Auspar Omalizumab 210415
Auspar Omalizumab 210415
Auspar Omalizumab 210415
for Omalizumab
April 2021
Therapeutic Goods Administration
About AusPARs
• An Australian Public Assessment Report (AusPAR) provides information about the
evaluation of a prescription medicine and the considerations that led the TGA to
approve or not approve a prescription medicine submission.
• AusPARs are prepared and published by the TGA.
• An AusPAR is prepared for submissions that relate to new chemical entities, generic
medicines, major variations and extensions of indications.
• An AusPAR is a static document; it provides information that relates to a submission at
a particular point in time.
• A new AusPAR will be developed to reflect changes to indications and/or major
variations to a prescription medicine subject to evaluation by the TGA.
Copyright
© Commonwealth of Australia 2021
This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal
use or, if you are part of an organisation, for internal use within your organisation, but only if you or your
organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all
disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or
allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any
part of this work in any way (electronic or otherwise) without first being given specific written permission from the
Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA
Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to
<tga.copyright@tga.gov.au>.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 2 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Contents
List of abbreviations 4
I. Introduction to product submission 6
Submission details____________________________________________________________6
Product background__________________________________________________________7
Regulatory status______________________________________________________________9
Product Information_________________________________________________________11
II. Registration timeline 11
III. Submission overview and risk/benefit assessment 12
Quality_________________________________________________________________________12
Nonclinical____________________________________________________________________12
Clinical_________________________________________________________________________13
Risk management plan______________________________________________________19
Risk-benefit analysis________________________________________________________19
Outcome_______________________________________________________________________29
Attachment 1. Product Information 30
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 3 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
List of abbreviations
Abbreviation Meaning
AE Adverse event
CI Confidence interval
CT Computerised tomography
IgE Immunoglobulin E
IL Interleukin
PD Pharmacodynamic(s)
PI Product Information
PK Pharmacokinetic(s)
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 4 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Abbreviation Meaning
SD Standard deviation
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 5 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Submission details
Type of submission: Extension of indication
Decision: Approved
Dose forms: Solution for injection in pre-filled syringe and powder for
injection vial with diluent
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 6 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Pregnancy category: B1
Drugs which have been taken by only a limited number of
pregnant women and women of childbearing age, without an
increase in the frequency of malformation or other direct or
indirect harmful effects on the human fetus having been
observed.
Studies in animals have not shown evidence of an increased
occurrence of fetal damage.
The use of any medicine during pregnancy requires careful
consideration of both risks and benefits by the treating health
professional. This must not be used as the sole basis of decision
making in the use of medicines during pregnancy. The TGA does
not provide advice on the use of medicines in pregnancy for
specific cases. More information is available from obstetric drug
information services in your State or Territory.
Product background
This AusPAR describes the application by Novartis Pharmaceuticals Australia Pty Ltd (the
sponsor) to register Xolair (omalizumab) 75 mg, 150 mg, solution for injection in pre-filled
syringe and powder for injection vial with diluent for the following extension of
indications:
Nasal Polyps
Xolair is indicated for adults (18 years of age and above) for the treatment of nasal
polyps with inadequate response to intranasal corticosteroids.
Nasal polyps develop as outgrowths of the nasal and paranasal sinus mucosa. 2,3 They are
known to be associated with conditions such as asthma, infection, bronchiectasis, cystic
fibrosis, granulomatous diseases, vasculitides, immunodeficiency, ciliary dysfunction and
aspirin sensitivity.3 Malignancies of the nasal mucosa and congenital abnormalities may
also present as ‘polyps’. There is a higher prevalence of nasal polyps in some subsets of
2
Newton JR, Ah-See KW. A review of nasal polyposis. Ther Clin Risk Manag. 2008 Apr;4(2):507-12.
3
Sedaghat A. Chronic rhinosinusitis. Am Fam Physician. 2017 Oct 15;96(8):500-506.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 7 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
patients: approximately 45% in patients with adult-onset asthma and approximately 30%
in patients with chronic rhinosinusitis.4 Presentation usually occurs in adults older than
20 years. They are uncommon in children under 10 years old but may be the presenting
feature of cystic fibrosis.
Nasal polyps, regardless of cause, may cause a range of symptoms including watery
rhinorrhoea, post-nasal drip, loss of sense of smell, nasal obstruction and sleep disorder.
Their presence is confirmed by anterior and posterior rhinoscopy at which single or
multiple polypoid masses, arising most frequently from the middle meatus and prolapsing
into the nasal cavity, may be seen. Computerised tomography (CT) scanning of the nasal
cavities and paranasal sinuses may be performed to determine the extent of the disease.
Differential diagnoses include congenital anomalies, benign or malignant tumours, and
polyps associated with underlying conditions as listed above.
Chronic rhinosinusitis has been defined as the presence of both subjective and objective
evidence of sinonasal inflammation that lasts for greater than 12 weeks duration.
