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ANIMESH ARYA
1
INTRODUCTION TO ALLERGIC RHINITIS
NEZACT
NEZACT
13–17%
AFRICA
10-32% AUSTRALIA
LATIN AMERICA
15%
Allergic rhinitis: Indian prevalence
Chandrika , D. Allergic rhinitis in India: an overview. Int J Otorhinolaryngol Head Neck Surg. 2017 January;
3(1)(1-6)..
Allergic rhinitis and asthma
19–38%
of patients with
allergic rhinitis
Prevalence of Incidence of Countries have
Asthma Allergic rhinitis concomitant
Low <5% Indonesia, Albania, Romania, asthma
prevalence Georgia and Greece
>30% 15-20% Australia, New Zealand and
the United Kingdom
had a high prevalence of
rhinitis
Ozdoganoglu T, Songu M. The burden of allergic rhinitis and asthma. Ther Adv Respir Dis. 2012 Feb;6(1):11-23.asthma
Allergic rhinitis: Common allergens
Food allergens
Pet dander
Allergic rhinitis: sizes of common allergens
Different species of grass pollen
35 14 20
microns microns microns
15-20
microns
Natural barrier for entry of allergens
• Barrier function
• Mucociliary clearance
• Antimicrobial peptides
• ROS
• Reactive nitrogen species
• Range of cytokines,
chemokines and growth
factors
Tight junctions, cell–cell adhesion complexes between
epithelial cells, are important for epithelial barrier function
Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway
inflammation. J Allergy Clin Immunol. 2014 Sep;134(3):509-20..
Fukuoka A, Yoshimoto T. Barrier dysfunction in the nasal allergy. Allergol Int. 2018 Jan;67(1):18-23. 10
1. Prevalence of AR in India is 10-30%
2. Prevalence of concomitant AR and asthma is
high
◦ United airway disease concept
3. Average size of the allergen is 15-20 microns
4. Mucosal layer vis a viz ‘the tight junctions’,
forms a natural protective barrier against
entry of allergens
INTRODUCTION TO ALLERGIC RHINITIS
NEZACT
13
Allergic rhinitis: Pathophysiology
DEP (HDM) allergen impairs nasal epithelial barrier
functions
• Monolayer RPMI 2650
cells cultured in
upper wells were
treated with DEP for
24 h.
Immunostaining for
ZO-1 (A)
• Transepithelial
electric resistance
(TER) was measured
(B)
• After 24 h of DEP
treatment, RPMI 2650
cells were incubated
Immunohistochemistry analysis showed that ZO- with FITC-dextran for
1 expression in nasal epithelia was decreased by 3 h, and then culture
treatment of DEP alone for 4 days supernatants were
collected
• Fluorescence
Fukuoka A, Yoshimoto T. Barrier dysfunction in the nasal allergy. Allergol Int. 2018 Jan;67(1):18-23.
intensity in culture
Dysfunctional nasal epithelial barrier leads to increase
uptake of allergens
Mutiple disorders >> asthma,
AR, IBD, functional dyspepsia,
and atopic dermatitis have been
linked to defective or altered TJ
function
A dysfunctional epithelial
barrier might give rise to
enhanced uptake of allergens
and exogenous particles,
leading to more activation of
mast cells and nerve fibers”
Allergic
rhinitis
Damage nasal
epithelium
and impair
muco-ciliary
clearance
Allergic rhinitis: Diagnosis
Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on
Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
Allergic rhinitis: Comprehensive management
Allergen
avoidance
Pharmacotherapy
Patient
Education Allergen
specific
immunotherapy
Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma
(ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 2008; 63(suppl
86):8-160.
