JOURNAL REVIEW DONE BY DR SANTOSH NARAYANKAR AT NSCBMCH JABALPUR

1. OMALIZUMAB IN SEVERE ALLERGIC ASTHMA
INADEQUATELY CONTROLLED WITH
STANDARD THERAPY
GUIDE– DR D DUTTA
PRESENTED BY – DR SANTOSH NARAYANKAR

2. INTRODUCTION
 Omalizumab, a recombinant humanized
monoclonal antibody that binds to free IgE, is
currently approved by the U.S. Food and Drug
Administration for the treatment of adults and
adolescents (aged 12 years) with moderate to
severe persistent allergic asthma that is
inadequately controlled on ICS.
 GINA 2006 has included the omalizumab in step 5
management of asthma.

3. ROLE OF FUNDING SOURCE
 Sponsor: Gentech and Novartis Pharmaceuticals
 Information provided by: Novartis
 ClinicalTrials.gov Identifier:NCT00454051
 The funding sources were involved in the concept,
study design, interpretation of the data, and third
third party writing assistance and had a role in the
decision to submit the manuscript for publication

4. OBJECTIVE
 To evaluate the efficacy and safety of omalizumab
in patients with inadequately controlled severe
asthma who are receiving high-dose ICS and
LABAs, with or without additional controller therapy.

5.  Criteria
 Inclusion Criteria:
 Adults aged >= 18 years.
 Patients with severe persistent allergic asthma with the following
characteristics:
 FEV1 (Forced Expiratory Volume in One Second) <80% of predicted.
 Frequent daily symptoms (>=4 days/week on average) or nocturnal
awakening (>=1/week on average).
 Multiple severe asthma exacerbations: either >=2 severe asthma
exacerbations having required an unscheduled medical intervention
with systemic corticosteroid in the past year, or hospitalization
(including emergency room treatment) for an asthma exacerbation in
the past year.
 Despite a high dose inhaled corticosteroid 500 mcg fluticasone or
equivalent and a inhaled long-acting B2-agonist.
 With an allergy to a perennial allergen demonstrated with convincing
criteria, i.e. positive prick skin test or in vitro reactivity to a perennial
aeroallergen (RAST).
 Total serum IgE level >= 30 to <=700 IU/ml and suitable serum total
IgE level and weight 30- 150 kg.

6.  Exclusion Criteria:
 Age < 18 years.
 Smoking history > 20 pack years.
 Patients who have had an asthma exacerbation during the 4 weeks prior
to randomization
 History of food or drug related severe anaphylactoid or anaphylactic
reaction
 Elevated serum IgE levels for reasons other than allergy (e.g. parasite
infections, hyper immunoglobulin E syndrome, Wiskott-Aldrich Syndrome
or allergic bronchopulmonary aspergillosis).
 Patients with active cancer, suspicion of cancer or any history of cancer.
 Pregnant women.
 Known hypersensitivity to omalizumab or to one of its components.
 Patients already treated with omalizumab (indeed a previous treatment
with omalizumab could have modified the FceRI expression).
 Patients who had participated in a clinical trial in the past 3 months

7. METHODS
 Design
 This was a
prospective, multicenter, randomized, parallel-
group, double-blind, placebo-controlled trial. After a
run-in period of 2 to 4 weeks, eligible patients were
randomly assigned to receive either placebo or
omalizumab subcutaneously in a 1:1 ratio in
addition to high-dose ICS (equivalent to 500 mcg of
fluticasone twice daily) and LABAs for 48 weeks.

8. INTERVENTIONS
 The dose and dosing frequency of omalizumab, which
was administered subcutaneously, were based on body
weight and total serum IgE level at screening as
specified in the U.S. package insert. The dosing table
was designed to ensure a minimum dose of 0.008
mg/kg of body weight per IgE (IU/mL) every 2 weeks or
0.016 mg/kg per IgE (IU/mL) every 4 weeks. No dosage
modifications of omalizumab, high-dose ICS plus
LABAs, OCS, or any other controller medications were
permitted during the study (except for systemic
corticosteroids used to treat asthma exacerbation).
Inhaled corticosteroids and LABA were provided by the
sponsor; adherence to therapy with ICS and LABAs was
assessed at each visit during the run-in and study
periods.