Symptoms include anterior or posterior rhinorrhoea, nasal congestion, hyposmia and/or
facial pressure or pain. Approximately 30% of patients with chronic rhinosinusitis are
found to have nasal polyps, with these described as ‘inflammatory lesions that project into
the nasal airway, are typically bilateral, and originate from the ethmoid sinus’. Patients with
nasal polyps may have more severe symptoms than those without nasal polyps, although
there is considerable overlap.5,6
Patients with chronic rhinosinusitis with nasal polyps usually present in middle age, with
the age at diagnosis ranging from 40 to 60 years. The condition is more common in males.
There is a recognised association between chronic rhinosinusitis with nasal polyps and
asthma, with an asthma prevalence of 26 to 48% in these patients. Although there is an
association between chronic rhinosinusitis and allergic rhinitis (with prevalence of 40% to
84% in adults with chronic rhinosinusitis) this does not appear to hold for patients with
chronic rhinosinusitis with nasal polyps. Approximately 10% of patients with chronic
4
Passali, Desiderio, et al. Consensus Conference on Nasal Polyposis. Acta otorhinolaryngologica Italica : organo
ufficiale della Società italiana di otorinolaringologia e chirurgia cervico-facciale.2004, 24. 3-61.
5
Stevens WW, et al. Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol Pract. 2016;4(4):565–
572.
6
Rosenfeld, R. M, et al.. Clinical Practice Guideline (Update): Adult Sinusitis. Otolaryngology–Head and Neck
Surgery, 2015,152(2_suppl), S1–S39.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 8 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
rhinosinusitis with nasal polyps and asthma also have aspirin-exacerbated respiratory
disease (AERD).
Chronic rhinosinusitis, with or without nasal polyps, is considered a chronic inflammatory
condition with an unclear aetiology. According to the 2016 review article by Stevens et al.,
current theories as to aetiology hypothesise that ‘an impaired sinonasal epithelial barrier
could lead to increased exposures to inhaled pathogens, antigens and particulates that, in
the setting of a dysregulated host immune response, could promote chronic inflammation’.7
Patients with chronic rhinosinusitis may be considered as having two phenotypes
according to whether nasal polyps are present and the type of inflammation. 8 Chronic
rhinosinusitis without nasal polyps (CRSsNP) is characterised by type I inflammation, and
chronic rhinosinusitis with nasal polyps (CRSwNP), in Western countries, is characterised
by type II (or immunoglobulin E (IgE)-mediated) inflammation and tissue eosinophilia. A
number of studies have found increased levels of a wide variety of inflammatory
mediators and immune system cells in the tissues of patients with chronic rhinosinusitis
with nasal polyps. The initiating event(s) and sustaining processes are unclear. Possible
triggers may be allergens associated with fungi or bacteria, especially Staphylococcus
aureus enterotoxins, viruses, and environmental factors. This division of phenotypes does
not, however, hold for patients with chronic rhinosinusitis with nasap polyps in Asia as
these patients tend to have a mixed inflammatory picture without increased tissue
eosinophilia. 9
Intranasal and systemic/oral corticosteroids remain the mainstay of treatment of chronic
rhinosinusitis with nasap polyps, but many patients fail to achieve complete therapeutic
benefit with these medications and resort to functional endoscopic sinus surgery and
other complex sinus surgery. Although surgery and intranasal and oral corticosteroids are
useful and often effective in reducing the size of nasal polyps and associated symptoms,
many patients do not respond sufficiently and/or polyps return rapidly after medication
withdrawal or within months or years following surgery.
Omalizumab is a recombinant DNA-derived humanised monoclonal antibody that
selectively binds to human IgE. The antibody is a humanised immunoglobulin G1 kappa
monoclonal antibody that contains human framework regions with the complementary-
determining regions of a humanised murine antibody that binds to IgE. Omalizumab
selectively binds to human IgE at the same site as the high affinity IgE receptor (FcεRI),
thereby reducing surface IgE on basophils and mast cells and reducing basophil and mast
cell triggered type II inflammation.
Regulatory status
The product received initial registration on the Australian Register of Therapeutic Goods
(ARTG) on 13 June2002 for use in moderate allergic asthma. It was registered for use in
severe allergic asthma in 2005, and extended to be used in the paediatric population in
2016 as follows:
7
Stevens WW, Schleimer RP, Kern RC. Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol Pract.
2016;4(4):565-572.
8
Kato A. Immunopathology of chronic rhinosinusitis. Allergol Int; 64:121-30. Copy provided by the Applicant.
9
Chaaban MR, Walsh EM, Woodworth BA. Epidemiology and differential diagnosis of nasal polyps. Am J Rhinol
Allergy. 2013;27(6):473–478. doi:10.2500/ajra.2013.27.3981.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 9 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Allergic Asthma
Children 6 to < 12 years of age
In children aged 6 to < 12 years, Xolair is indicated as add‐on therapy to improve
asthma control in patients with severe allergic asthma who have documented
exacerbations despite daily high dose inhaled corticosteroids, and who have
immunoglobulin E levels corresponding to the recommended dose range (see Table 1
in Section 4.2 dose and method of administration).
