab added to high-
dosage ICS/LABA in patients with
uncontrolled asthma
ZONDA3
Efficacy and safety study of
benralizumab to
reduce OCS use in patients with
uncontrolled asthma on high-
dosage ICS/LABA and chronic
OCS therapy
BORA7
Safety extension study of
benralizumab in asthmatic adults
and adolescents on ICS/LABA
GREGALE6
Functionality and reliability of the
APFS in an at-home setting and
performance of the APFS after
use
BISE5
Efficacy and safety study of
benralizumab in adults with mild
to moderate persistent asthma
Windward Programme: 6 studi fase III

22. STUDY N° of
patients
(A/Plac)
Duration
(wks)
Asthma level Outcomes
SIROCCO 798/407 56 Severe • Reduction of
exacerbation
• Improvement of FEV1
CALIMA 866/440 56 Severe • Reduction of
exacerbation
• Improvement of FEV1
ZONDA 145/75 28 OCS dependent Oral steroid reduction
Benralizumab: 3 Studi Registrativi

23. 2016
Benralizumab Placebo
Treatment allocation N. 267 267
Age 47.6 48.6
Gender, females N. (%) 174 (65) 180 (67)
Baseline pre-bronchodilator
FEV1 (mean L)
1.66 1.65
Baseline pre-bronchodilator
FEV1 (%)
55.5 56.4
Blood eosinophil count, mean
cells/ml
500 500
Bleecker ER et al, The Lancet (2016), Vol 388, October 29
48W

24. Bleecker ER et al, The Lancet (2016), Vol 388, October 29
AER

25. Bleecker ER et al, The Lancet (2016), Vol 388, October 29
FEV1

26. 2016
FitzGerald JM et al, The Lancet (2016), Vol 388, October 29
Benralizumab Placebo
Treatment allocation N. 239 248
Age 49.6 48.5
Gender, females N. (%) 138 (58) 145 (58)
Baseline pre-bronchodilator
FEV1 (mean L)
1.76 1.82
Baseline pre-bronchodilator
FEV1 (%)
57.0 58.2
Blood eosinophil count, mean
cells/ml
500 510
56W

27. FitzGerald JM et al, The Lancet (2016), Vol 388, October 29
AER

28. FitzGerald JM et al, The Lancet (2016), Vol 388, October 29
FEV1

29. Fattore geografico ambientale

31. FitzGerald JM et al, The Lancet vol 6, January 2018
AER
FEV1

32. 75
73
73
2017
Nair P et al, The N Engl J Med (2017), 376; 25, June 22

33. Nair P et al, The N Engl J Med (2017), 376; 25, June 22

34. Nair P et al, The N Engl J Med (2017), 376; 25, June 22

35. Nair P et al, The N Engl J Med (2017), 376; 25, June 22
OCS reduction
AER

36. Within the literature chronic OCS use has been
reported in 11-46% of patients with severe asthma
In the United States 11-38% of patients with
severe asthma receive chronic OCS
In Europe 16-57% of patients with severe asthma
receive OCS therapy

37. 2017
Costi sociali legati agli
effetti collaterali degli OCS

38. 2016

39. Benralizumab: Safety Profile
Nair P et al, The N Engl J Med (2017), 376; 25, June 22

40. STUDY CALIMA SIROCCO BISE ZONDA
Any drug-related adverse
event
54 (13%) 281 (71%)
(any AE)
4 (4%) 55 (75%)
Nasopharingitis 79 (18%) 46 (12%) 8 (8%) NR
Asthma 47 (11%) 45 (11%) 4 (4%) NR
Bronchitis 44 (10%) 19 (5%) NR NR
URI (Upper Resp Inf) 36 (8%) 32 (8%) 5 (5%) NR
Local reaction at injection
site
9 (2%) 9 (2%) 0 0
Hypersensitivity 13 (3%) 11 (3%) 1 (1%) 3 (4%)
Benralizumab: Safety Profile

