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

1. Evidenza di efficacia e sicurezza
nell’utilizzo di benralizumab
Francesco Menzella
S.C. Pneumologia
Arcispedale S. Maria Nuova- IRCCS
Reggio Emilia

2. Business Use Only 2
Moore et al2 U-BIOPRED4
1 2 3n=163 n=726 n=2985 4n=311
59%
77% 80% 78.3%
EU USA EU EU
1. The ENFUMOSA Study Group Eur Respir J 2003
2. Moore WC, et al. AM J of resp and criti care med 2010
3. Haselkorn T, et al. J Asthma 2006
4. Shaw DE et al., Eur Respir J 2015
✓ Eosinophilia is present in about 50% of cases of
asthma and is predominantly associated with
severe forms with persistent eosinophilia
despite high doses of ICS
✓ Some studies also show that the percentage of
patients with severe allergic asthma with a "T2-
high" inflammatory micro-environment + IgE>
400 UI / ml is much higher than those with mild-
to-moderate forms
1. Haldar P, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med.
2008;178:218-24.
2. Davila I et al; SIGE Study Group. Relationship between serum total IgE and disease severity in
patients with allergic asthma in Spain. J Investig Allergol Clin Immunol. 2015;25(2):120-7.
Severe asthma, eosinophilia and atopy: a close relationship
Frequency of patients with allergic asthma in severe asthma
studies

3. Heterogeneity of bronchitis in asthma
A small proportion of patients have persistent airway eosinophilia despite OCS
n=1850 patients
at exacerbations
n=1200 patients (60%)
with sputum eosinophils >3%
high ICS
low
ICS
OCS
eos
neutro
eos+
neutro
Normal
/NA
D’Silva et al. Can Respir J. 2011;18:144–8.

4. IL-5
IL-4
IL-13
Salter BM and Sehmi R. Chest. 2017;152:410–6.
Hemopoietic processes in asthma

5. Taken from Patterson MF et al. 2015
1. Patterson MF et al. Journal of Asthma and Allergy 2015; 8: 125-134
2. Busse WW et al. J Allergy Clin Immunol 2010; 125: 1237–44
3. Laviolette M et al. J Allergy Clin Immunol 2013; 132: 1086–96
4. Tan LD, et al. J Asthma Allergy. 2016; 9: 71-81
Eosinophil targets for biologics: IL5 ligand and anti-eosinophil

6. 1. Abonia JP et al. Expert Rev Clin Immunol. 2011;7(4):411-417.
2. Patino E, et al. Structure. 2011;19:1864-1875.
3. Chan A et al, Therapeutic antibodies for autoimmunity and inflammation, 2010: p306,A

7. 1. AstraZeneca Pipeline. Accessed February 17, 2016.
2. Molfino NA et al. Clin Exp Allergy. 2012;42:712-737.
3. Tan LD, et al. J Asthma Allergy. 2016;9:71-81.
4. Busse WW, et al. Eosinophils in Health and Disease. 2013:587-591.
5. Ghazi A et al. Expert Opin Biol Ther. 2012;12:113-118.
ADCC = antibody-dependent cell-mediated cytotoxicity; IL-5Rα = interleukin-5 receptor α; NK = natural killer
Benralizumab: How does it work?

8. 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
Matucci A.; Vultaggio A. Master in Allergologia; Napoli 2015.

9. Benralizumab showed enhanced ADCC of eosinophils in vitro
ADCC of human eosinophils
ADCC, antibody-dependent cell-mediated cytotoxicity; FcγRIIIa; Fc gamma receptor subclass IIIa; IL-5Rα,
interleukin-5 receptor α;
mAb, monoclonal antibody; NK, natural killer
Kolbeck R, et al. J Allergy Clin Immunol 2010;125:1344–1353.
• Binding affinity of benralizumab for human FcγRIIIa increased 6-fold compared
with fucosylated parental antibody
• In the presence of NK effector cells, benralizumab induced eosinophil and
basophil apoptosis via ADCC

10. Ther Adv Resp Dis. 2016;7(6):260-277.

11. Benralizumab: Rapid peripheral blood eosinophil depletion
1. Laviolette M et al. J Allergy Clin Immunol 2013;132:1086–1096.