Adults and adolescents ≥ 12 years of age
Xolair is indicated for the management of adult and adolescent patients with
moderate to severe allergic asthma, who are already being treated with inhaled
steroids, and who have serum immunoglobulin E levels corresponding to the
recommended dose range (see Table 1 in Section 4.2 dose and method of
administration)
A new strength was registered in 10 January 2006 and a new presentation was included
on 19 August 2013.
The TGA approved an extension of indication for Xolair on 6 November 2014, for the
following indication:
Chronic Spontaneous Urticaria (CSU)
Xolair is indicated for adults and adolescents (12 years of age and above) with
chronic spontaneous urticaria who remain symptomatic despite H1 antihistamine
treatment.
At the time the TGA considered this application, similar applications had been approved in
the European Union on 31 July 2020, the United States of America (USA) on 30 November
2020 and in Singapore on 15 December 2020. A similar application was also under
consideration in Canada (submitted in August 2020).
Table 1: Foreign regulatory status of chronic rhinosinusitis with nasal polyps
indication
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 10 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Product Information
The Product Information (PI) approved with the submission which is described in this
AusPAR can be found as Attachment 1. For the most recent PI, please refer to the TGA
website at <https://www.tga.gov.au/product-information-pi>.
Description Date
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 11 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Description Date
Quality
There was no requirement for a quality evaluation in a submission of this type.
Nonclinical
During the evaluation, in response to recommendations made by the clinical evaluator, the
wording of the proposed indication was revised to the following:
Xolair is indicated as add-on treatment in adult patients (18 years of age and above)
for the treatment of CRSwNP [Chronic rhinosinusitis with nasal polyps] with
inadequate response to intranasal corticosteroids and who have serum
immunoglobulin E levels corresponding to the recommended dose range (see Dosage
and Administration)
A separate set of dosing instructions for the chronic rhinosinusitis with nasal polyps
indication was removed from the proposed PI document so that dose levels now match
those approved for allergic asthma.
With the maximum recommended clinical dose now unchanged, the revised nonclinical
risk assessment is no longer required. No nonclinical data specifically relating to efficacy
in the proposed new indication were submitted (in the current application or previous
ones). This is acceptable; the efficacy assessment for the new indication will rely on
clinical data only.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 12 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Clinical
The clinical dossier consisted of:
• two pivotal Phase III studies, Study GA39688 and Study GA39855;
• safety data from an interim analysis of a Phase III open label extension study, Study
WA40169;
• an exposure-response and free-IgE response analysis of omalizumab in nasal polyps;
and
• a prospective observational study of the use of omalizumab in pregnant women, the
EXPECT trial, for the PI update.
Pharmacology
Pharmacokinetics
There are limited pharmacokinetics (PK) investigations of the use of omalizumab in the
treatment of patients with chronic rhinosinusitis with nasal polyps. Although exposure-
response analyses were conducted in the Phase III studies, there were uncertainties about
the appropriate posology for the newly proposed indication.
Overall, the PK and pharmacodynamics (PD) effect of omalizumab appears to be
adequately characterised and does not appear to be different in subjects with nasal polyps
compared to subjects with allergic asthma (this has been adequately reflected in the PI).
Pharmacodynamics
The PD data from the two clinical studies demonstrate that omalizumab dosing according
to the dosing table using baseline IgE level and body weight was effective in reducing free
IgE serum concentration during treatment. Using the proposed posology (based on weight
and baseline IgE), free IgE suppression at 24 weeks was achieved in 93.0% of the subjects
on active. Slight positive trend between omalizumab concentration and Nasal Polyp Score
(NPS) response is observed with the lowest concentration tertile group, however, a clear
trend between the Week 24 omalizumab concentration, or free IgE, and the change from
Baseline in efficacy endpoints is not observed.
Efficacy
The clinical development plan for the proposed indication of the treatment of patients
with chronic rhinosinusitis with nasal polyps did not include dose finding studies. Only
one dosing regimen (the regimen approved by the European Medicines Agency (EMA) for
use in severe asthma) was used in the two clinical studies. Since the Phase III studies were
to be conducted in adult patients and nasal polyps rarely occurs in patients less than 18
years of age, the posology of omalizumab used in these two nasal polyp studies was
adopted from the allergic asthma dosing table by excluding cells of which the bodyweight
is less than 30 kg.
Study GA39688 and Study 39855
Studies GA39688 and GA39855 were replicate Phase III, randomised, multicentre, double-
blind, placebo-controlled, clinical studies that were conducted in parallel with identical
study designs (as shown in Figure 2, below). They were conducted concurrently across
different sites in 15 countries across Europe and North America. Each study was designed
to enrol approximately 120 adult patients with nasal polyps who had an inadequate
response to standard of care treatments (daily treatment with intranasal corticosteroid
therapy).
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 13 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
1°EP = co-primary end point; Q2W = every 2 weeks; Q4W = every 4 weeks; SFU = safety follow-up; wk =
week. Note: All patients were treated during the entire study with intranasal corticosteroids
(mometasone nasal spray) as background therapy.
The co-primary efficacy endpoints were:
• the change from Baseline at Week 24 in Nasal Polyp Score (NPS); and
• the change from Baseline at Week 24 in average daily Nasal Congestion Score (NCS),
averaged over the prior 7 days.
