JOURNAL REVIEW

MODERATOR : MADHUKAR RAI S.R.SRUTHI MEENAXSHI

• Asthma is one of the most common chronic immunological
diseases.

• Approximately 20 %of patients with asthma have uncontrolled,

moderate to severe disease with recurrent exacerbation and
persistent symptoms despite maximized standard of care controller
therapy.

• Many of these patients have substantially reduced lung function,

despite maximum treatment, and face a further loss of lung
function over time

• Treatment guidelines have mostly recommended empirical

approaches on the basis of clinical measures of disease severity
rather than on the basis of the underlying mechanisms of
pathogenesis.
• An important molecular mechanism of asthma is type 2
inflammation.

• Type 2 inflammation, mediated by cytokines such as

interleukin- 4 , interleukin -5, and interleukin -13,
occurs in approximately 50 % of patients with asthma .

• Blood and sputum levels of eosinophils , fraction of

exhaled nitric oxide (FENO ) and serum IgE level have
been linked to mechanisms involved in type 2
inflammation.

• Biological agents targeting these cytokines are

currently approved for treatment of severe asthma .
 Biological agents in asthma
• Omalizumab(Genentech/Roche and
Novartis)Humanized IgG1IgE
• Mepolizumab(GlaxoSmithKline)Humanized
IgG1IL-5
• Benralizumab (MedImmune/
AstraZeneca)Humanized IgG1IL-5Rα
• Reslizumab(Teva Pharmaceutical
Industries)Humanized IgG4IL-5
• Dupilumab(Regeneron Pharmaceuticals)Human
IgG4IL-4Rα
 Dupilumab (DupixentTM)
• Binds to alpha subunit of the interleukin 4
receptor ( IL-4Rα), making it a receptor
antagonist
• FDA approved to treat moderate to severe
atopic dermatitis ( CHRONOS Trial )
• Developed by Regeneron and Sanofi
 LIBERTY ASTHMA QUEST STUDY
DESIGN
• Randomised
• Double blinded
• Placebo controlled
• Parallel group
• Phase 3 trail
• Intervention period : 52 week ( from may 2015
through September 2016)
• Sponsored by sanofi and Regeneron
Pharmaceuticals )
 Inclusion Criteria
• Patients 12 years of age or older with physician diagnosed
pesisitent asthma for 12 months or more . According to Global
Initiative for Asthma 2014 guidelines with following key
criteria
 Current treatment with medium to high dose inhaled
glucocorticoid ( fluticasone propionate at a total daily dose
of ≥500 ug or equipotent equivalent) plus additional
controllers ( a long acting β2 agonist or Leukotriene receptor
antagonist )
 A forced expiratory volume in 1 second (FEV1) before
bronchodilator use of 80 % or less of the predicted normal
value
 FEV1 reversibility of at least 12 % and 200 ml

 A Score on the 5 item Asthma control questionnaire (

ACQ -5 )of 1.5 or higher ( on a scale from 0 ( no
impairment )to 6 (maximum impairment
 Exclusion criteria
• Patients with chronic obstructive pulmonary disease or other
lung diseases (i.e. idiopathic pulmonary fibrosis, Churg-Strauss
syndrome, etc.)
• Patients with evidence of lung disease(s) other than asthma,
chest X-ray was performed at screening visit if there is no
chest imaging (chest X-ray, CT)available within 3 months prior
to screening to exclude patients with suspected active or
untreated latent tuberculosis
• Current smoker or cessation of smoking within 6 months prior
to Visit 1
• Previous smoker with a smoking history >10 pack-years
Methodology
 METHODOLOGY
• Among the 4148 eligible patients , 1902
patients were included in the study based on
inclusion and exclusion criteria
• The were randomised into 4 groups in 2:2:1:1
ratio to receive add on dupilumab at a dose of
200 or 300 mg every 2 weeks or matched
volume placebos for a period of 52 weeks
 Primary end points
• Annualized Rate of Severe Exacerbation Events Duing The 52-
Week Treatment Period: Intent-to-Treat (ITT) Population]
A severe exacerbation was defined as a deterioration of
asthma requiring: use of systemic corticosteroids for ≥3 days;
or hospitalization or emergency room visit because of
asthma, requiring systemic corticosteroids.

Annualized event rate was the total number of exacerbations

that occurred during the treatment period divided by the total
number of participant-years treated.

.
• Absolute Change From Baseline in Pre-
Bronchodilator Forced Expiratory Volume in 1
Second (FEV1) at Week 12: ITT Population
[ Time Frame: Baseline, Week 12 ]FEV1 was
the volume of air exhaled in the first second of
a forced expiration as measured by spirometer
 Secondary endpoints
Percent change from baseline in pre-
bronchodilator FEV1 at week 12

Annualized Rate of Severe Exacerbation Events

During The 52-Week Treatment Period: ITT
Population With Baseline Eosinophil ≥300 cells/ul

