A Phase II, Randomized, Blinded, Sham Procedure-Controlled, Parallel-Group Trial to Evaluate the Efficacy, Safety and Tolerability of LYR-210 in Adult Subjects With Chronic Sinusitis (LANTERN Study)
Phase: PHASE2
Conditions: Chronic Sinusitis, Chronic Rhinosinusitis (Diagnosis)
Sponsor: Lyra Therapeutics

LYRA THERAPEUTICS, INC.
STUDY LYR-210-2018-002
VERSION 8.0 (30JUN2020)
PROPRIETARY AND CONFIDENTIAL
PAGE 1 OF 129
COVER PAGE
CLINICAL STUDY PROTOCOL
Protocol Number:
LYR-210-2018-002
Study Title:
A Phase II, Randomized, Blinded, Sham Procedure-
Controlled, Parallel-Group Trial to Evaluate the Efficacy,
Safety and Tolerability of LYR-210 in Adult Subjects with 
Chronic Sinusitis (LANTERN Study)
EUDRACT Number:
2018-004621-89
Sponsor:
Lyra Therapeutics, Inc.
480 Arsenal Way
Watertown, MA USA 02472
Current Version 8.0:
30 June 2020
Confidentiality Statement
The information contained in this document, is the property of the Sponsor and is confidential. 
This information may not be disclosed, reproduced or distributed to anyone other than personnel 
directly involved in the conduct of the study and in response to a relevant Institutional Review 
Board/Ethics Committee and Review by a Regulatory Authority as required by the applicable 
laws and regulations, without the written authorization of the Sponsor, except to the extent 
necessary to obtain written informed consent from those individuals to whom the study drug may 
be administered. These restrictions will continue to apply after the study has closed.

LYRA THERAPEUTICS, INC. 
STUDY LYR-210-2018-002
VERSION 8.0 (30JUN2020) 
PROPRIETARY AND CONFIDENTIAL
PAGE 2 OF 129
SPONSOR SIGNATURE PAGE
Protocol Number:
LYR-210-2018-002
Study Title:
A Phase II, Randomized, Blinded, Sham Procedure-Controlled, 
Parallel-Group Trial to Evaluate the Efficacy, Safety and Tolerability 
of LYR-210 in Adult Subjects with Chronic Sinusitis (LANTERN 
Study) 
Sponsor:
Lyra Therapeutics, Inc.
480 Arsenal Way
Watertown, MA USA 02472 
Current Version 8.0:
30 June 2020
Signed:  
Yina Kuang, Ph.D. 
Senior Manager, Clinical and Preclinical Sciences
Date:  
(DD-MMM-YYYY)
Signed:  
Vineeta Belanger, Ph.D. 
Senior Vice President, Clinical Affairs
Date:  
            (DD-MMM-YYYY) 
Signed:  
Yina Kuang, Ph.D. 
Senior Manager, Clinical and Preclinical Sciences
Date:  
(DD
(
-MMM-
M YYYY)
Y
Signed:  
Vineeta Belanger, Ph.D. 
Senior Vice President, Clinical Affairs
Date:  
           (DD
(
-MMM-
M YYYY) 
Y

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VERSION 8.0 (30JUNE2020)
PROPRIETARY AND CONFIDENTIAL
PAGE 3 OF 129
INVESTIGATOR AGREEMENT SIGNATURE PAGE
I hereby agree to participate in this clinical investigation sponsored by Lyra Therapeutics, Inc., (hereinafter 
“Study Sponsor”). I agree to conduct this investigation in accordance with this version of the protocol. I 
agree to protect the rights, safety, and welfare of subjects under my care. I agree that the study will be 
conducted according to the principles of the ICH E6 guideline for GCP, the ethical principles that have their 
origins in the World Medical Association Declaration of Helsinki, and local regulatory authority or ethics 
committee requirements as appropriate. I agree to supervise all use of the investigational product and to 
ensure appropriate informed consent is obtained from all subjects prior to inclusion in this study.
I understand that this investigation will be monitored by the Study Sponsor and/or a designee employed by 
the Study Sponsor. This monitoring will involve periodic inspection of my investigational site and ongoing 
review of the data that is submitted by me to the Study Sponsor. I am also aware that I may be inspected by 
a representative of the local regulatory authority or ethics committee to verify compliance with applicable 
federal regulations related to clinical research on human subjects.
I am aware that the Study Sponsor reserves the right to discontinue this investigation at any time. In the 
event that I decide to discontinue my participation as an Investigator in this study, I will notify the Study 
Sponsor with suitable written notice and in accordance with the Clinical Trial Agreement prior to 
discontinuing. I understand that I am obligated to complete the follow up of the subjects already 
participating in the investigation.
I agree to provide to the Study Sponsor my current curriculum vitae along with the current curriculum vitae 
of those physicians at this institution who will be using this investigational product or participating in this 
study as Sub-Investigators under my supervision. These CVs include education, training, and the extent and 
type of our relevant experience with pertinent dates and locations. I certify that I have not been involved in 
an investigation that was terminated for noncompliance at the insistence of a Study Sponsor, or a local 
regulatory authority or ethics committee. 
I understand that this investigation, protocol, and trial results are confidential, and I agree not to disclose 
any such information to any person other than a representative of Study Sponsor or local regulatory 
authority or ethics committee without the prior written consent of the Study Sponsor.
Investigational Site:
Name: 
Phone Number: 
Address: 
Investigator:
Name (Print): 
Signature: 
Date of Signature:  
(DD-MMM-YYYY) 