The Nasal Polyp Score is performed with intranasal endoscopy, and the right and left
nostrils are assessed separately on a scale from 0 to 4 (total maximum 8).
The nasal congestion score (0 to 3) is based on daily patient reports using the mean value
of the last 7 days.
The secondary efficacy endpoints included:
• change from Baseline to Week 24 in the:
– average daily Total Nasal Symptom Score (TNSS);
– average daily sense of smell;
– average daily posterior and anterior rhinorrhoea score;
– health related quality of lifeaccording to the Sino-Nasal Outcome Test-22 (SNOT-
22);
– Asthma Quality of Life Questionnaire (AQLQ, in patients with asthma
co-morbidity); and
– University of Pennsylvania Smell Identification Test (UPSIT).
• change from Baseline to Week 16 in the co-primary end-points;
• reduction in need for surgery; and
• requirement for rescue treatments
A planned total of 120 patients were to be enrolled. The sample size of 120 patients
(102 patients divided by 0.85 assuming a 15% early withdrawal rate) provided at least
85% power to independently detect both a 0.56-point difference between treatment
groups in change from Baseline at Week 24 in the average daily Nasal Congestion Score
(assuming standard deviation (SD) = 0.75) and a 1.50-point difference between treatment
groups in change from Baseline at Week 24 in Nasal Polyp Score (assuming SD = 2.0).
As the changes from Baseline to Week 24 in Nasal Polyp Score and the average daily Nasal
Congestion Sscore were co-primary endpoints, both null hypotheses for these endpoints
had to be rejected, with parameter estimates showing a significant benefit of omalizumab
over placebo, for the study to be deemed positive.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 14 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 15 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Table 3: Studies GA39688 and GA39855 Baseline disease characteristics for the
individual studies (full analysis set population), and combined studies (pooled full
analysis set population)
ARS = anterior rhinorrhoea score; NCS = Nasal Congestion Score; NPS = Nasal Polyp Score; PRS =
posterior rhinorrhoea score; SNOT-22 = Sino-Nasal Outcome Test 22; SSS = Sense of Smell Score; TNSS =
Total Nasal Symptom Score; UPSIT = University of Pennsylvania Smell Identification Test.
a) at or relative to randomisation.
b) the last assessment on or before the date of randomisation.
c) Baseline was defined as the average of the daily values recorded during the 7-day interval ending on
the latest day prior to randomisation such that the prior 7-day interval includes a recorded value on at
least 4 of the 7 days of that interval.
d) relative to first study visit (Day-35). No patients used systemic corticosteroids or had nasal surgery
between the first study visit and randomisation.
e) a history of asthma at screening and having used medication for asthma or with a prescription for
asthma medication in the last 12 months.
Percentages for asthma severity are based on the number of patients with asthma
Results
Co-primary endpoints
In both of the pivotal, Phase III Studies GA39688 and GA39855, the co-primary endpoints
of the changes from Baseline at Week 24 in Nasal Polyp Score and the average daily Nasal
Congestion Score were met. For each of the co-primary endpoints, the between-treatment
difference in the adjusted mean changes at Week 24 was statistically significant in favour
of omalizumab.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 16 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Table 4: Studies GA39688 and GA39855 Absolute change from Baseline at Week 24
in the Nasal Polyp Score (co-primary endpoint) for the individual studies(full
analysis set populations), and combined studies (pooled full analysis set
population)
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 17 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Nasal Polyp Score and Nasal Congestion Sscore: There were no significant differences in
the treatment effect between any pre-specified subgroup and its complementary group, as
indicated by overlapping 95% CIs for respective estimated between-treatment difference
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 18 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
within subgroups. The results for the subgroups is consistent with the result for all
patients.
Safety
The safety database for the new indication consists of data from the two pivotal clinical
trials, Studies GA39688 and GA39855. Both studies had identical inclusion and exclusion
criteria, study assessments, and safety endpoints; therefore, pooling of safety data is
considered acceptable. Supportive data from an interim analysis of the ongoing, open label
extension Study WA40169, are also included.
In the two pivotal studies, a total of 135 patients received omalizumab, and 130 patients
received placebo. A total of 249 patients from the completed pivotal studies enrolled into
the open label extension Study WA40169 and started open label omalizumab treatment
(parent study drug treatment received: omalizumab 124, placebo 125). The safety
database presented with this application is considered to be relatively small. Considering
the relative similarity between the patient population with nasal polyps and the patient
population with allergic asthma, it is considered acceptable to extrapolate the safety from
the existing safety database (pre and post-approval).
In the two parent studies, adverse event (AE) rates were overall similar in the placebo and
omalizumab arm with the majority of AEs having mild or moderate intensity. Those AEs
that were reported in numerically greater numbers in the omalizumab arm (headache,
injection site reaction, arthralgia, dizziness, and upper abdominal pain) are consistent
with the known safety profile of omalizumab. Treatment with omalizumab was not
associated with any increase risk compared to placebo of severe AEs, serious adverse
events (SAE) and adverse events of special interest. No patient died in these two studies
and there were no clinically relevant changes in clinical laboratory evaluations or vital
signs in either treatment arm.