41. Ferguson et al,Journal of Asthma and Allergy 2018

42. ADA : Anti - Drug Antibodies
Prevalence : 15% (17/116)
Incidence : 11% (13/116)
Ferguson et al,Journal of Asthma and Allergy 2018

43. SIROCCO
CALIMA

44. Adverse Events During On-Treatment Period
BORA Benralizumab Q4W plus ICS/LABA Benralizumab Q8W plus ICS/LABA
SIROCCO/CALIMA Benralizumab
Q4W
(n=518)
Placebo
(n=265)
Benralizumab
Q8W
(n=512)
Placebo
(n=281)
Any AE 364 (70%) 181 (68%) 361 (71%) 183 (65%)
Any AE leading to treatment discontinuation 10 (2%) 8 (3%) 8 (2%) 5 (2%)
AEs in ≥10% of patientsa
Viral upper respiratory tract infection
Worsening asthma
78 (15%)
49 (9%)
36 (14%)
27 (10%)
80 (16%)
41 (8%)
41 (15%)
19 (7%)
• Similar percentages of patients experienced AEs in BORA and SIROCCO/CALIMA (65–
71% vs. 71–75%, respectively)1,2
• Comparable percentages of patients had AEs leading to discontinuations
in BORA and SIROCCO/CALIMA (2–3% vs. 2%, respectively)1,2
Data are n (%), where n is the number of patients. aAs defined in the Medical Dictionary for Regulatory Activities version 20.0.
1. Bleecker ER, et al. Lancet. 2016;388:2115–27. 2. FitzGerald JM, et al. Lancet. 2016;388:2128–41.

45. Serie Generale n. 96 del 26-4-2018
Fasenra è indicato come terapia
di mantenimento aggiuntiva in
pazienti adulti con asma
eosinofilo severo non
adeguatamente controllato
malgrado l’impiego di
corticosteroidi per via inalatoria
a dosi elevate e beta2 agonisti a
lunga durata d’azione.

46. SEVERE
ASTHMA
Airflow
limitation
Atopic
status
OCS use
AER
Age of onset
Total IgE
level
Nasal polyps
Blood
eosinofilia
Benralizumab: esiste il paziente ideale?
FeNO

47. Chipps BE et al, AnnAll Asthma Immunol 120 (2018)
IgE high > 150 kU/L
Placebo BNZ Q4W BNZ Q8W Placebo BNZ Q4W BNZ Q8W
AER Rate estimate 1.09 0.69 0.63 1.21 0.65 0.68
AER RR vs Plac - 0.64 0.58 - 0.54 0.57
Nominal P 0.0004 0.0001 0.0001 0.0004
Pre-BD FEV1 change
vs Plac
- 0.120 0.123 - 0.098 0.138
Nominal P 0.0042 0.0034 0.405 0.041
IgE high < 150 kU/L

48. Chipps BE et al, AnnAll Asthma Immunol 120 (2018)
-41% -37%

49. Baseline factor effect on
annual exhacerbation rate
with BNZ every 8w
Bleecker ER et al, Eur Respir J 2018, 52

50. Baseline factor effect on Pre-
BD FEV1 change with BNZ
every 8w
Bleecker ER et al, Eur Respir J 2018, 52

51. > 300 cell/mcl
< 300 cell/mcl
EXACERBATIONS

52. PRE-BRONCHODILATOR FEV 1
> 300 cell/mcl
< 300 cell/mcl
Bleecker ER et al, Eur Respir J 2018, 52

53. Take home messages
Benralizumab ha un effetto diretto sull’eosinofilo diversamente dagli altri anti-IL5
L’apoptosi NK dipendente dell’eosinofilo avviene senza il rilascio di mediatori tossici
La deplezione degli eosinofili è molto rapida ed avviene in tutti i distretti, anche nelle vie aeree
Il miglioramento degli outcome clinici è maggiore nei pz più gravi
Trends futuri: allo studio nuovi scenari terapeutici

54. GRAZIE
Dott.ssa Mariaelisabetta Conte
SSD Immunologia ed Allergologia
Ospedale di Pordenone