OCS DEPENDENT SEVERE ASTHMA-

END OF THE ROAD?

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AGENDA

Treating SEA Patients Now

01 Severe asthma in India 04 & Beyond

Severe asthma and

02 bEOS
05 Impact of OCS Usage

WHAT does GINA What are the better

03 recommend for SEA
06 alternatives for your SEA
management patients
•01 Severe asthma in India

IE-4926 | May 2023

AGE-STANDARDIZED PREVALENCE OF ASTHMA PER 100,000
POPULATION IN 2019

2000 - <4000
per 1 lakh population

Wang, Z., Li, Y., Gao, Y. et al. Global, regional, and national burden of asthma and its attributable risk factors from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019. Respir Res 24,
169 (2023). https://doi.org/10.1186/s12931-023-02475-6
 AGE-STANDARDIZED DEATH RATE OF ASTHMA PER 100,000
POPULATION IN 2019

20 - <40
per 1 lakh population

Wang, Z., Li, Y., Gao, Y. et al. Global, regional, and national burden of asthma and its attributable risk factors from 1990 to 2019: a systematic analysis for the Global
5 Burden of Disease Study 2019. Respir Res 24, 169 (2023). https://doi.org/10.1186/s12931-023-02475-6
 ASTHMA IN INDIA

While the exact prevalence of severe asthma remains inconclusive, the prevalence of Asthma is increased by 20 -
25% in around half of the states in India over the past 15 years 1
Global Asthma Report 2022, shows that about 35 million people suffer from asthma in India, in which India accounts
for more than 13% of global asthma burden & 42% Global asthma deaths 2
6 1. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(18)30409-1/fulltext
2. http://globalasthmareport.org/burden/burden.php
 SEVERE ASTHMA IN INDIA

5- 10%
Of the total asthma population have
severe asthma1

Among subjects
with severe asthma, 68–70% of
subjects were never clinically
diagnosed with asthma2

1. Eileen Wang, Michael E. Wechsler, Trung N. Tran, Liam G. Heaney, Rupert C. Jones, Andrew N. Menzies-Gow, John Busby, David J. Jackson,et, al, Characterization of Severe Asthma Worldwide: Data From the International Severe Asthma
Registry,Chest,Volume 157, Issue 4,2020,Pages 790-804,ISSN 0012-3692,
https://doi.org/10.1016/j.chest.2019.10.053
2. . Singh S, Salvi S, Mangal DK, et al. Prevalence, time trends and treatment practices of asthma in India: the Global Asthma Network study. ERJ Open Res 2022; 8: 00528-2021 [DOI: 10.1183/ 23120541.00528-2021].
 UNCONTROLLED ASTHMA INCLUDES ONE OR BOTH OF THE
FOLLOWING:

• Poor symptom control

(frequent symptoms or reliever use, activity limited by asthma, night waking due to asthma)

• Frequent exacerbations(≥2/year) requiring OCS, or serious exacerbations(≥1/year) requiring

hospitalization.

UNCONTROLLED ASTHMA

DIFFICULT-TO-TREAT ASTHMA SEVERE ASTHMA

8
Porsbjerg, Celeste , et.al (2018). Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults. European Clinical Respiratory Journal. 5. 1440868. 10.1080/20018525.2018.1440868.
 HOW TO DIAGNOSE A SEVERE ASTHMA PATIENT

9
 DIFFICULT-TO-TREAT ASTHMA SEVERE ASTHMA

• It is asthma that is uncontrolled despite • It is a subset of difficult-to-treat asthma.

prescribing of medium or high dose ICS-
LABA treatment or • It means asthma that is uncontrolled
that requires high dose ICS-LABA despite
treatment to maintain good symptom 1. Correct Inhaler technique
control and reduce exacerbations.
2. Adherence with maximal optimized
high dose ICS-LABA therapy and
• In many cases, asthma may appear to be 3. Management of contributory factors,
difficult-to-treat because of modifiable or
factors such as 4. That worsens when high dose
1. Incorrect inhaler technique, treatment is decreased.
2. Poor adherence,
3. Smoking or comorbidities, 5. Approximately 3-10% people with
4. or because the diagnosis is asthma have severe asthma
incorrect.
10 Porsbjerg, Celeste , et.al (2018). Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults. European Clinical Respiratory Journal. 5. 1440868. 10.1080/20018525.2018.1440868.
 • Severe asthma and
•02 elevated blood
eosinophils