Allergic rhinitis: Management
Allergen First step
avoidance
1. AR is an Ig E mediated disease
2. In AR there is a vicious cycle of nasal inflammation
and dysregulation of natural protective barrier
3. Allergen avoidance is the first step in the
management of allergic rhinitis
4. ARIA guidelines recommends a step wise approach
for treating AR patients
INTRODUCTION TO ALLERGIC RHINITIS
NEZACT
-5%
-10%
-14%
1
daily TNSS
-15%
spray
-20% bid
-24%
-25%
-26%
2 2
-29%
sprays sprays
-30% 2 bid
sprays bid
-35% bid
75% of symptoms are not controlled with Azelastine
treatment
Unmet need with existing therapy
Reductions in total nasal symptom scores:
Fluticasone
-10%
-20%
-30%
daily rTNSS
-40% -46%
P < 0.001
-50%
-60% -66%
-70% P < 0.001
-80% -85%
-90% P < 0.001
A dysfunctional epithelial
barrier might give rise to
enhanced uptake of allergens
and exogenous particles,
leading to more activation of
mast cells and nerve fibers”
HEPA filter
Removal of carpets
Washing
Practical issues with allergen avoidance
Disadvantag
Advantages
es
Challenges because of outdoor allergens…….
Solution…….?
1. There are practical challenges in
implementing allergen avoidance measures
2. Outdoor allergens also remains a challenge
3. With existing therapies, reduction in
symptoms
• 25% with intra-nasal anti-histamines
• 70% with intra-nasal corticosteroids is nearly
4. Nearly 20% of the patients have uncontrolled
allergic rhinitis
5. Dysfunctional barrier with increased allergen
penetration is one of the cause
There is a need to re-inforce
and protect the natural nasal
mucosal barrier
34
INTRODUCTION TO ALLERGIC RHINITIS
NEZACT
Contains
• Proprietary grade of
micronized cellulose powder
of HPMC (98.5%)-active
ingredient
• Peppermint powder (1.5%)
Product characteristics:
36
Innovator: Registered as a Medical Device in over 50
countries
United
Kingdom
Canada
class I Russia
device
Denmark
Germany
Greece
class II N America Finland
Norway
device Belgium China
Switzerland
Spain
Bahrain
UAE
Qatar Hong Kong
Uruguay Saudi Singapore
Arabia Thailand
Brazil South
Africa
Peru
Australia
New
Zealand
Delivery system
Delivered via a bespoke puffer bottle
made of materials compliant with
③ The nozzle
pharmaceutical industry use
delivers a
fine mist of
powder All components tested for
biocompatibility meeting ISO 10993
standards
The air and
② powder
travel up
the hollow
delivery
tube to the
nozzle
When the
bottle is
squeezed,
air forces
① Nezact Intra-nasal delivery
powder up
the hollow
Chemistry
Hydroxypropylmethylcellulos
e
Gel like
barrier
Airborne allergens can be
entrapped and therefore be
prevented from reacting with
receptors
BEFORE-Nezact AFTER-Nezact Emberlin JC, et al. Curr Med Res Opin 2006;
powder powder 22(2): 275-85
Andersson M. et al. Curr Med Res Opin
Mechanism of action
41
Mechanism of action
Allergic
rhinitis
Damage nasal
epithelium
and impair
muco-ciiliary
clearance
Mechanism of action
100x
magnification
Pharmacokinetics/pharmacodynamics
Distribution
Time to onset of Cellulose gel is
considered inert and
action
does not penetrate the
3 mins
dermal layer of the skin.
There is no systemic
absorption
44
Safety
GENERALLY
GRA RECOGNIZE
D AS SAFE
S
There are no contraindications
for use
Usage in special population
47
1. Proof of concept study
2. Pilot study
3. Clinical efficacy study
4. Proof of gel like barrier concept
5. Studies in persistent perennial rhinitis
6. Monotherapy
7. Studies as on add-on therapy
8. Studies as on add-on to nasal sprays
9. Studies in paediatric population
48
1. Proof of concept study
2. Pilot study
3. Clinical efficacy study
4. Proof of gel like barrier concept
5. Studies in persistent perennial rhinitis
6. Monotherapy
7. Studies as on add-on therapy
8. Studies as on add-on to nasal sprays
9. Studies in paediatric population
49
During pollen season
Day 0 6 weeks
Population:102
volunteers (36 M; 66
F) suffering from
seasonal AR in UK
• Effectiveness of pharmaceutical treatment 5-
Evaluation: point scale
• Day/time for recovery
Proof of concept study: Results
Use of cellulose powder for the treatment of seasonal allergic rhinitis.