12. RESULTS

13. PRIMARY EFFICACY END POINT
 The protocol-defined asthma exacerbation rate
during the 48-week treatment period was
significantly lower in the omalizumab group than in
the placebo group (incidence rate, 0.66 vs. 0.88; P
0.006) .
 This corresponds to a 25% relative reduction in the
asthma exacerbation rate for patients who received
omalizumab compared with placebo (IRR, 0.75
[95% CI, 0.61 to 0.92]).
 In addition, omalizumab increased the time to first
asthma exacerbation (hazard ratio, 0.74 [CI, 0.60 to
0.93]; P 0.008) .

16. SECONDARY EFFICACY END POINTS
 In analyses using mixed-effects models, patients
who received omalizumab had greater increases in
mean AQLQ(S) scores (0.29 point [CI, 0.15 to
0.43]), decreases in mean daily albuterol puffs
(0.27 puff/d [CI, 0.49 to 0.04]), and decreases in
mean asthma symptom score(0.26 [CI, 0.42 to
0.10]) compared with the placebo group during the
48-week study period.
 Omalizumab also increased the proportion of
patients who had improvement from baseline to
week 48 in the overall AQLQ(S) score that
exceeded the minimal clinically important difference
(67.8% vs. 61.0%; P 0.042).

18. RESCUE MEDICATION PUFFS AND TOTAL ASTHMA
SYMPTOM SCORE OVER 48 WEEKS.

19. EXPLORATORY EFFICACY END POINT
Four hundred six patients provided FeNO samples at
baseline for the study. Of these, 394 were included
in the analysis because their FeNO levels at
baseline were above the detection limit (5 ppb).
There were no substantive differences in baseline
clinical or demographic characteristics in persons
who were and were not included in the FeNO
analysis. During the 48 weeks, the reduction in
FeNO from baseline was greater in the omalizumab
group compared with the placebo group at all visits

20. EXPLORATORY EFFICACY END POINT

21. SAFETY AND TOLERABILITY

22. DISCUSSION
 This study demonstrates that treatment with
omalizumab conferred a 25% reduction in asthma
exacerbations among patients with severe asthma
that was inadequately controlled with high-dose ICS
and LABAs and, in many cases, additional
controller medications. Add-on treatment with
omalizumab also improved asthma-specific quality
of life.
 The change from baseline in total asthma symptom
score and rescue 2-agonist use was consistently
improved for omalizumab compared with placebo at
each visit during the study.

23.  In conclusion, this study demonstrated that
omalizumab conferred clinically meaningful efficacy
when added to high-dose ICS and LABA therapy in
patients with severe allergic asthma that is
inadequately controlled. This study also indicated
that omalizumab was not associated with an
increased rate of common adverse events
compared with placebo.

24. LIMITATIONS
 The results are limited by early patient
discontinuation(20.8%).
 The study was not powered to detect rare safety
events.

25. THANK YOU
THANK YOU

27. PATIENT SELECTION FOR OMALIZUMAB
THERAPY
1. Multiple documented severe asthma
exacerbations.
2. Symptomatic despite high dose ICS and LABA
therapy.
3. Frequent daytime symptoms or night time
awakenings.
4. Reduced lung function (FEV1 < 80%).
5. Positive skin test or invitro reactivity to a perennial
allergen.
6. Body weight between 20-150 kg and total IgE 30-
1500 IU/ml.

28. COST OMALIZUMAB
 Xolair is very expensive, ranging from $500 to
$2000 per month.
 Cost per 150 mg vial 256 dollars
Adverse effects
 Injection site reaction.(45%)
 Headache .(15%)
 Viral infections.(23%)
 Rarely anaphylactic reactions (0.1%).