IE-4926 | May 2023

EOSINOPHILS ARE A KEY DRIVER OF THE INFLAMMATORY
PATHWAY IN PATIENTS WITH SEVERE ASTHMA1-7

Insult: allergic or Airway inflammation and

non-allergic hyperactivity

Eosinophilic activation Airway

Mucus
secretion modelling

Effects on airways and

Epithelial stimuli
inflammatory pathway

Cytotoxicity Inflammation

Eosinophils can perpetuate the cycle of inflammatory damage

References:
1. Carr, et al. World Allergy Organ J 2016; 9: 21; 2. Trivedi and Lloyd, Cell Mol Life Sci 2007; 64(10): 1269–89; 3. Mukherjee, et al. World Allergy Organ J 2014; 7(1) :32; 4. Lambrecht and Hammad, Nat Immunol 2015;16(1):
45–6; 5. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention 2023 https://ginasthma.org/wp-content/uploads/2023/05/GINA-2023-Full-Report-2023-WMS.pdf (accessed May 2023); 6.
Israel and Reddel, N Engl J Med 2017; 377(10): 965–76; 7. Gandhi, et al. Nat Rev Drug Discov 2016; 15(1): 35–50.
 RESULTS FROM ISAR :
MAJORITY OF PATIENTS (83%) WITH SEVERE ASTHMA HAVE AN
EOSINOPHILIC PHENOTYPE1
Grade 3 (most likely):
Blood eosinophils ≥300 or
receiving anti-IL-5 therapy
or blood eosinophils ≥150–
<300 with either OCS or ≥2
of: nasal polyps, elevated
FeNO (≥25 ppb) or late-
onset disease1

Grade 0 (non-
eosinophilic): Blood
eosinophils <150 and no
long-term OCS use, nasal
polyps, elevated FeNO or
late-onset disease1

Figure adapted from: Heaney LG et al. Chest 2021; 160(3): 814–830.

ISAR - International Severe Asthma Registry | ppb = parts per billion

Reference:
1. Heaney LG et al. Chest 2021; 160(3): 814–830.
•03 WHAT does GINA
recommend

IE-4926 | May 2023

 IDENTIFICATION OF SEVERE ASTHMA PATIENTS

1. Confirm the diagnosis 3. Optimize Management including

Diagnosis:
“Difficult- 1. Look for factors contributing to symptoms, • Asthma Education
to-treat exacerbations and poor quality of life:
asthma” • Optimize treatment (e.g. check
• Incorrect inhaler technique and correct inhaler technique
• Suboptimal adherence and adherence)
• Comorbidities including obesity, GERD, chronic
rhinosinusitis, OSA • Treat Co-morbidities and
For adolescents • Modifiable risk factors and triggers at home or modifiable risk factors.
and adults with work, including smoking, environmental exposures,
symptoms and/or allergen exposure (if sensitized) • Consider non biologic add-on
exacerbations • Overuse of SABA relievers therapy (e.g.LAMA, LTRA, if not
despite medium or
used)
high dose ICS-
LABA, or taking
maintenance OCS
If Asthma Still uncontrolled
4. Review response after 3 months
Diagnosis is Severe Asthma
1. ginasthma.org
15 2. Global Initiative for Asthma (GINA) Strategy 2021 – Executive Summary and Rationale for Key Changes. American Journal of Respiratory and Critical Care Medicine. 205. 10.1164/rccm.202109-2205PP.
 Severe asthma patient
with EOS > =150/µl are
categorised as T2 High

GINA recommends
Assessment of consideration of
inflammatory phenotype maintenance OCS
only as last resort,
If blood eosinophils not elevated, because of serious
repeat up to 3 times, at least 1– cumulative adverse
2 weeks after stopping OCS, or effects
on lowest possible OCS dose

16
© Global Initiative for Asthma 2022, www.ginasthma.org
 GINA recommends consideration of
maintenance OCS only as last resort,
because of serious cumulative adverse
effects
17
© Global Initiative for Asthma 2022, www.ginasthma.org
 SEVERE ASTHMA: STEP 5 PATIENTS
Asthma medication options for STEPS 3-5:
Adjust treatment up and down for individual patient needs