Josling, Steadman. Adv Ther. 2003;20(4):213–219.
52
Study done during
Gp A pollen season
Design: Double blind HPMC powder (N=47)
randomized placebo
controlled study in UK
Age and gender
Gp B matched
60
40
Percentage of participants
30 Significant differences in
57% of the
20
the amount of rescue subjects
10
medication usage controlled
(P<0.05) with HPMC
0
alone
Conclusions:
Cellulose powder reduces the need to take
rescue medication for the symptoms of
hay fever
1. Proof of concept study
2. Pilot study
3. Clinical efficacy study
4. Proof of gel like barrier concept
5. Studies in persistent perennial rhinitis
6. Monotherapy
7. Studies as on add-on therapy
8. Studies as on add-on to nasal sprays
9. Studies in paediatric population
57
Study done during
Gp A spring season
Design: Double blind HPMC powder (N=54)
randomized placebo
controlled study in
Ukraine
Gp B
Placebo (N=53)
Population: 107 adults
with grass pollen
allergy. Conventional Day 0 2 4
medication used for 1 weeks
rescue only
Daily symptom score (scale 1-6)
• Nasal
Evaluation : • Ocular
• Bronchial
Clinical efficacy study: Results
A nasally applied cellulose powder in seasonal allergic rhinitis in adults with
grass pollen allergy: a double-blind, randomized, placebo-controlled, parallel-
group study
Aberg N, Ospanova ST, Nikitin NP Emberlin J, Dahl Å. Int Arch Allergy Immunol. 2014;163 (4):313–318..
• ~50%
Good effect 12 (22.6%) 32 (59.3%)
reduction :
Don’t know 12 (22.6%)
• Nasal (p<0.001)
1. Proof of concept study
2. Pilot study
3. Clinical efficacy study
4. Proof of gel like barrier concept
5. Studies in persistent perennial rhinitis
6. Monotherapy
7. Studies as on add-on therapy
8. Studies as on add-on to nasal sprays
9. Studies in paediatric population
60
Proof of gel like barrier concept
Study Proof of concept that HPMC gel delays Der p1 diffusion in vitro
Diethart B, et al. Natural Science 2010: 2: 79-84
Allergen
151 ng/ml Der
P1
AGA AGA
R R
HPMC CONTRO
AGAR: Simulates the nasal Measure: L
mucosa Amount of allergen penetrating
through the AGAR gel at
different time points by ELISA
technique
Proof of gel like barrier concept
Study Proof of concept that HPMC gel delays Der p1 diffusion in vitro
Diethart B, et al. Natural Science 2010: 2: 79-84
Conclusions:
• Diffusion of allergen through Nezact showed a significant reduction
at all time points
• After 360 mins only 14% had diffused through
• Nezact forms a gel barrier which prevents allergens from diffusion
Clinical studies
63
Period 1 Period 2
N=15
Placebo Placebo
Wash
with 2.5 Drug Same procedure
ml saline applicati Within 7
on days
• Der p1 Skin Baseline Allergen
24 hrs
test challeng
positive e Evaluation:
• Persistent
symptoms Total symptoms score
for last 2 Peak nasal inspiratory flow
yrs
Peak nasal expiratory flow
Effectiveness against persistent perennial rhinitis:
Results
A double blind, placebo-controlled crossover trial of cellulose powder by nasal
provocation with Der p1 and Der f1
Emberlin JC, et al. Curr Med Res Opin 2007; 23(10): 2423-2431
PNIF an PEF:
Mean
difference in
favour of
Nezact(P≤
0.05)
Conclusions:
Nezact significantly reduces persistent perennial rhinitis
1. Proof of concept study
2. Pilot study
3. Clinical efficacy study
4. Proof of gel like barrier concept
5. Studies in persistent perennial rhinitis
6. Monotherapy
7. Studies as on add-on therapy
8. Studies as on add-on to nasal sprays
9. Studies in paediatric population
66
Design: Open label,
single arm study
Conclusions
• After 3 weeks of use, 85% of participants realized
improvement in their allergy symptoms
• After 6 weeks of use, 90% of participants realized
improvement in their symptoms
1. Proof of concept study
2. Pilot study
3. Clinical efficacy study
4. Proof of gel like barrier concept
5. Studies in persistent perennial rhinitis
6. Monotherapy
7. Studies as on add-on therapy
8. Studies as on add-on to nasal sprays
9. Studies in paediatric population
69
Design: comparator HPMC powder + standard therapy (N=20)
study, 2:1 study
design
Standard therapy:
cetririzine, topical
glucocorticoids
Evaluation : Symptom score
Quality of life
HPMC as an add-on to conventional therapy:
Results
The efficiency of cellulose powder extract in complex therapy of patients
with pollen allergic rhinitis.