12. Laviolette M et al. J Allergy Clin Immunol 2013;132:1086–1096.
Benralizumab: Mechanistic effects from bone marrow to sputum

13. The effect of benralizumab is independent of the IL-5 circulating level, which tends to
increase during asthma exacerbation
The depletion of eosinophils through ADCC prevents the effects of a possible activation by
other cytokines (IL-3 and GM-CSF), as may occur with mepolizumab and reslizumab
The absence of the fucose sugar residue in its molecular structure gives benralizumab much higher affinity to the
human FcγRIIIa receptor, overcoming the inhibitory effects determined by serum IgGs
J Allergy Clin Immunol. 2010;125(6):1344-1353
Benralizumab: what else?

14. The Windward Program
SIROCCO/CALIMA trial design
✓Randomized, double-blind, parallel-group, placebo-controlled Phase III
trials
❖Trials recruited patients with baseline blood eosinophils ≥300 and <300 cells/µL
(2:1 ratio)
•All adolescent patients enrolled in the European Union were randomized to receive benralizumab 30 mg Q8W or placebo to limit their drug burden.
Q4W: once every 4 weeks; Q8W: once every 8 weeks (first three doses Q4W); SC: subcutaneous.
Benralizumab 30 mg SC Q4W
Benralizumab
30 mg SC Q4W
Benralizumab 30 mg SC Q8W
(placebo at 4-week interim)
Placebo SC Q4W
Treatment period (48 weeks SIROCCO/56 weeks CALIMA)Screening/run-in (4 weeks) Follow up (8/4 weeks)
Week −4 0 12 48/56 56/60
E
N
R
O
L
L
M
E
N
T
Run-in
Randomization
1:1:1
−3 −1
Primary endpoint
Week 48/56
F
O
L
L
O
W
U
P

15. Original trial endpoints
•aMultiplicity [type 1 error]‒protected at Week 48.
•ACQ-6: Asthma Control Questionnaire 6; AQLQ(S)+12: Asthma Quality of Life Questionnaire
(standardized) for 12 years and older; FEV1: forced expiratory volume in 1 s.
• Annual exacerbation ratePrimary endpoint
• Prebronchodilator FEV1
• Total asthma symptom score
Key secondary
endpointsa
The primary analysis population was patients with
blood eosinophils ≥300 cells/µL at baseline
• ACQ-6 score
• AQLQ(S)+12 score
Other secondary
endpoints

16. Lancet 2016; 388: 2115–27.
✓ Compared with placebo, benralizumab reduced the annual
asthma exacerbation rate over 48 weeks when given Q4W or
Q8W
✓ Both benralizumab dosing regimens significantly improved
prebronchodilator FEV1 in patients at week 48 compared with
placebo
✓ Compared with placebo, asthma symptoms were improved by the
Q8W regime but not the Q4W regimen
✓ The most common adverse events were worsening
asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%]
of 407 placebo-treated patients) and nasopharyngitis
(93 [12%] vs 47 [12%])
1205 PATIENTS RANDOMIZED

17. FitzGerald M, et al. Lancet. 2016;388(10056):2128-2141.
Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg
every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4
weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by
baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per
μL, respectively
Benralizumab significantly reduced annual exacerbation rates and was generally
well tolerated for patients with severe, uncontrolled asthma with blood
eosinophils 300 cells per μL or greater. Our data further refine the patient
population likely to receive the greatest benefit from benralizumab treatment
1306 PATIENTS RANDOMIZED

18. Curr Med Res Opin. 2017;33(9):1605-1613.
Benralizumab reduced asthma exacerbation rates by 42% in SIROCCO and 36% in CALIMA (eosinophil cutoff of
≥150 cells/μL≤300 cells/μl)