STEP 3 STEP 4 STEP 5

TRACK 1 PREFERRED
Add-on LAMA With low dose
CONTROLLER and
PREFERRED RELIEVER Low dose
Medium dose Refer for phenotypic assessment ICS-formoterol as the
maintenance
(Track 1). Using ICS-formoterol
maintenance ICS- ± anti-IgE, anti-IL5/5R, anti-IL4R, reliever, is the preferred
as reliever reduces the risk of ICS+formoterol
exacerbations compared with forrmoterol antiTSLP approach
using a SABA reliever Consider high dose ICS-formoterol
RELIEVER: As-needed low-dose ICS-formoterol

CONTROLLER and
ALTERNATIVE RELIEVER
(Track 2). Before considering a
regimen with SABA reliever,
check if the patient is likely to
be adherent with daily
controller
TRACK 2 ALTERNATIVE
Add-on LAMA
With SABA as the reliever,
Low dose maintenance Refer for phenotypic assessment ±
Medium/high dose is an alternative approach
ICS-LABA maintenance ICS-LABA anti-IgE, anti-IL5/5R, anti-IL4R
Consider high dose ICS-LABA if Track 1 is not possible,
or is not preferred by a patient
with no exacerbations on their
RELIEVER: As-needed short-acting ß2-agonist
current therapy

Medium dose ICS, or Add azithromycin (adults) or LTRA,

Other controller options add LTRA, or add Add LAMA or LTRA, or
for either track HDM SLIT switch to high dose ICS add low dose OCS but consider side-
effects

Redrawn from the GINA treatment strategy for adults & adolescents 12+ years with moderate-to-severe asthma

18 Image is used for educational purpose only. AstraZeneca is not responsible for data and copyrights
GINA Global Strategy for Asthma Management and Prevention 2021
•04 Treating SEA Patients
Now & Beyond…

IE-4926 | May 2023

 HOW ARE INDIAN ASTHMA PATIENTS TREATED NOW
Asthma Insights and Management in India: (AP-AIM) Study. Salvi S et al .

Exacerbations

On average, asthmatics in India reported:

8.4 exacerbations per year, each lasting a mean of 4 days.

OCS burden

Oral steroids were used during the previous year by 89% of patients.
On average, patients reported using oral steroids 10.5 times in a year.

Sundeep S Salvi et al. asthma Insights and Management in India: Lessons Learnt from the Asia Pacific – Asthma Insights and Management (AP-AIM) Study; Journal of The Association of Physicians of India;Vol. 63 ;September 2015

20
 HOW ARE INDIAN SEA PATIENTS TREATED NOW
AN EARLY INDIAN EXPERIENCE WITH BENRALIZUMAB
Case 1 Case 2 Case 3 Case 4 Case 5 Case 6

Blood EOS 1460 cells/μL 328 cells/μL 360 cells/μL 1400 cells/μL 290 cells/μL 250 cells/μL

IgE 1403 IU/mL 381 IU/mL 120 IU/mL 504 IU/mL

Exacerbations Recurrent >2 in a year 2 hospitalisations 5 / year

last year

Other morbidities Type 2 DM Obstructive sleep

Brain stroke apnea
Osteoporosis
OCS Use 4-6 times/yr Multiple times/yr Multiple times/yr Multiple times/yr 3-4 bursts/ yr 6 courses of oral
prednisolone 40
mg for 5–7 days

All the patients are using OCS multiple times a year

21
Talwar D, Yadav M, Maturu N et al. Case 3| An early Indian experience with benralizumab - A compendium on severe asthma cases: a case series [version 1; peer review: 1 approved]. F1000Research
2023, 12:1225
AN EARLY INDIAN EXPERIENCE WITH BENRALIZUMAB

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6

OCS Use 4-6 times/yr Multiple times/yr Multiple OCS Multiple times/yr 3-4 bursts/ yr 6 courses of oral
bursts given to along with ICS prednisolone 40
the patient 500μg mg for 5–7 days
fluticasone along with
frequent steroid
consumption

After Benralizumab Elimination of No OCS was No OCS bursts No OCS was No OCS burst No OCS burst
treatment OCS use in this administered required by the administered to required along required with
patient, during the patient and ACT the patient with reduction of QOL
improvement in treatment was improved during treatment ICS to 250μg for improvement
osteoporosis only ICS for the 2 months , then
other comorbid discontinued
condition