Penechko EM, Sizyakina LP. Rossiyskiy Allergologicheskiy J. 2011;(3):101–104.
71
HPMC as an add-on to conventional therapy:
Results
The efficiency of cellulose powder extract in complex therapy of patients
with pollen allergic rhinitis.
Penechko EM, Sizyakina LP. Rossiyskiy Allergologicheskiy J. 2011;(3):101–104. 0 - No adverse effects,
Standard therapy 1 - Almost no adverse effects
3 2 - Mild adverse effects,
2.5 3 - Moderate adverse effects,
4 - Strong adverse effects,
2 5 - Very strong adverse
effects,
1.5 6 - Severe adverse effects,
both before and after
1 treatment.
0.5
0
Statistically
significant
difference in
favour of HPMC
(P<0.05)
Conclusions
• Nezact as part of the complex treatment for intermittent allergic rhinitis
is beneficial
Study done during
Gp A pollen season
Design: Open label HPMC powder+ oral cetirizine
trial
N=74
Gp B
Population: 74
subjects with mild SAR Placebo + oral cetirizine
Evaluation : 5-point
symptom
scale Day 0 5 10 days
Conclusion
s:
Percentage of subjects on cetirizine+ HPMC
scoring ‘major’ or ‘complete relief’ was more
when compared to cetirizine alone
1. Proof of concept study
2. Pilot study
3. Clinical efficacy study
4. Proof of gel like barrier concept
5. Studies in persistent perennial rhinitis
6. Monotherapy
7. Studies as on add-on therapy
8. Studies as on add-on to nasal sprays
9. Studies in paediatric population
74
Concept of muco-adhesion leading to
synergism
Conventiona
l nasal spray
75
Concept of muco-adhesion leading to
synergism
Application of
Nezact
‘Sealing ’ effect of
the intra-nasal
spray to the nasal
mucosa will create a
synergism
More drug is
available at the site
of action
76
Gp A
1 puff of
Design: Double blind Oxymetazoline rescue
oxymetazoline+ 1
randomized placebo medication only
puff of HPMC powder
controlled study
Population: 40 adults
with perennial Gp B
1 puff of
persistent AR Oxymetazoline rescue
oxymetazoline+ 1
medication only
puff of placebo
Day 1 7 15 days
77
P= P=
0.042 0.006
78
- - - Placebo
Nezact
- - - Placebo
Nezact
Conclusions
• HPMCenhances the decongestant effect of nasal oxymetazoline
in patients with allergic rhinitis.
• The effect carries over for another week after its discontinuation
1. Proof of concept study
2. Pilot study
3. Clinical efficacy study
4. Proof of gel like barrier concept
5. Studies in persistent perennial rhinitis
6. Monotherapy
7. Studies as on add-on therapy
8. Studies as on add-on to nasal sprays
9. Studies in paediatric population
80
Pediatric population
A nasally applied cellulose powder in seasonal allergic rhinitis
(SAR) in children and adolescents; reduction of symptoms and
relation to pollen load.