19. N Engl J Med. 2017;376(25):2448-2458.
✓ The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28
✓ Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed

20. ✓ Randomized, double-blind, parallel-group, placebo-controlled Phase III trial
– Recruited patients with asthma with baseline blood eosinophils ≥150 cells/µL to <300 cells vs.
≥300 cells per cubic millimeter, receiving high-dosage ICS/LABA plus OCS (all patients switched to
prednisone at trial entry)
28-week treatment period
Benralizumab 30 mg SC Q4W
Benralizumab 30 mg SC
Q4W
Benralizumab 30 mg SC Q8W
(placebo at 4-week interim)
Placebo SC Q4W
Randomization
1:1:1
V1
End
of
treatment
Enrollment Induction
Maintain
OCS
V6 V13V7 V8 V9 V10 V11 V12 V14 V15V2 V3 V4 V5
OCS
optimization
OCS reduction
Follow
up
Sputum
Blood
Nair P, et al. New Engl J Med. 2017;376:2448–58.
ZONDA Study Design

21. N Engl J Med. 2017;376(25):2448-2458.
✓ The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as
with placebo
✓ Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual
exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P = 0.003),
and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that
was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001)
✓ At 28 weeks, there was no significant effect of either benralizumab regimen on the forced
expiratory volume in 1 second (FEV1), as compared with placebo

22. Objectives
✓ To determine the relationship between benralizumab’s clinical efficacy versus
baseline blood eosinophil counts and exacerbation history
✓ To identify other intrinsic and/or extrinsic factors that might influence
benralizumab’s efficacy
Lancet Respir Med. 2017 Sep 8.

23. Secondary Analysis: Methods
✓Analysis Set: Pooled results for SIROCCO and CALIMA for age ≥12 years receiving high-dosage
ICS/LABA
✓Analyses were reweighted to account for the original 2:1 blood eosinophil stratification
✓Efficacy Measures: Asthma exacerbation rate, FEV1, total asthma symptom score, ACQ-6, and
AQLQ(S)+12
Evaluations
• Efficacy by baseline blood eosinophil counts (cumulative, categorical, and LOESS regression plots)
• Influence of other baseline factors on exacerbation rate and change in FEV1
▪ Potentially clinically relevant subgroups within the eosinophils ≥300 cells/µL analysis set
o e.g., frequent exacerbator, nasal polyposis status, OCS use, etc
▪ Unbiased structured analysis in the overall population (eosinophils ≥300 and <300 cells/μL)
o Ranking of intrinsic and extrinsic factors by gradient-boosted regression modelling

24. Annual asthma exacerbation rate reduction with benralizumab
Q8W by eosinophil ranges (full analysis set, pooled)
•Estimates calculated by a negative binomial model with adjustment for treatment, study code, region, oral corticosteroid use, and prior exacerbations.
The estimates were weighted to account for the 2:1 randomization ratio of patients with baseline blood eosinophil counts ≥300 cells/μL or <300 cells/μL.
CI: confidence interval; Q8W: every 8 weeks (first three doses every 4 weeks).
1,16 1,14 1,14
1,25
0,75 0,72
0,65 0,62
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
≥0 cells/µL ≥150 cells/µL ≥300 cells/µL ≥450 cells/µL
Annualexacerbationrate
estimate(95%CI)
n=770
(1.05–1.28)
(0.66–0.84)
(1.02–1.28)
(0.63–0.82)
(1.00–1.29)
(0.56–0.75)
(1.06–1.47)
(0.51–0.76)
n=751 n=648 n=646 n=511 n=499 n=306 n=298
−37% −43% −50%−36%
BenralizumabPlacebo