OCS – Oral Corticosteroid | ICS – Inhaled Corticosteroid | QOL – Quality of Life | ACT - Asthma Control Test
Talwar D, Yadav M, Maturu N et al. Case 3| An early Indian experience with benralizumab - A compendium on severe asthma cases: a case series [version 1; peer review: 1 approved].
F1000Research 2023, 12:1225
•05 Impact of OCS Usage

IE-4926 | May 2023

PRISM: BURDEN OF POTENTIALLY ORAL CORTICOSTEROID-
RELATED COMORBIDITIES IN PATIENTS WITH SEVERE ASTHMA
WORLDWIDE (ISAR)
Prevalence estimates:
Any potentially OCS-related
Dyslipidaemia Coronary heart disease
67% comorbidity 16% 9%
N=6,849; 4 countries N=11,039; 22 countries
(N=11,809; 22 countries)

Obesity Anxiety/depression Pneumonia

42% 14% 9%
(N=11,583; 22 countries) N=11,019; 21 countries N=10,300; 20 countries

Hypertension Osteoporosis Other significant infections

23% 13% 8%
N=9,252; 12 countries N=10,742; 21 countries N=6,918; 20 countries

Sleep apnoea Diabetes Other*

22% 10,094 (21 countries) 12% N=11,422; 22 countries
13% N=6,149–11,032; 3–21 countries

*Includes peptic ulcer (3%), pulmonary embolisms/venous thromboembolism (3%), cataract (2%), renal failure (2%), adrenal insufficiency (1%), glaucoma (1%), cerebrovascular accident (1%)
Image: Adapted from Scelo G et al. 2022
ISAR, International Severe Asthma Registry; OCS, oral corticosteroid
1.Scelo G et al. Am J Respir Crit Care Med. 2022; 205: A1306 [Presented at ATS 2022]
PERIODIC/ REGULAR USAGE OF OCS LEADS TO
MULTIFOLD RISK OF CVD & CANCER AMONG ASIAN
PATIENTS

Raja Dhar, et al.,10 June 2023 Respirology.2023;28:744–757.

•06 What are the better
alternatives

IE-4926 | May 2023

 STUDY DESIGN

Multicenter, open-label study of benralizumab in OCS-dependent patients with asthma

Population (N=598)1,2
Objectives
̶ To evaluate how quickly and safely OCS doses can be tapered to physiological doses (≥5 mg/day EOS ≥150 cells/µL or
prednisone or equivalent) EOS ≥300 cells/µL in
past 12 months
̶ To demonstrate how to manage AI and how to taper OCS dose if AI is present

Enrollment Induction OCS Reduction Phase Maintenance phase Follow-up

period phase (Variable duration based on period
(~24 to 32 weeks)
(≤2 weeks) (4 weeks) personalized OCS tapering)a (4 weeks)

Benralizumab Q8W x 3 doses

Stable OCS Begins after the 2 nd
benralizumab dose No OCS down-titration Follow-up
contact
Benralizumab 30 mg treatment period (12 weeks after
(Q4W for the first 3 doses then Q8W until EOT) last dose of
benralizumab)
HD ICS + LABA with/without additional controller medications EOTb visit (8 weeks
after last dose of
benralizumab)

a
Guided by schema of OCS reduction defined in the study protocol; bEOT will vary from 32 to 42 weeks depending on patients baseline OCS dose and other factors.
AI = adrenal insufficiency; EOS = eosinophils; EOT = end of treatment; HD = high-dose; ICS = inhaled corticosteroid; LABA = long-acting β2 agonist; OCS = oral corticosteroids;
27Q4W = every 4 weeks; Q8W = every 8 weeks.
1. Menzies-Gow A et al. ERJ Open Res. 2019;5:00009-2019; 2. Study NCT03557307. ClinicalTrials.gov website.
 PRIMARY ENDPOINTS - ELIMINATION OR REDUCTION OF OCS

The majority of OCS-dependent asthma patients eliminated or reduced OCS dose

100% reduction in OCS dosea 100% reduction or

daily OCS doses of ≤5 mg, if AIa

62.2% 80.6%
(58.18, 66.11) (77.20, 83.70)

OCS elimination or daily dose

OCS elimination reductionb (≤5 mg/d)
(n=372/598) (n=473/598)