Design: Double blind randomized placebo controlled study in Sweeden
Aberg N, Dahl A, Benson M. Pediatr Allergy Immunol. 2011;22(6):594–599
Conclusions:
HPMC significantly reduces nasal symptoms in
Allergic conjunctivitis 50% 53% 48% 57%
Х Х
Pediatric population
efficacy of the Inert Cellulose Powder in children with AR during the first two weeks (р<0,05)
Х Х Family history of allergic illnesses 20 (66,7%) 22 (73,3%) 15 (75,5%) 20 (66,7%)
Intranasal Results:
inert cellulose powder in prevention 1.8and
management of SAR in
Blocked B
within 6nasal
weekspassages 0.7 Powder).
children
oms of allergic rhinitis in scores in Group 1 (the Inert Cellulose
Efficacy of the Inert Cellulose Powder in children with seasonal s Is
Geppe NA, et al. Poster presentation at European Academy of
Itching in the nose 1.1Allergy
and Clinical Immunology Meet, London 2010
Rhinorrhea
0.5 in the nose
Itching Sneezing
Sneezing
Sneezing
1.5
0.5
N = 110 (Itchingmeanin the nose 2
a
age 8.5 yr) Blocked nasal passages Rhinorrhea
0.8
1.8
children* Р <with
0,05
positive history
V isit 4
of SAR
y of the Inert Cellulose Powder in children with AR during the first two weeks (р<0,05)
HPMC grouppassages =
1.8
• Blocked nasal 0.7
Inert Cellulose Montelukast Sodium
Powder Cromoglicate
Budesonide Before Inert Cellulose Montelukast Sodium
Issiue Powder Cromoglicate
Budesonide
20
• Budesonide 50
mcg TID/QID =
30with seasonal symptoms AR within 6 weeks compared with other variants of treatment.
r in children
Sneezing
Conclusion:
Rhinorrhea Blocked nasal passages
FU visits @ 2, 4,
Visit 1
wder
and
Cellulose 6 weeks
Montelukast Sodium
Cromoglicate
Budesonide Inert Cellulose Montelukast Sodium
Powder Cromoglicate
Budesonide
After 6
Inert Cellulose Montelukast Sodium Budesonide
Powder Cromoglicate
weeks
Pediatric population
Study of mucociliary clearance in children with allergic rhinitis, before and after a
6-week therapy with natural cellulose powder
Aivazis V, et al. Poster presented at World Allergy Congress, Munich, June 2005 Published: Nea Pediatrica Chronica 2005
Results
N = 100 (mean age 7.9 yr) children with
positive history of AR Mucocilary clearance
Before After
78/93 children (83.8%) had high total
IgE titres, specific IgE ABs, or positive 39 min 18.5 min
skin tests
51 children with prolonged clearance
Mucociliary clearance determined by Mucocilary clearance
non-invasive dye method before and
Before After
after therapy for 6 weeks
55.2 min 21.1 min
Conclusions:
• Significant decrease in mucociliary clearance is due to effect of
cellulose, as no other therapy was used
• Cellulose enhances nasal mucus which allows filtration of
allergens, allowing only clean air to reach the lungs
Nezact
Evidence from clinical trials
Paediatric Adult
Reviews 20 successful clinical
population population trials conducted on
Nezact
• Aivazis, et al (2005) • Josling, et al (2003) • Prof Patrick, et al
• Aberg, et al (2010) • Vlahtis, et al (2004) (2008) Showing statistically
Emberlin, et al (2004) • Popov et al (2017)
Geppe, et al (2009) significant symptom relief
• •
• Emberlin, et al (2006)
• Emberlin, et al (2007) and published in quality
• Zakharzhevskaya, et al journals
(2009)
• Ilina, et al (2011) Research carried out in
• Diethart, et al (2010) UK, China, Sweden,
• Penechko, et al (2011) Ukraine, Russia, Bulgaria
Angotoyeva, et al
and Greece
•
(2011)
• Aberg, et al (2014)
• Valerieva, et al (2015) Proven efficacy in children
• Popov, et al (2016) and adults against pollen
• Lanlan, et al (2015) and house dust mite
allergen
NEZACT
93