25. Annual asthma exacerbation rate reduction with benralizumab
Q4W by eosinophil ranges (full analysis set, pooled)
•Estimates calculated by a negative binomial model with adjustment for treatment, study code, region, oral corticosteroid use, and prior exacerbations.
The estimates were weighted to account for the 2:1 randomization ratio of patients with baseline blood eosinophil counts ≥300 cells/μL or <300 cells/μL.
CI: confidence interval; Q4W: every 4 weeks.
1,16 1,14 1,14
1,25
0,73 0,69 0,68 0,73
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
≥0 cells/µL ≥150 cells/µL ≥300 cells/µL ≥450 cells/µL
(1.05–1.28)
(0.65–0.82)
(1.02–1.28)
(0.61–0.79)
(1.00–1.29)
(0.59–0.78)
(1.06–1.47)
(0.61–0.89)
Annualexacerbationrate
estimate(95%CI)
−39% −41% −41%−37%
n=770 n=748 n=648 n=647 n=511 n=511 n=306 n=295
BenralizumabPlacebo

26. Prebronchodilator FEV1 increase with benralizumab Q8W by
eosinophil categories (full analysis set, pooled)
•Estimates calculated using a negative binomial model, with adjustment for treatment group, study, region, oral corticosteroid use at time of randomization, prior exacerbations, baseline
eosinophil count category, and treatment group × baseline eosinophil count interaction. EOT visit at Week 48 (SIROCCO) or 56 (CALIMA).
CI: confidence interval; EOT: end of treatment; FEV1: forced expiratory volume in 1 s; LS: least squares; Q8W: every 8 weeks (first three doses every 4 weeks).
170
151
252
194
214 211
286
417
0
50
100
150
200
250
300
350
400
450
500
<150 cells/µL 150–299 cells/µL 300–449 cells/µL ≥450 cells/µL
PrebronchodilatorFEV1changefrom
baselinetoEOT,LSmean(mL)
44
mL
60
mL
34
mL
224
mL
BenralizumabPlacebo
n=117 n=101 n=134 n=145 n=201 n=200 n=300 n=295

27. Annual asthma exacerbation rate reduction with benralizumab
Q8W by eosinophil ranges (full analysis set, pooled)
•Estimates calculated by a negative binomial model with adjustment for treatment, study code, region, oral corticosteroid use, and prior exacerbations.
The estimates were weighted to account for the 2:1 randomization ratio of patients with baseline blood eosinophil counts ≥300 cells/μL or <300 cells/μL.
CI: confidence interval; Q8W: every 8 weeks (first three doses every 4 weeks).
1,16 1,14 1,14
1,25
0,75 0,72
0,65 0,62
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
≥0 cells/µL ≥150 cells/µL ≥300 cells/µL ≥450 cells/µL
Annualexacerbationrate
estimate(95%CI)
n=770
(1.05–1.28)
(0.66–0.84)
(1.02–1.28)
(0.63–0.82)
(1.00–1.29)
(0.56–0.75)
(1.06–1.47)
(0.51–0.76)
n=751 n=648 n=646 n=511 n=499 n=306 n=298
−37% −43% −50%−36%
BenralizumabPlacebo

28. Annual asthma exacerbation rate reduction with benralizumab
Q4W by eosinophil ranges (full analysis set, pooled)
•Estimates calculated by a negative binomial model with adjustment for treatment, study code, region, oral corticosteroid use, and prior exacerbations.
The estimates were weighted to account for the 2:1 randomization ratio of patients with baseline blood eosinophil counts ≥300 cells/μL or <300 cells/μL.
CI: confidence interval; Q4W: every 4 weeks.
1,16 1,14 1,14
1,25
0,73 0,69 0,68 0,73
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
≥0 cells/µL ≥150 cells/µL ≥300 cells/µL ≥450 cells/µL
(1.05–1.28)
(0.65–0.82)
(1.02–1.28)
(0.61–0.79)
(1.00–1.29)
(0.59–0.78)
(1.06–1.47)
(0.61–0.89)
Annualexacerbationrate
estimate(95%CI)
−39% −41% −41%−37%
n=770 n=748 n=648 n=647 n=511 n=511 n=306 n=295
BenralizumabPlacebo