Note: Data are provided with 95% confidence interval calculated using the Clopper-Pearson exact method. Analyses were descriptive only; no formal hypotheses were tested.
a
Sustained over at least 4 weeks without worsening of asthma. bIf reason for further reduction was AI.
AI = adrenal insufficiency; OCS = oral corticosteriod.
28
Menzies-Gow A et al. Poster presented at: AAAAI Annual Virtual Meeting; February 26-March 1, 2021. Poster L45.
 OCS REDUCTION BY BASELINE EOSINOPHIL COUNTS

OCS reductions achieved irrespective of baseline blood eosinophils count

100 91.1 91.0

91.3 91.9
80.6 82.9
75.6 80.5
80 67.1
60.2
62.2
Patients (%)

60 58.1

40

20

n= 372 74 173 122 473 91 210 167 522 106 229 181
0
100% reduction in OCS dose a 100% reduction or daily OCS doses of Daily OCS doses of ≤5 mga
≤5 mg, if reason for no further OCS
reduction is AIa
Baseline eosinophil count (cells/µL): Overall <15 ≥150 and <300 ≥300
0
Note: Confidence interval calculated using the Clopper-Pearson exact method. Overall N=598; EOS ≥300, n=210; EOS <300, n=381. Analyses were descriptive only; no formal
hypotheses were tested.
a
Sustained over at least 4 weeks without worsening of asthma.
AI = adrenal insufficiency; EOS = eosinophil; OCS = oral corticosteroids.
29
Menzies-Gow A et al. Poster presented at: Virtual AAAAI Annual Meeting; February 26-March 1, 2021. Poster L45.
 EFFECTS ON ASTHMA EXACERBATION RATES

Despite OCS dose reduction/elimination, few patients had asthma exacerbations

Exacerbations 12 months prior to enrollment Exacerbations during OCS reduction phase

8.1%
2 exacerbations

15.6% 74.2%
84.4% Zero exacerbations 17.7% Zero exacerbations
≥1 exacerbations 1 exacerbation

0 exacerbations
1 exacerbation
2 exacerbations

Median number of exacerbations: 2 Annualized asthma exacerbation rate: 0.64

30OCS = oral corticosteriod.

Menzies-Gow A et al. Poster presented at: Virtual AAAAI Annual Meeting; February 26-March 1, 2021. Poster L45.
ALGORITHM FOR OCS-TAPERING AND EVALUATION OF ADRENAL
FUNCTION
Fast reductions from high OCS doses to
7.5mg/d followed by individualized tapering
based on adrenal function

Baseline OCS OCS reduction to reach a prednisone dose of:

dose
(mg/day) 20 mg/d 10 mg/d 7.5 mg/d 5 mg/d

>20 5 mg/d Q1W 5 mg/d Q2W 2.5 mg/d Q2W 2.5 mg/d Q4W

>10 to ≤20 5 mg/d Q2W 2.5 mg/d Q2W 2.5 mg/d Q4W

>7.5 to ≤10 2.5 mg/d Q2W 2.5 mg/d Q4W

>5 to ≤7.5 2.5 mg/d Q4W

• Note: If there are signs/symptoms of AI, physicians should reduce OCS more slowly (1 mg/Q4W), regardless of cortisol concentrations but no further tapering in the OCS dosage in
the case of complete AI.
• ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; d = day; HPA = hypothalamic-pituitary-adrenal; IV = intravenous; OCS = oral corticosteroid(s); Q1W = every 1 weeks;
Q2W = every 2 weeks; Q4W = every 4 weeks.
• Menzies-Gow A et al. ERJ Open Res. 2019;5:00009-2019.
 ZONDA: STUDY DESIGN
TWO DOSING REGIMENS OF BENRALIZUMAB VERSUS PLACEBO X 28 WEEKS

Benralizumab 30 mg Benralizumab 30 mg
E SC every 4 weeks SC every 4 weeks Primary
n
r endpoint at
Benralizumab 30 mg
ol
Randomization Benralizumab 30 mg Week 28: %
l Run-in SC every 8 weeks with placebo
m
1:1:1 SC every 4 weeks
SC at 4 week interim
reduction in
e final OCS
n
t Placebo SC Placebo SC dose
every 4 weeks every 4 weeks
OCS optimized up to
6 weeks

↓ 1st dose IP V8 ← attempt OCS reduction → V13 V14 (EOT)