Safety results as reported in the interim analysis from the open label extension study were
consistent with the results reported for the parent studies.
Risk-benefit analysis
Delegate’s considerations
The Delegate makes a decision under the therapeutic goods act in relation to quality,
safety and efficacy.
In relation to quality:
The nonclinical evaluator has confirmed that there are no other outstanding issues. The
proposed PI document is acceptable.
10
The sponsor must still comply with routine product vigilance and risk minimisation requirements.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 19 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
In relation to efficacy:
In support of this new indication application, the sponsor conducted two identical pivotal
Phase III, randomised, multicentre, double-blind, placebo-controlled clinical studies to
assess the efficacy and safety of omalizumab in patients with nasal polyps
(Studies GA39688 and GA39855). The studies length was 24 weeks, with a 5-week run-in
period and a 4-week safety follow-up period. Nevertheless, the sponsor has conducted the
polyp studies for 24 weeks and has initiated an open-label extension Study WA40169,
with safety as primary objective.
Although exposure response analyses were conducted in the Phase III studies, there were
uncertainties about the appropriate posology for the newly proposed indication. Overall,
the PK and PD effect of omalizumab has been adequately characterised and does not
appear to be different in subjects with nasal polyps compared to subjects with allergic
asthma. Based on the current knowledge about the pathophysiology of chronic
rhinosinusitis with nasal polyps and its similarity to allergic asthma, and similar
mechanism of action of omalizumab, it appears reasonable that the same dosing regimen
can be chosen for both allergic asthma and chronic rhinosinusitis with nasal polyps. The
description of mechanism of action in the new indication in section 5.1 as well as the
dosing regimen proposed in section 4.2 of the PI.
There were two co-primary endpoints; that is, change in Nasal Polyp Score and change in
7-day average of daily Nasal Congestion Score at Week 24. This approach appears
reasonable as change in nasal polyp size on its own is not considered sufficient but adding
an endpoint evaluating the impact of symptoms is of importance in measuring outcomes in
nasal polyposis.
Both studies met their primary objectives and demonstrated that omalizumab was
statistically more effective in the treatment of nasal polyps compared with placebo in
patients with inadequate response to intranasal corticosteroids and who were on
background intranasal mometasone therapy. Subgroup analyses showed no relevant
differences in the co-primary endpoints.
There appears to be no consistently applied definition of disease severity in chronic
rhinosinusitis with nasal polyps. Severe disease may be defined by the treatment
interventions required such as prior polyp surgery or systemic steroid treatment or it may
be defined by scoring systems such as the Nasal Polyp Score and the Sino-Nasal Outcome
Test-22 or by the presence of comorbid allergic asthma. The studies investigating the use
of biologics in the treatment of chronic rhinosinusitis with nasal polyps have sought to
investigate patients with severe disease but have used different definitions.
Although results should be interpreted with caution as there are differences in study
designs and included populations, comparison of the baseline disease characteristics
tables in the published studies show that, on the basis of prior surgery and systemic
corticosteroid use, populations with more severe disease were investigated in the
mepolizumab and dupilumab studies. However, the mean Nasal Polyp Score and Sino-
Nasal Outcome-22 scores indicate similar disease severity across the studies.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 20 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Numbers represent ranges or approximation of numbers as extracted by the evaluator from the baseline
disease characteristics tables in the related publications
On review of the applicant’s materials and other literature, the Delegate thinks that those
patients with chronic rhinosinusitis with nasal polyps who enrolled in the replicate
omalizumab studies should be considered as having ‘severe’ disease based on baseline
severity scores.
For the secondary endpoints, Total Nasal Symptom Score, Sino-Nasal Outcome Test-22
score, and University of Philadelphia Smell Identification Test scores, omalizumab showed
improvement compared to placebo (p-value of < 0.05 in both studies).
In relation to safety:
The overall safety profile as recorded from the two pivotal Studies GA39688 and GA39855
supports the known safety profile of Xolair in its currently approved indications. The
longer-term safety data will be available from the ongoing open label extension study.
Proposed action
Chronic rhinosinusitis with nasal polyps is a heterogeneous disease characterised by
inflammation of the nose and paranasal sinuses, tissue oedema, nasal obstruction, and
increased mucus production causing symptoms including nasal congestion/obstruction,
loss of sense of smell, and rhinorrhoea. Nasal polyposis is not a potential fatal condition,
but severe polyposis can contribute to symptoms and conditions associated with a
substantial impact on quality of life and health.
11
Gevaert P, et al. Efficacy and Safety of omalizumab in nasal polyposis: 2 randomized Phase 3 trials. J Allergy Clin Immunol; 2020,
146:595-605 (published report of Studies GA39688 and GA39855)
12
Bachert C, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial. J Allergy Clin
Immunol; 2017,140 (4):1024-1031.e14.