29. Total asthma symptom score ACQ-6
0,22
0,19
0,30
0,35
0,0
0,1
0,2
0,3
0,4
AQLQ(S)+12
Greater improvement in symptoms and asthma-related quality of life
with benralizumab Q8W with increasing baseline blood eosinophil
counts
•Data are LS mean difference (95% CI). Estimates calculated by a mixed-effects model for repeated measures analysis with adjustment for treatment,
study code, baseline value, region, oral corticosteroid use at time of randomization, visit, and visit × treatment. The estimates were weighted to account for the 2:1
randomization ratio of patients with baseline blood eosinophil counts ≥300 cells/μL or <300 cells/μL. EOT visit at Week 48 (SIROCCO) or 56 (CALIMA). ACQ-6: Asthma
Control Questionnaire 6; AQLQ(S)+12: Asthma Quality of Life Questionnaire (standardized) for 12 years and older;
CI: confidence interval; EOT: end of treatment; LS: least squares; Q8W: every 8 weeks (first three doses every 4 weeks).
-0,19 -0,19
-0,26
-0,35
-0,4
-0,3
-0,2
-0,1
0,0
LSmeandifferencevs.placebo(95%CI)
-0,23
-0,18
-0,29
-0,31
-0,4
-0,3
-0,2
-0,1
0,0
LSmeandifferencevs.placebo(95%CI)
p≤0.003
vs. placebo
n=
740
n=
637
n=
493
n=
294
n=
746
n=
642
n=
495
n=
296
LSmeandifferencevs.placebo(95%CI)
n=
720
n=
619
n=
475
n=
283
–0.19 –0.19
–0.26
–0.35
–0.31
–0.29
–0.23
–0.18
≥0
cells/µL
≥150
cells/µL
≥300
cells/µL
≥450
cells/µL
≥0
cells/µL
≥150
cells/µL
≥300
cells/µL
≥450
cells/µL
≥0
cells/µL
≥150
cells/µL
≥300
cells/µL
≥450
cells/µL
p≤0.003
vs. placebo
p≤0.002
vs. placebo
–0.1
–0.2
–0.3
–0.4
–0.1
–0.2
–0.3
–0.4

30. GREGALE: Study Objectives
•APFS = accessorized pre-filled syringe; OCS = oral corticosteroid; PD = pharmacodynamics; PK = pharmacokinetics.
Ferguson GT et al. Poster presented at: ATS; May 19-24, 2017; Washington, DC, Poster P1011.
To assess patient- or caregiver-reported functionality and reliability of
the benralizumab APFS (Accessorized Pre-Filled Syringe) in an at-home
setting and performance of the APFS after use
To assess the effect of benralizumab on standard measures of asthma
control, including PK, PD, and immunogenicity

31. GREGALE: Efficacy and Safety Endpoints
ACQ-6 = Asthma Control Questionnaire-6; ADA = anti-drug antibodies; AE = adverse events; APFS = accessorized pre-filled syringe; PC = product complaint; PK = pharmacokinetics; SC =
ssubcutaneous.
Ferguson GT et al. Poster presented at: ATS; May 19-24, 2017; Washington, DC, Poster P1011.
Endpoint Description
Co-primary Endpoints
• Percentage of patients/caregivers who successfully administered benralizumab 30
mg SC by injection with an APFS at home (Week 12 and Week 16)
• Percentage of returned APFS used to administer benralizumab at home evaluated
as functional
• Percentage of APFS used to administer benralizumab at home or in the clinic
reported as malfunctioning (PC)
Key Secondary Endpoints
• Change from baseline in mean ACQ-6 score
• PK parameters
• Peripheral blood eosinophil levels
• ADA
Safety Endpoints • AEs and serious AEs

