This document summarizes a presentation about eosinophilic asthma and biological drugs that target interleukin-5 (IL-5). It discusses the role of eosinophils and IL-5 in asthma, clinical studies of anti-IL-5 drugs like mepolizumab and benralizumab, and real-world experience with these therapies. The presentation covers the pathophysiology of eosinophilic asthma, how anti-IL-5 drugs work, results from major clinical trials showing reduced exacerbations and oral corticosteroid use, and insights from real-world studies on treatment response and outcomes. It emphasizes the importance of patient phenotypes and endotypes in guiding therapy selection for severe asthma.
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201911 - Conte - Asma eosinofilico: i farmaci biologici che contrastano l'azione della IL-5
1. Asma eosinofilico: i
farmaci biologici che
contrastano l'azione
della IL-5
Dott.ssa Mariaelisabetta Conte
SSD Immunologia ed
Allergologia
Ospedale di Pordenone
NOVITÀ
Diagnostico-Terapeutiche in
Allergologia
e
Immunologia
Clinica
Sabato 9 novembre 2019
TORINO
2. 1. Asma eosinofilo
2. Il ruolo dell’eosinofilo e dell’IL-5
3. Farmaci anti-IL-5: dagli studi clinici alla real life
Agenda
3. Agache I, Seminars of Immunology, Aug 2019
Severe asthma phenotypes and endotypes
4. Fisiopatologia dei diversi fenotipi dell’asma
Brusselle G et al. Ann Am Thorac Soc. 2014:11;S322–S328.
Macrophages
NKT
cells
IL-33
Allergens
Goblet cells
Pollution, microbes
IL-33
IL-25
TSLP
Dendritic cells
IL-33
IL-25
TSLP
IgE
B cells
Eosinophils
Smooth muscle cells
Neutrophils
Naive
T cells
Airway
epithelium
ILC2
Basophils
Mast
cells
IL-9
IL-13 IL-13
TH2
IL-5
IL-13
IL-4,IL-13
IL-5
IL-13
Atopic eosinophilic asthma Non-atopic eosinophilic asthma Neutrophilic asthma
CXCL8
GM-CSF
Th17
cells
IL-17A
IL-17R
1
Phisiopatological mechanisms in different asthma
endotypes
Brusselle G et al, Ann Am Thorac Soc 2014; 11: s322- s329
5. Allergic
Asthma
Intrinsic
Asthma
Elisabeth H Bel, Chest; December 2017
Eosinophilic airway inflammation is considered the most treatable trait of
chronic airway diseases
Type 2 high aiway inflammation
7. Schleich F, et al. Resp Med 2014; 108: 1723 - 1732
Caratteristiche demografiche:
✓ Sesso femminile 57%
✓ Atopia 70%
✓ Late-onset ( ≥ 40 a) 31%
8. 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
9. Price DB et al, The Lancet Resp 2015 Nov (3)
The higher eosinophil count the higher the severity
All’aumentare dell’eosinofilia periferica:
❖ aumenta il numero delle
riacutizzazioni
❖ diminuisce il livello di controllo
≥ 400
10. 1. Asma eosinofilo
2. Il ruolo dell’eosinofilo e dell’IL-5
3. Farmaci anti-IL-5: dagli studi clinici alla real life
Agenda
11. In 1879 Paul Ehrlich mentions the eosinophil for the first time while
publishing the method for differential blood cell counting
The Nobel Prize in Physiology or Medicine 1908 was awarded jointly to
Ilya Ilyich Mechnikov and Paul Ehrlich "in recognition of their work on
immunity."
Early history of a cell
In 1843 he observed granular cells into inflammatory exudates
(pleural and pericardial effusions from pneumonia) and sputum of
patients with bronchitis, tracheitis
Julius Vogel
(1814–1880)
12. Eosinophils as highly conserved cells
Evolutionary considerations suggest that the eosinophil lineage is several hundred million years old.
The survival of this cell type to the test of time highlights the important benefits provided to its host