13
Bachert C, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP
SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group
phase 3 trials. Lancet; 2019, 394 (10209):1638-1650.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 21 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Although exposure response analyses were conducted in the Phase III studies, there were
uncertainties about the appropriate posology for the newly proposed indication. Overall,
the pharmacokinetics and pharmacodynamics effect of omalizumab has been adequately
characterised and does not appear to be different in subjects with nasal polyps compared
to subjects with allergic asthma (this has been adequately reflected in the PI). Based on
the current knowledge about the pathophysiology of chronic rhinosinusitis with nasal
polyps and its similarity to allergic asthma, and similar mechanism of action of
omalizumab, it appears reasonable that the same dosing regimen can be chosen for both
allergic asthma and chronic rhinosinusitis with nasal polyps, although advice is sought
from the committee regarding this issues.
Therapeutic indication proposed (Post TGA questions):
Chronic rhinosinusitis with nasal polyps (CRSwNP): Xolair is indicated as add-on
treatment in adult patients (18 years of age and above) for the treatment of CRSwNP
with inadequate response to intranasal corticosteroids and who have serum
immunoglobulin E levels corresponding to the recommended dose range
The Delegate thinks that those patients with chronic rhinosinusitis with nasal polyps who
enrolled in the replicated omalizumab studies should be considered as having ‘severe’
disease based on baseline severity scores and this should be reflected in the indication, ‘…
for the treatment of severe CRSwNP…’- although advice is sought from the committee
regarding the wording of the indication.
Based on the above points, the Delegate considers the benefit-risk of Xolair in the
proposed indication, for the treatment of severe CRSwNP (indication wording to be
finalised post Advisory Committee on Medicines(ACM)), as favourable although advice is
sought from the committee regarding the specific issues raised above.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 22 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
• The observed PK and PD profiles of omalizumab in patients with nasal polyps were
adequately predicted using the established population PK/PD model that was used for
asthma patients. More importantly, omalizumab demonstrated comparatively effective
free IgE suppression in patients with nasal polyps. By following the baseline IgE and
body weight-based posology used in asthma patients, omalizumab showed consistent
free IgE inhibition across the entire nasal polyp patient population. Disease
demographics had no meaningful impact on the PK/PD of omalizumab.
• Analyses of exposure/IgE-clinical efficacy response relationships as well as the
covariate effect on these relationship curves provided general support to the use of the
baseline IgE and body weight based posology. There was no clear or consistent trend
between the omalizumab or free IgE levels and the clinical response with most of the
clinical endpoints at Week 24. These results support the benefit of using an
individualised dosing algorithm, which accounted for the effect of covariate factors
(baseline IgE and body weight) into the adjustment of the omalizumab dosage for each
patient. This posology is further supported by the fact that covariates of different
demographics had no clear impact on the clinical response of the drug.
Table 8: Baseline IgE and omalizumab posologies in independent investigator
studies of patients with nasal polyps
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 23 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
section of the PI and thus should aid prescribers to identify patients who might benefit
from omalizumab treatment.
In Australia, some physicians define severe chronic rhinosinusitis with nasal polyps as
patients with inadequate response to prior surgery or prior use of systemic
corticosteroids, whilst others assess severity on baseline Nasal Polyps Score, Lund-Mackay
Score, Nasal Congestion Score,, Sino-Nasal Outcome Test results or lack of responsiveness
to standard therapies. To exemplify the heterogeneity of views amongst the local
omalizumab prescribing community, please see Table 9 (shown below), which provides a
sample of feedback from various local prescribers. Physicians who assess severity based
solely on recurrent nasal polyposis following polypectomy would fail to capture a subset
of patients who are in need of a biologic treatment to treat their chronic rhinosinusitis
with nasal polyps. It is important to note that prior surgery or prior use of systemic
corticosteroids were not actual inclusion criteria for the pivotal trials.
Availability of a safe, efficacious biological treatment is important for Australian chronic
rhinosinusitis with nasal polyps patients as it provides an alternative to endoscopic sinus
surgery and systemic corticosteroid therapies. The former is an invasive option and often
results in reoccurrence of the nasal polyps and the latter is troubled with adverse effects
after long-term treatment. For those local prescriber’s who consider omalizumab should
be used post-surgery and/or post systemic corticosteroid use, this belief is actually not
supported by the evidence provided in our application. Subgroup analysis was performed
using the pooled data from the pivotal studies for the co-primary endpoints of change
from Baseline at Week 24 in Nasal Polyp Score and change from Baseline at Week 24 in
average daily Nasal Congestion Score. The subgroup analysis looked at the baseline
disease factors such as prior sinonasal surgery or use of systemic corticosteroids within
the prior 12 months. Importantly, there was no notable difference in the treatment effect
between patients with or without prior sinonasal surgery as well as patients with or
without prior use of systemic corticosteroids as indicated by the overlapping 95% CIs.
Whilst it is acknowledged that prior surgery and/or prior use of systemic corticosteroids
were potentially predictive for NCS outcomes, there was no clear suggestion of these
factors predicting response for the NPS outcome. Furthermore, it is important to note that
the between-treatment differences at Week 24 favoured omalizumab in all the subgroups.