32. GREGALE: Study Design
•aPatients returned used APFS to the study site.
•Admin = administration; Benra = benralizumab; EOT = end of treatment; Q4W = every
4 weeks; SC = subcutaneous.
Ferguson GT et al. Poster presented at: ATS; May 19-24, 2017; Washington, DC, Poster P1011.
Weeks 12-16
Phase III, multicenter, open-label, functionality, reliability, and performance
study of benralizumab administered SC Q4W at home through Week 16 with an
accessorized pre-filled syringe in 120 adult patients with severe asthma
Visit reminder call
• ≤48 hours prior to home admin
PartA
Home admin
• By the patient or caregiver
PartB
Follow-up visit study site
• ≤48 hours after home admin
PartC
Treatment Period
V8V1 V7V5 V6V2
Week -2 Week 28
Home Administration
Benra 30 mg x 2 doses
Clinical Site Administration
Benra 30 mg x 3 doses
Screening EOT Follow-up
0 12 16 20
V3 V4

33. GREGALE: Successful Administration of Benralizumab SC by
Patient or Caregiver Using an APFS at Home
•Note: The n values on the bars represent the number of patients.
•aThe N values below the graph represent the number of patients who were qualified for administration at home and were still in the study (all patients). The N values for the self-administered patient group
and the administered via caregivers group represent the patients who self-administered at home or administered via caregivers and returned the questionnaire.
•AEs = adverse events; APFS = accessorized pre-filled syringe; d/c = discontinued; SC = subcutaneous.
•Ferguson GT et al. Poster presented at: ATS; May 19-24, 2017; Washington, DC, Poster P1011.
Co-primary Endpoint: Percentage of Patients/Caregivers who Successfully Administered Benralizumab 30
mg SC by Injection With an APFS at Home (Week 12 and Week 16)
✓ The majority of patients and caregivers successfully administered benralizumab at home via an APFS at Week 12 (98% [112 of 114]) and Week 16
(99% [108/109])
98 99
93
0,0
20,0
40,0
60,0
80,0
100,0
12 16 12-16
PatientsorCaregivers,%
Weeks
n=106
n=108n=112
N = 114 109 114
5 of 8 unsuccessful at-
home administrations
due to patient d/c from
Week 12 to Week 16

34. GREGALE: Most Returned APFS Used to Administer
Benralizumab SC at Home Were Considered Functional
•APFS = accessorized pre-filled syringe; SC = subcutaneous.
1. Ferguson GT et al. Poster presented at: ATS; May 19-24, 2017; Washington, DC, Poster P1011. 2. Ferguson GT et al. Presented at: ATS Meeting; May 19-22, 2017; Washington, DC. Abs
•A6008
99 99
93
0,0
20,0
40,0
60,0
80,0
100,0
12 16 12 and 16
FunctionalReturnedAPFS,%
Weeks
Co-primary Endpoint: Percentage of Returned APFS Used to Administer Benralizumab 30 mg SC
at Home Evaluated as Functional at Week 12 and Week 161,2
✓ The majority of returned APFS (99%) used to administer benralizumab SC at home were considered functional at Week 12 (113 of 114) and Week 16
(108 of 109). The two patient-use errors were failure to remove the syringe cap and patient sneezed during injection
n=106
n=108n=113
N = 114 109 114

35. GREGALE: Change in Blood Eosinophil Count by ADA
Status Over Time
Note: Error bars indicate the first and third quartiles.
ADA = anti-drug antibody; EOS = eosinophil; Tx = treatment.
Ferguson GT et al. Poster presented at: ATS; May 19-24, 2017; Washington, DC, Poster P1011.
✓ Benralizumab treatment induced near complete depletion of blood EOS at Weeks 20 and 28
✓ ADA was detected at any time point during the study, including pre- and post-treatment, in 17 (14.7%)
patients13 (11%) patients were ADA-positive post-treatment
Last Tx Dose
Week 16
600
500
400
300
200
0
100
Baseline 20Weeks
MedianEOSCount,cells/μL
28
All Patients
ADA Positive
ADA Negative