V2 → → V5
Week
-8 -2 Week 0 Week 4 Week 28 Week 36
-10
OCS
Run-in Run-in
Optimization up Treatment Period
(2 weeks) to 6 weeks (2 weeks)

V1 V2 Induction Maintenance Follow-up

OCS Reduction (Weeks 4-24) Extension Study
(Weeks 0-4) (Weeks 24-28) (Weeks 28-36)
V5 V6 Week 4 Week 24
baseline for
optimization
OCS stable run-in: Tx baseline
V6 - every 4 week dosing
32EOT = end of treatment; IP = investigational product; OCS = oral corticosteroid; SC = subcutaneous; Tx = treatment; V = visit.
1. Nair P et al. N Engl J Med. 2017;376:2448-2458; 2. Nair P et al. Protocol. N Engl J Med. 2017;376:2448-2458.
 ZONDA: BENRALIZUMAB SIGNIFICANTLY REDUCED FINAL
OCS DOSES AT WEEK 28 WHILE MAINTAINING ASTHMA
CONTROL VS. PLACEBO (FULL ANALYSIS SET)
Primary Analysis Categorical Analysis
Series1
Reduction in
0 Placebo Benra 30 mg Benra 30 mg
Final OCS Dose,
N=75 Q4W, N=72 Q8W, N=73
-10 n (%)
≥90% 9 (12) 24 (33) 27 (37)
Median Reduction in Daily

-20 -25
≥75% 15 (20) 38 (53) 37 (51)
-30
≥50% 28 (37) 48 (67) 48 (66)
OCS Dose, %

-40 >0% 40 (53) 55 (76) 58 (79)

-50 No change or any
increase in OCS 35 (47) 17 (24) 15 (21)
-60 dose
-70 -75 -75 OR (95 %CI) ─ 4.09 (2.22 – 7.57) 4.12 (2.22 – 7.63)

-80 p-value ─ <0.001 <0.001

p<0.001

-90
p<0.001 • Reduction in final OCS daily dose was 4X greater with
-100
Placebo Benralizumab Q4W Benralizumab Q8W benra vs. placebo (median baseline OCS dose was
10 mg/d in all groups)

33benra = benralizumab; CI = confidence interval; OCS = oral corticosteroid; OR = odds ratio; Q4W = every 4 weeks; Q8W = every 8 weeks.
Nair P et al. N Engl J Med. 2017;376:2448-2458.
 ZONDA: BENRALIZUMAB SIGNIFICANTLY REDUCED
ANNUAL AER WHILE REDUCING OCS DOSES AT WEEK 28
Both Dosing Regimens Significantly Reduced Annual AER While Reducing OCS Dose Compared
to Placebo at Week 281

2.5 -70% (p< 0.001) Exacerbation definition (at least 1)2

-55% (p=0.003) • A temporary bolus/burst of systemic
Placebo
2.0 corticosteroids for at least 3 days to
Annual AER (rate ratio)

(1.33-2.50) Benralizumab Q4W

treat symptoms of asthma
1.83 Benralizumab Q8W worseninga
1.5
• An emergency room visit due to
asthma that required systemic
1.0 corticosteroids, or
(0.55-1.26)
0.83 • An inpatient hospitalization due to
(0.34-0.88)
0.5 0.54
asthma

0.0
N= 75 72 73

Values above bars represent 95% CI.

a
OCS burst should be at a dose at least 1 level higher than the current titration step
34AER = asthma exacerbation rate; CI = confidence interval; OCS = oral corticosteroid; Q4W = every 4 weeks; Q8W = every 8 weeks.
1. Nair P et al. Supplementary appendix. N Engl J Med. 2017;376:2448-2458; 2. Nair P et al. Protocol online. N Engl J Med. 2017;376:2448-2458.
 ZONDA: BENRALIZUMAB DECREASED EXACERBATIONS
REQUIRING HOSPITALIZATION OR ED VISIT OVER 28
WEEKS
-93% (p=0.018) Placebo
-56% (p=0.187) Benralizumab Q4W
0.4
Benralizumab Q8W

Annual Estimated Rate

0.35 (0.16-0.65)
0.3
0.25
0.2
0.15 0.32 (0.05-0.38)