Overall, the results of the subgroup analyses presented are consistent with those seen in
the overall population.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 24 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Lastly, it is important to note that while differences in trial design preclude direct
comparisons across the dupilumab and omalizumab Phase III trials there are key
differences among the patient populations studied including that patients were not
required to have prior sino-nasal surgery or prior systemic corticosteroid usage for
inclusion in the omalizumab Phase III trials. The reported use of systemic corticosteroids
in the preceding two years was 74% in the overall dupilumab population; and 22% in the
overall omalizumab population in the previous year. In addition, despite similar levels of
asthma comorbidity, there were potentially higher levels of asthma severity among the
Phase III dupilumab trials. Overall, this suggests that dupilumab enrolled patients may
display a more severe form of the disease compared to omalizumab enrolled patients.
These relative differences should also translate into the wording of the indications
keeping the omalizumab indication naive of the word ‘severe’.
In conclusion, the sponsor believes that its proposed indication which specifies ‘patients
with inadequate response to intranasal corticosteroids’ already appropriately captures the
patient population, as defined by patients who are unresponsive to conventional topical
therapies. This is less confusing, reflects trial conditions and focuses on a stepwise
approach to therapy in line with the current Australian clinical practice.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 25 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
3. There are no established limits for clinically relevant effect for the co-primary
endpoints of Nasal Polyp Score and Nasal Congestion Sscore. However,
omalizumab was statistically significantly better than placebo in both pivotal
studies and both co-primary endpoints.
The sponsor acknowledges that no thresholds of meaningful change (between-groups
difference or individual-patient responder definitions) have been established to date for
the co-primary endpoints Nasal Polyp Score and Nasal Congestion Score.
As pointed out by the Delegate a 0.56-point difference for Nasal Congestion Score and 1.50
for Nasal Polyp Score was used as basis for the samples size calculations. While it is
acknowledged that the observed results in the pivotal Phase III studies were
comparatively smaller than those chosen for the sample size calculation, it should be
noted that these estimates were used solely to determine sample size and power
calculations; and not because they were deemed to be thresholds of clinical relevance or
the expected effect in the Phase III studies. Most importantly, the observed treatment
effects were all statistically significant at 5% significance level.
It is worth noting that, unlike the Phase II proof of concept study, omalizumab efficacy in
the Phase III studies was shown on top of daily background therapy with intranasal
corticosteroids and that asthma comorbidity (a condition associated with nasal polyp
severity) was only reported by 57% of the patients.
In order to establish meaningful change thresholds for Nasal Polyp Score and Nasal
Congestion Score and provide context to the results of the two nasal polyp pivotal studies,
a post-hoc analysis was conducted to determine the meaningful change thresholds and
minimal important difference for the co-primary endpoints Nasal Polyp Score and Nasal
Congestion Score with the support of the data from the secondary endpoint, the Sino-Nasal
Outcome Ttest-22, a validated disease-specific health related quality of life instrument,
where omalizumab led to significant and substantial improvements in quality of life in
both studies. The SSino-Nasal Outcome Test-22 has a commonly accepted minimal
important difference of 8.9 points. The full post-hoc analysis report was provided in our
response to the clinical evaluation report [not shown here]. A summary of the results is
provided below for convenience.
Anchor-based methods were used to define the meaningful change thresholds and
minimal important differences. Correlations were calculated between the Nasal Polyp
Score and Nasal Congestion Score and the following variables to determine the most
appropriate anchors: the Sino-Nasal Outcome Test-22.
Total score, and Sino-Nasal Symptoms Subscale (SNOT-22 SNSS) score (proposed based
on prior published exploratory analysis. To determine the anchor-based meaningful
change, patients were grouped by change in disease severity on the identified anchors.
Patients were classified into response groups depending on their level of change over the
course of the study (improvement, no change/worsening based on previously identified
meaningful change thresholds and minimal important differences associated with the
anchor). For the Nasal Polyp Score, the ‘much improved’ group provided the best
separation between the curves, according to both the SNOT- 22 and SNOT-22 SNSS, for
each study separately and combined. For the Nasal Congestion Score, there was sufficient
separation between the ‘improved’ group and ‘no change’ groups, particularly in
Study GA39855, for both SNOT-22 and SNOT-22 SNSS. These groups were thus used to
estimate the mean Nasal Polyp Score and Nasal Congestion Score change scores associated
with meaningful improvement (to estimate the meaningful change thresholds), and to
estimate the mean difference between patients that improved and those that did not (to
estimate the minimal important differences).
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 26 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
For the Nasal Polyps Score, a within-patient meaningful change threshold was identified to
be -1.0, meaning that a change in one category of the Nasal Polyps Score (0 to 8 rating
scale) (an 11% change) is meaningful for an individual patient. This is consistent with the
mean change of the ‘much improved’ groups for both SNOT-22 and SNOT-22 SNSS, in each
study separately and combined. The between-groups minimal important difference was
estimated to be -0.5. This is consistent with the differences in mean group change between
the ‘improved vs no change’ groups in each study separately and combined,and is larger
than/the same as the distribution-based estimates (range 0.47 to 0.50 for each study
separately and combined).