36. GREGALE: Most Common Adverse Events
Ferguson GT et al. Poster presented at: ATS; May 19-24, 2017; Washington, DC, USA. Poster P1011.
Most Common Adverse Events (≥5% in Any Group) During the On-Treatment Period
Adverse Events, n (%) Benralizumab Q4W
N=116
Asthma exacerbations 19 (16)
Nasopharyngitis 16 (14)
Upper respiratory tract infection 13 (11)
Headache 6 (5)
Sinusitis 6 (5)

37. GREGALE: Summary of Efficacy and Safety Data
ACQ-6 = Asthma Control Questionnaire-6; AEs = adverse events; APFS =accessorized pre-filled syringe; EOT = end of treatment; PC = product complaint; SC = subcutaneous.
Ferguson GT et al. Poster presented at: ATS; May 19-24, 2017; Washington, DC, Poster P1011.
✓ Co-primary endpoint results were positive for functionality and reliability of an APFS
to administer benralizumab SC in an at-home setting
─ The majority of patients or caregivers were able to successfully administer
benralizumab 30 mg SC via an APFS at-home at Week 12 (98%) and Week 16
(99%)
─ Nearly all of the APFS returned to the sponsor after home administration (99%)
were evaluated as functional at Weeks 12 and 16
─ Only 1 of the 573 dispensed APFS malfunctioned (PC)
✓ Improvements in mean ACQ-6 scores were observed at all time points compared to
baseline
✓ Near complete depletion of blood eosinophils was observed at Week 20 (EOT) and
Week 28 (follow-up) with benralizumab 30 mg SC administered via an APFS
compared to baseline

38. Lancet Respir Med. 2017;5(7):568-576.
Benralizumab resulted in an 80 mL (95% CI 0–150; p=0·04)
greater improvement (least-squares mean difference) in
prebronchodilator FEV1 after 12 weeks than did placebo.
The lung function improvement did not reach the minimum
clinically important difference of 10%
The most common adverse events for both groups were
nasopharyngitis (eight [8%] patients in each group) and upper
respiratory tract infections (five [5%] patients in each group).
Serious adverse events occurred in two (2%) patients each in
the benralizumab (pancytopenia and a suicide attempt, both
considered unrelated to treatment) and placebo (cervix
carcinoma and colon adenoma) groups

39. ✓ Compared with placebo, 1 dose of benralizumab
reduced asthma exacerbation rates by 49% (3.59 vs
1.82; P=.01) and exacerbations resulting in
hospitalization by 60% (1.62 vs 0.65; P=.02) in the
combined groups
✓ Benralizumab reduced blood eosinophil counts but
did not affect other outcomes, while
demonstrating an acceptable safety profile
Am J Emerg Med. 2015;33(1):14-20.

40. J Asthma. 2017 Jun 16:1-9.
Overlap in treatment eligibility varied; in mepolizumab-eligible patients not currently receiving omalizumab, 27–
37% were omalizumab-eligible and 18% were reslizumab-eligible.
Conclusions
Treatment eligibility for mepolizumab and omalizumab was higher than that for reslizumab.

41. ‡The EU label for omalizumab invites varying interpretation, thus two definitions were considered in this analysis. EU2 criteria for omalizumab eligibility additionally
included ACQ ≥1.5 and ≥2 exacerbations of asthma in the past 12 months compared with ≥1exacerbations in EU1 criteria.
1. Cinqaero : EPAR - Public assessment report http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_
_Public_assessment_report/human/003912/WC500212252.pdf
Eligibility for Treatment with Biologicals

42. •"In the Total Cohort, 137 subjects (20.4%) were eligible for mepolizumab, and 257, 205, and 275 subjects (38.4%, 30.6%, and 41% respectively) met the requirements for the
EU1, EU2, and AUS, CAN, US eligibility criteria for omalizumab respectively. Thirty-four subjects (5.1%) met the criteria for reslizumab treatment **In subjects who were eligible
for mepolizumab and were currently being treated with omalizumab (N = 36), 14% percent of subjects were also eligible for reslizumab
Eligibility Overlap for Biologicals in Severe Asthma
Total Cohort (N=670)
Albers FC, et al. J Asthma. 2017 Jun 16:1-9.