0.1
0.14 (0.00-0.18)
0.05 0.02
0
Series1
N= 75 72 73

• The rate of asthma exacerbations requiring hospitalization or ED visits were decreased with both benralizumab
30 mg Q4W (numerical) and Q8W over 28 weeks compared to placebo
Values in parentheses above bars represent 95% CI.
35Cl = confidence interval; ED = emergency department; Q4W = every 4 weeks; Q8W = every 8 weeks.
Nair P et al. Supplementary appendix. N Engl J Med. 2017;376:2448-2458.
 ZONDA: CHANGE IN FEV1 OVER TIME (FULL ANALYSIS
SET)
Change From Baseline in Pre-bronchodilator FEV1
0.50
Benralizumab Q4W Benralizumab Q8W Placebo
Change From Baseline, LSM (L)

0.40

0.30

0.20

0.10

0.00

-0.10

-0.20
Weeks 4 8 12 16 20 24 28
28 wks Group LSM (mL) LSM Difference (95% CI)
Q4W – placebo 232 vs. 126 105 (-40 to 251); p=0.153
Q8W – placebo 239 vs. 126 112 (-33 to 258); p=0.129
• Benralizumab led to a numerically greater improvement in lung function (pre-bronchodilator FEV 1) with both dosing schedules compared to
placebo in the ZONDA trial (small sample size not powered for FEV 1)
Note: p<0.05 for Q4W vs placebo for all time points except Week 28; p<0.05 for Q8W vs placebo for all time points except Weeks 24 and 28. Error bars represent 95% CIs.
36FEV = forced expiratory volume in 1 second; LSM = least square means; Q4W = every 4 weeks; Q8W = every 8 weeks.
1
Nair P et al. Supplementary appendix. N Engl J Med. 2017;376:2448-2458.
 ZONDA: CHANGE IN ACQ-6 SCORE OVER TIME (FULL
ANALYSIS SET)
0.2 Change From Baseline in ACQ-61
LSM Difference Compared With • Benralizumab Q4W (n=72)
0.0
• Benralizumab Q8W (n=73)

-0.2 • Placebo (n=74)

-0.4
Baseline

-0.6
Nominal P values were
-0.8
calculated using the repeated
measures analysis. P<0.05 for
-1.0
Benralizumab Q8W vs.
placebo
-1.2

-1.4
Weeks 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Results at 28 Weeks
ACQ-6 Placebo Q4W Q8W
Mean change vs. Placebo — -0.24 (p=0.139) -0.55 (p=0.001)
Proportion MCID responders (%)2 54.7 56.9 63
37ACQ-6 = Asthma Control Questionnaire 6; LSM = least squares mean; MCID = minimally clinically important difference; Q4W = every 4 weeks; Q8W = every 8 weeks. Error bars represent 95% CIs.
1. Nair P et al. Supplementary appendix. N Engl J Med. 2017;376:2448-2458; 2. In House Data, AstraZeneca Pharmaceuticals LP. CSR D3250C00020.
 ZONDA: CHANGE IN AQLQ(S) + 12 SCORE OVER TIME
(FULL ANALYSIS SET)
1.50 Change From Baseline in AQLQ(S) + 12 Score1 • Benralizumab Q4W (n=70)
• Benralizumab Q8W (n=72)
LSM Difference Compared With
1.25
• Placebo (n=75)

1.00
Baseline

0.75

0.50
•

0.25

0.00
4 8 12 16 20 24 28
Weeks

Results at 28 Weeks1
AQLQ(S) + 12 score Placebo Q4W Q8W
Mean change vs. Placebo — 0.23 (p=0.151) 0.45 (p=0.004)
Proportion MCID responders (%)2 52.0 59.7 60.3
AQLQ(S) + 12 = Asthma Quality of Life Questionnaire for 12 years and older; LSM = least squares mean; MCID = minimally clinically important difference; Q4W = every 4
38weeks; Q8W = every 8 weeks.
1. Nair P et al. Supplementary appendix. N Engl J Med. 2017;376:2448-2458; 2. In House Data, AstraZeneca Pharmaceuticals LP. CSR D3250C00020.
 SUMMARY