Change from baseline in Asthma Control

Questionnaire (ACQ)-5 score (for adults) at Weeks
2, 4, 8, 12,24, 36, and 52
RESULTS
BASELINE CHARACTERISITICS
 Results
 47.7 Percent lower annualized rate of severe
exacerbation with dupilumab 200 mg than
with the placebo, P < 0.001)
 46 % lower annualized rate of exacerbation
with dupilumab 300 mg than with the
placebo , P < 0.001)
 Results
• According to baseline eosinophil count , significant
differences in exacerbation rate were observed with
either dose of dupilumab as compared with matched
placebo among patients with eosinophil count of 300
or more per cubic millimeter.
• The rate was 0.37 ( 95 % CI, 0.29 to 0.48 ) with lower
dose dupilumab versus 1.08 ( 95% CI, 0.85 to 1.38 )
with matched placebo.
• 65.8 % lower rate of exacerbation with higher dose of
dupilumab than with placebo ( P<0.001)
• 67.8 % lower rate of exacerbation with lower dose of
dupilumab than with placebo ( P <0.001)
• According to baseline FENO , it was observed that there
was greater benefit of dupilumab with respect to
exacerbation rate among patients with a higher FENO
(≥25 TO <50 parts per billion [ppb] or ≥50 ppb )
 FEV1 OUTCOMES
 The change from baseline in FEV1 before bronchodilator
use at week 12 was 0.32 liters with lower dose dupilumab
versus 0.18 liters with matched placebo (difference, 0.14
liters; P<0.001)

 The change was 0.34 liters with higher dose dupilumab

versus 0.21 liters with matched placebo, ( difference ,0.13
liters;P<0.001)

 The benefit of dupilumab with respect to FEV1 was found

to be greatest among patients with blood eosinophil count
of 300 or more per cubic milliliter at baseline.
Dupilumab improves lung function!
The percentage change from baseline to week
12 in FEV1 before brochodilator use was
greater with dupilumab than with placebo

The difference as compared with matched

placebo was 9.2 percentage points (95 %CI
,5.5 to 12.9 ) with lower dose dupilumab and
9.4% points (95 % CI, 5.7to 13.1) with higher
dose dupilumab ( p < 0.001)
 ACQ-5 scores were lower ( indicating better
asthma control ) with dupilimab than placebo as
early as week 2 and the effect was sustained over
52 week intervention period

 Dupilumab also showed benefits over matched

placebo with respect to global score on the
asthma quality of life questionaire , morning and
evening asthma symptoms and Peak expiratory
flow at weeks 24 and 52
 Exploratory outcomes
Patients who received dupilumab had greater
reductions from baseline during the
intervention period in the FENO , levels of
total Ig E , periostin, eotaxin -3 than did
patients who received matched placebo.
 ADVERSE EVENTS
 The incidence of the adverse events emerged during the
trial period was similar across the intervention groups ( 81%
in combined dupilumab groups and 83.1 % in combined
placebo group)

 Injection site reaction was the most frequent adverse

effect observed in patients receiving dupilumab than the
placebo ( 15.2 % in low dose , 18.4 % in higher dose vs 5.4
% and 10.3% in matched placebo)

 Pneumonia was the most frequent serious adverse event

reported in 104( 8.2 %) patients who received dupilumab
and 53 patients(8.4 %) who received placebo .
 Other adverse events were URTI, sinusitis, bronchitis, rhinitis
, headache , UTI.

 Eosinophilia was reported as adverse event in (52 patients

)4.1 % patients who received dupilumab compared to (4
patients) 0.6 % who received placebo

 Total of 8 adverse event of eosinophilia resulted in

permanent discontinuation of assigned treament ( all the
cases had eosinophila >3000 cells per cubic millimeter)

 A total of 5 patients ( 0.4 %) who received dupilumab and 3

patients (0.5%) who received placebo died. All deaths were
considered by the investigator unrelated to the intervention.
ADVERSE EVENTS
 DISCUSSION
 This phase 3 trial suggested that in patients with
uncontrolled severe asthma the annualised rate of severe
asthma exacerbation was significantly lower with either
dose of dupilumab than with matched placebo , with
greater treatment effects observed with increasing
baseline levels of blood eosinophils and FENO.

 Assessment of FEV 1 and Asthma control over time

showed that dupilumab showed significant differences
versus placebo seen at the first evaluation in week 2 and
maintained throughout the 52 week intervention period.
 Furthermore, an analysis of postbronchodilator
FEV1 Slope showed loss of lung function in
patients who received placebo and no loss in
those who received dupilumab , the findings
that suggest a potential effect of dupilumab on
airway remodelling.

 The results of the trial confirm that interleukin -

4 and interleukin 13 are key proximal drivers of
type 2 inflammation in asthma .Dupilumab
significantly reduced the FENO, in addition to
other biomarkers of systemic type 2
inflammation such as IgE , confirming its
biological activity on airway remodelling.
 In this trial patients who received dupilumab
had a greater mean transient increase from
baseline in blood eosinophil counts than did
patients who did received placebo.

 The possible explanation being the increase in

blood eosinophil counts is consistent with
hypothesis that dupilumab blocks interleukin 4
and interleukin 13 function of eosinophil
survival,activation and recruitment to tissues
but not egress from bone marrow , which is
influenced by interleukin 5.
 CONCLUSION

• Systemic glucocorticoids act non selectively and

are associated with considerable multiorgan toxic
effects and broad immunosuppression.

• Biological agents dupilumab targeting cytokines

IL4 has currently become promising therapy not
only in controlling exacerbation of asthma
symptoms but also improves the lung function
with much favourable safety profile.