43. Wich would you choose?
In the DREAM study, mepolizumab resulted in a significant reduction in asthma exacerbations regardless
of the level of total IgE at baseline and the presence and degree of atopy [Pavord ID et al. Lancet. 2012;
380 (9842): 651-9]
In the EXTRA study, omalizumab was more effective in patients with higher blood eosinophilia (> 260
cells / μL), high levels of FeNO and periostin (Hanania NA et al. Am J Respir Crit Care Med. 2013; 187 (8): 804-11]
In the light of the partial overlap between the populations of eligible patients for omalizumab and
mepolizumab, head-to-head comparative trials will be needed to evaluate the relative efficacy of the
two bio-drug classes
Allergic / eosinophilic severe refractory asthma
Omalizumab? Anti IL-5?
In the XPORT study, patients with higher levels of blood eosinophilia during treatment with omalizumab
have a greater risk of exacerbations after its withdrawal [Ledford D et al. J Allergy Clin Immunol. 2016:
S0091-6749 (16) 31274-X]

44. Severe asthma: inflammatory phenotypes
Sputum/ blood eosinophils, FeNO, plasma periostin/ DPP4
Eosinophilic
Corticosteroids
Anti-Eosinophils
Anti-IgE
Anti-IL5
Anti-IL13
Anti-TSLP
Anti-IL33
CrTh2 Antagonists
«T2 High» «T2-Low»
Neutrophilic
Steroid-Insensitive
Anti-Neutrophils
Macrolides
CXCR2 Antagonists
Anti-TNF
Anti-IL1
Anti-IL17
P38 MAPK Inhibitors
PDE4 Inhibitors
Paucigranulocytic
Steroid-Insensitive
LAMA
LAMA+LABA Combo
Bronchial Thermoplasty
Barnes PJ, ACAAI Boston, October 2017

45. Severe refractory asthma
Omalizumab
(Ideal setting: allergic severe
refractory asthma)
• Serum total IgE level ≥ 30 ≤ 1500 IU/ml
• Positive skin prick tests or specific serum IgE
for perennial allergens
Blood eosinophils > 300 cells / µl
• High rate of exacerbations despite best standard
therapy / OCS
• Spirometry FEV1 < 80%
Continue
Mepolizumab
therapy
yes
Mepolizumab
(Ideal setting: severe uncontrolled
eosinophilic asthma regardless of
atopic or non-atopic state )
Responder
Continue
Omalizumab
therapy
no
yes
no
yes no
Bronchial
Thermoplasty Bronchial
Thermoplasty
yes no
Responder
no
Mepolizumab
yes
Bronchial Thermoplasty
(Ideal setting: severe uncontrolled
asthma with FEV1> = 60%
unsuitable for the currently
available bio-drugs)
Blood eosinophils > 300 cells / µl
Consider ongoing protocols on experimental
compounds for non-eligible / unresponsive
patients to available therapeutic approaches
Patients eligible to both Mepo- and
Omalizumab
• Blood eosinophils > 300 cells / µ
• Serum IgE ≥ 30 ≤ 1500 IU/ml
• Perennial allergens sensitization
Menzella F, et al. J Asthma Allergy. 2017;10:237-247.

47. ✓ Benralizumab is an effective and safe therapeutic option
Summary
✓ Given the increasing number of therapeutic options and the consequent risk
of overlap and drop-out it is mandatory to improve the management of this
kind of patients
✓ Asthma exacerbation rates are more pronounced in patients with higher blood
eosinophil count
✓ Benralizumab is an “anti-eosinophil” mAb with distinctive and peculiar
characteristics that differentiate it significantly

48. Thank you for your
attention!