1. There are long term & short term adverse effects of oral corticosteroid usage in asthma, like CVS disease,
risk of cataracts, osteoporosis, dyslipidemia , hyperglycemia, to name a few
2. GINA recommends consideration of maintenance OCS only as last resort
3. Add on biologics can help reduction of OCS doses and discontinuation
4. Benralizumab has shown to be effectively reducing AER while reducing OCS dose (ZONDA)
5. Benralizumab achieved OCS reductions irrespective of baseline blood eosinophils count (PONENTE)
6. The Indian compendium on severe asthma cases established the use of oral corticosteroids was
tapered/discontinued in all

39
Data on file
 FASENRA ABBREVIATED PRESCRIBING INFORMATION
Rx
FASENRA
FASENRA ™ 30mg/mL

BENRALIZUMAB™ is available as a single dose pre-filled syringe for subcutaneous injection only.
COMPOSITION: Each prefilled syringe contains 30 mg Benralizumab in 1 mL.
MECHANISM OF ACTION : Benralizumab is an anti-eosinophil, humanised afucosylated, monoclonal antibody (IgG1, kappa). Benralizumab binds to the alpha subunit of the human interleukin-5
receptor (IL- 5Rα) with high affinity (16 pM) and specificity. The IL-5 receptor is specifically expressed on the surface of eosinophils and basophils. The absence of fucose in the Fc domain of
benralizumab results in high affinity (45.5 nM) for FcɣRIII receptors on immune effector cells such as natural killer (NK) cells leading to apoptosis of eosinophils and basophils through enhanced
antibody-dependent cell-mediated cytotoxicity (ADCC)..
INDICATIONS AND USAGE: BENRALIZUMAB™ is indicated as an add-on maintenance treatment for severe asthma with an eosinophilic phenotype in adult patients.
DOSAGE AND ADMINISTRATION: The recommended dose is 30 mg of BENRALIZUMAB™ by subcutaneous injection every 4 weeks for the first 3 doses, and then every 8 weeks thereafter.
In adolescents aged 12 to less than 18 years no posology recommendations can be made although data is available. The safety and efficacy of BENRALIZUMAB™ in children aged 6 to 11 years
have not been established.
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE
General: BENRALIZUMAB™ should not be used to treat acute asthma exacerbations. Patients should be instructed to seek medical advice if their asthma remains uncontrolled or worsens after
initiation of treatment. Abrupt discontinuation of corticosteroids after initiation of BENRALIZUMAB™ therapy is not recommended. Reduction in corticosteroid doses, if appropriate, should be gradual
and performed under the supervision of a physician. Hypersensitivity reactions : Hypersensitivity reactions (e.g. anaphylaxis, angioedema, urticaria, urticaria papular, rash) have occurred following
administration of BENRALIZUMAB™. In the event of a hypersensitivity reaction, BENRALIZUMAB™ should be discontinued. Parasitic (Helminth) Infection :Eosinophils may be involved in the
immunological response to some helminth infections. Treat patients with pre-existing helminth infections before initiating therapy with BENRALIZUMAB™. If patients become infected while receiving
treatment with BENRALIZUMAB™ and do not respond to anti-helminth treatment, discontinue treatment with BENRALIZUMAB™ until infection resolves.
CONTRAINDICATIONS: BENRALIZUMAB™ is contraindicated in patients who have known hypersensitivity to benralizumab or any of its excipients
PREGNANCY and LACTATION: It is preferable to avoid the use of BENRALIZUMAB™ during pregnancy or lactation. Administration of BENRALIZUMAB™ to pregnant women should only be
considered if the expected benefit to the mother is greater than any possible risk to the fetus. It is unknown whether benralizumab or its metabolites are excreted in human or animal milk, therefore
risk to the breastfed child cannot be excluded
ADVERSE REACTIONS: The common adverse reactions in patients treated with BENRALIZUMAB in clinical trials and postmarketing are Headache. Pharyngitis, Pyrexia, Injection site reactions,
Hypersensitivity reactions.
INCOMPATIBILITIES: Not applicable. SHELF LIFE: Refer outer pack.
STORAGE: Store in a refrigerator (2°C - 8°C). Store the prefilled syringe in the original package in order to protect from light. Do not freeze. PACK SIZE: Refer to outer carton
BENRALIZUMAB™ is a Applied Trademark of the AstraZeneca group of companies.

For Further Information Contact: AstraZeneca Pharma India Limited

Block N1, 12th Floor, Manyata Embassy Business Park, Outer Ring Road, Bangalore-560045

For more information refer full prescribing information Version 3.0 dated 18th December 2020