For the Nasal Congestion Score, a within-patient meaningful change threshold was
identified to be -0.5, meaning that a change of -0.5 in the weekly average Nasal Congestion
Score (0 to 3 rating scale) (a 12.5% change) is deemed meaningful for an individual
patient. This is consistent with the mean change of the ‘improved’ groups for both the
SNOT-22 and SNOT-22 SNSS, in each study separately and combined. The between-groups
minimal important difference was estimated to be -0.35 (Table 10). This is consistent with
the differences in mean group change between the ‘improved versus no change’ in each
study separately and combined (range -0.1 to -0.5), and larger than/the same as the
distribution-based estimates (range 0.32 to 0.35 for each study separately and combined).
Table 10: Final estimates of meaningful change threshold and minimal important
difference for the Nasal Polyps Score and Nasal Congestion Score (pooled data)
The estimates of meaningful change threshold were used in unblinded responder analyses
to compare the proportions of patients in each study group achieving a meaningful
improvement on both the Nasal Polyps Score and Nasal Congestion Score. These results
are presented in Table 11. Overall, around twice as many patients achieved a meaningful
change in the Nasal Polyps Score in the omalizumab group as in the placebo group, with
highly statistically significant differences between the treatment groups. The cumulative
distribution function plots for the pooled studies are displayed in Figure 4. Similarly,
around twice as many patients achieved a meaningful change in the Nasal Congestion
Score in the omalizumab group as in the placebo group, with highly statistically significant
differences between the treatment groups. The cumulative distribution function plots for
the pooled studies are displayed in Figure 5.
Table 11: Proportion of patients achieving minimal important difference for the
Nasal Polyps Score and Nasal Congestion Score (pooled data)
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 27 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
In summary, the totality of the evidence based on the post-hoc analysis for meaningful
change threshold and minimal important difference for Nasal Congestion Score and Nasal
Polyps Score showed a meaningful change (improvement for the patient) and statistical
significance between treatment groups and these results are considered clinically
meaningful.
Figure 4: Cumulative distribution functions of Nasal Polyps Score improvement by
treatment group (pooled data)
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 28 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
14
The ACM provides independent medical and scientific advice to the Minister for Health and the Therapeutic
Goods Administration (TGA) on issues relating to the safety, quality and efficacy of medicines supplied in
Australia including issues relating to pre-market and post-market functions for medicines.
The Committee is established under Regulation 35 of the Therapeutic Goods Regulations 1990. Members are
appointed by the Minister. The ACM was established in January 2017 replacing Advisory Committee on
Prescription Medicines (ACPM) which was formed in January 2010. ACM encompass pre and post-market
advice for medicines, following the consolidation of the previous functions of the Advisory Committee on
Prescription Medicines (ACPM), the Advisory Committee on the Safety of Medicines (ACSOM) and the Advisory
Committee on Non-Prescription Medicines (ACNM). Membership comprises of professionals with specific
scientific, medical or clinical expertise, as well as appropriate consumer health issues relating to medicines.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 29 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
Outcome
Based on a review of quality, safety and efficacy, the TGA approved the registration of
Xolair (omalizumab) 75 mg, 150 mg, solution for injection in pre-filled syringe and powder
for injection vial with diluent, for the following extension of indications:
Chronic rhinosinusitis with nasal polyps (CRSwNP)
Xolair is indicated as add‐on treatment in adult patients (18 years of age and above)
for the treatment of severe CRSwNP with inadequate response to intranasal
corticosteroids.
Recommended dosing is determined by serum immunoglobulin E levels and body
weight corresponding to the recommended dose range in the Product Information
(see Section 4.2 dose and method of administration).
As such, the full indications at this time were:
Allergic Asthma
Children 6 to < 12 years of age
In children aged 6 to < 12 years, Xolair is indicated as add‐on therapy to improve
asthma control in patients with severe allergic asthma who have documented
exacerbations despite daily high dose inhaled corticosteroids, and who have
immunoglobulin E levels corresponding to the recommended dose range (see Table 1
in Section 4.2 dose and method of administration).
Adults and adolescents ≥ 12 years of age
Xolair is indicated for the management of adult and adolescent patients with
moderate to severe allergic asthma, who are already being treated with inhaled
steroids, and who have serum immunoglobulin E levels corresponding to the
recommended dose range (see Table 1 in Section 4.2 dose and method of
administration)
Chronic rhinosinusitis with nasal polyps (CRSwNP)
Xolair is indicated as add‐on treatment in adult patients (18 years of age and above)
for the treatment of severe CRSwNP with inadequate response to intranasal
corticosteroids.
Recommended dosing is determined by serum immunoglobulin E levels and body
weight corresponding to the recommended dose range in the Product Information
(see Section 4.2 dose and method of administration).
Chronic Spontaneous Urticaria (CSU)
Xolair is indicated for adults and adolescents (12 years of age and above) with
chronic spontaneous urticaria who remain symptomatic despite H1 antihistamine
treatment.
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 30 of 32
FINAL 15 April 2021
Therapeutic Goods Administration
AusPAR - Xolair – omalizumab – Novartis Pharmaceuticals Australia Pty Ltd PM-2019-05980-1-5 Page 31 of 32
FINAL 15 April 2021
Therapeutic Goods Administration