Bochner B Ann All Asthma & Immunol 2018
13. Marichal T et al, Frontiers in Med, July 2017
Homeostatic Eosinophils
14. Eosinophils: are they friends, enemies of something in between?
Chusid et al, J All Clin Immunol Pract 2018 (6)2018
Eosinophils clearly must play
an overall positive role in the
health of their host. The task
that remains is to continue to
more fully define exactly what
all the positive roles of
eosinophils may entail
15. Does eosinopenia associate with disease ?
Krause JR Am J Hematol. 1987
Search for eosinopenia in hospitalized patients with normal blood leukocyte
concentration
The consequences of not having eosinophils
Gleich GJ et al, Allergy 2013 (68)
Targeted delection of a high affinity GATA1 binding site in the GATA-1 promoter
leads to selective loss of the eosinophil lineage in vivo
Yu C et al, J Exp Med 2002 (195)
There is no evident consequence of
the lack of eosinophils in humans
and in animal models
16. 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
Functions of Eosinophils
17. E a sua volta modula la
funzione di una
moltitudine di cellule della
risposta immune innata ed
adattativa
Varricchi G et al, Curr Opin Allergy Clin Immunol 2016
Functions of Eosinophils
18. Pelaia C et al, Bio Med Res Int 2018
IL-5 effects on blood eosinophils
19. mature Eos
healthy state asthmatic
Siglec-8+
IL-3Rhigh
CD62Llow
Siglec-8+
IL-3Rlow
HUMANS
Molecular diversity of Eosinophils: the lung
O’ Sullivan J J Allergy Clin Immunol 2018
20. L’eosinofilo residente a livello
bronchiale pare avere un
grado di maturazione
maggiore che lo rende meno
sensibile all’azione di IL-5
Lung resident Eosinophils
21. 1. Asma eosinofilo
2. Il ruolo dell’eosinofilo e dell’IL-5
3. Farmaci anti-IL-5: dagli studi clinici alla real life
Agenda
22. Mc Gregor MC et al, Am J Resp Crit Care Med, 199 (4) 2019 Feb
23. Killing dell’eosinofilo
attraverso due
meccanismi:
✓ Blocco della
sopravvivenza IL-5
mediata
✓ Induzione dell’apoptosi
NK mediata (ADCC)
Yanagibashi T et al, Cytochine 98 (2017)59-70
Blocking of IL-5 to target eosinophils
25. Ortega et al, New Eng J Med, Sept 2014
Significantly reduced asthma exacerbation rate:
- 47% 75 mg iv
- 53% 100 mg sc
FEV1 > 100 ml
SGRQ
ACQ 5
26. Bel EH NEJM 2014
Despite receiving a reduced
glucocorticoid dose, patients in the
mepolizumab group, had a relative
reduction of 32% in the annualized rate
of exacerbations.
Da 90 a 100% in 23% pz
Da 70 a 90% in 17% pzOCS
Riduzione complessiva mediana OCS del 50%
28. 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
Clinical development programme for Benralizumab
29. Lavoiette M et al, JACI 132 (2013), November
Studio Fase I
Bone marrow
eosinophilis and
eosinophil precursors
Induced sputum eosinophils
- 95,1%
EOS NEUT
30. Benralizuma
b
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
50% delle riacutizzazioni
FEV1
AER
31. 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
AER
FEV1
30% delle riacutizzazioni
32. Benralizumab: Safety Profile
Nair P et al, The N Engl J Med (2017),June 22
STUDY CALIMA SIROCCO BISE ZONDA
Any drug-related AE 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 inject site 9 (2%) 9 (2%) 0 0
Hypersensitivity 13 (3%) 11 (3%) 1 (1%) 3 (4%)
33. Nair P NEJM 2017
Benralizumab showed significant, clinically
relevant benefits, as compared with placebo,
on oral glucocorticoid use and exacerbation
rates. These effects occurred without a
sustained effect on the FEV1.
AER
OCS
OCS > 90% in 37% pz
Riduzione complessiva mediana OCS del 75%
34. Diamant Z et al, Allergy 2019 (74)
Severe Asthma: does the ideal biomarker exist?
39. Caminati M et al, Expert Rev Resp Med 2019 Oct
Real life experience
1 mese
Eosinofili
40. The greatest clinical change in terms of FEV1 and ACT in comparison with the baseline values was
observed within the first month after the treatment start, suggesting that treatment continuation in
patients without a clinical response within the first month should be carefully evaluated.
Caminati M et al, Expert Rev Resp Med 2019 Oct
Real life experience
6 mesi
43. Take home messages
Il tratto eosinofilico (Type 2 high) è il tratto infiammatorio maggiormente trattabile
I farmaci anti-IL-5 si sono dimostrati efficaci e al momento sicuri anche a medio
termine
L’eterogeneità dell’asma è una delle maggiori barriere nella gestione del paziente
Il ruolo omeostatico dell’eosinofilo deve essere ancora chiarito a fondo
Gli studi in real life su grandi numeri sono indispensabili in particolare per
identificare i fattori predittivi di risposta al trattamento
Tutte le caratteristiche fenotipiche ed endotipiche del paziente sono necessarie
per guidarci nella scelta della giusta terapia
44. Dott.ssa Mariaelisabetta Conte
SSD Immunologia ed
Allergologia
Ospedale di Pordenone
NOVITÀ
Diagnostico-Terapeutiche in
Allergologia
e
Immunologia
Clinica
Sabato 9 novembre 2019
TORINO
GRAZIE
DELL'ATTENZIONE!