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PAGE 4 OF 129
TABLE OF CONTENTS
COVER PAGE...............................................................................................................................1 
SPONSOR SIGNATURE PAGE..................................................................................................2 
INVESTIGATOR AGREEMENT SIGNATURE PAGE ..........................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES.........................................................................................................................8 
LIST OF FIGURES.......................................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................10 
1.
SYNOPSIS ............................................................................................................................12 
2.
INTRODUCTION................................................................................................................31 
2.1 
Chronic Sinusitis ........................................................................................................31 
2.2 
Product Rationale .......................................................................................................31 
2.3 
Study Rationale ..........................................................................................................32 
3.
STUDY OBJECTIVES AND ENDPOINTS ......................................................................34 
4.
INVESTIGATIONAL PLAN..............................................................................................40 
4.1 
Overall Study Design .................................................................................................40 
4.1.1 
Screening Stage........................................................................................42 
4.1.2 
Treatment Stage........................................................................................42 
4.1.3 
Post-Treatment Follow-Up Stage.............................................................43 
4.1.4 
End of the Trial.........................................................................................43 
4.2 
Rationale for Study Design ........................................................................................43 
4.3 
Discontinuation of Study Subjects .............................................................................43 
4.4 
Criteria for Study Termination...................................................................................44 
4.5 
Data Monitoring Committee (DMC)..........................................................................44 
5.
SELECTION OF SUBJECTS.............................................................................................46 
5.1 
Subject Screening.......................................................................................................46 
5.2 
Subject Informed Consent..........................................................................................46 
5.3 
Inclusion Criteria........................................................................................................46 
5.4 
Exclusion Criteria.......................................................................................................47 
6.
TREATMENT OF SUBJECTS ..........................................................................................50 
6.1 
Randomization............................................................................................................50 
6.2 
Study Product Administration....................................................................................50 
6.2.1 
Pre-procedure Medication........................................................................50 
6.2.2 
Study Product Preparation........................................................................50 
6.2.3 
Study Product Administration..................................................................50 
6.2.4 
Enrollment Failure....................................................................................51 
6.2.5 
End of Day 1 Visit....................................................................................51 
6.3 
Blinding......................................................................................................................51 
6.3.1 
Procedures for Breaking the Blind Prior to Study Completion................52 
6.3.2 
Revealing Randomization ........................................................................52 
6.4 
Prior and Concomitant Medications...........................................................................52 
6.4.1 
Prior Medications .....................................................................................52 
6.4.2 
Prohibited Concomitant Medications.......................................................53 
6.4.3 
Permitted Concomitant Medications........................................................53 
6.4.4 
Rescue Concomitant Medications and Treatment....................................54 

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6.5 
Removal Procedure ....................................................................................................54 
6.6 
Treatment Compliance ...............................................................................................55 
7.
DRUG PRODUCT MATERIALS AND MANAGEMENT .............................................56 
7.1 
Investigational Product...............................................................................................56 
7.1.1 
Product Description..................................................................................56 
7.1.2 
Dosage and Administration......................................................................56 
7.1.3 
Active Ingredient: Mometasone Furoate..................................................57 
7.1.4 
Inactive Ingredients..................................................................................57 
7.1.5 
Applicator.................................................................................................57 
7.2 
Drug Product Management ........................................................................................58 
7.2.1 
Packaging and Labeling ...........................................................................58 
7.2.2 
Storage......................................................................................................58 
7.2.3 
Product Traceability .................................................................................58 
7.2.4 
Product Accountability.............................................................................58 
7.2.5 
Product Return..........................................................................................59 
8.
STUDY ASSESSMENTS.....................................................................................................60 
8.1 
Study Schedule of Assessment...................................................................................60 
8.2 
Assessment of Subject Characteristics.......................................................................64 
8.2.1 
Demographics...........................................................................................64 
8.2.2 
Medical and Surgical History...................................................................64 
8.3 
Assessment of Efficacy ..............................................................................................64 
8.3.1 
Subject Reported Outcomes.....................................................................64 
8.3.1.1 
Chronic Sinusitis Cardinal Symptom 
Assessment ........................................................................65 
8.3.1.2 
22-Item Sino-Nasal Outcome Test (SNOT-22)
Questionnaire.....................................................................65 
8.3.1.3 
Saline Irrigation Use..........................................................66 
8.3.1.4 
36-item Short Form Health Survey version 2
(SF-36v2®) Questionnaire .................................................66 
8.3.1.5 
End-of-Treatment Questionnaire.......................................67 
8.3.2 
Sinus Inflammation Imaging....................................................................67 
8.3.3 
Nasal Polyp Assessment...........................................................................67 
8.3.4 
The University of Pennsylvania Smell Identification Test 
(UPSITTM) ................................................................................................68 
8.4 
Assessment of Safety..................................................................................................68 
8.4.1 
Physical Examination...............................................................................68 
8.4.2 
Vital Signs................................................................................................68 
8.4.3 
Laboratory Assessments...........................................................................68 
8.4.3.1 
Hematology........................................................................69 
8.4.3.2 
Blood Chemistry................................................................69 
8.4.3.3 
Morning Serum Cortisol....................................................69 
8.4.4 
Nasal Endoscopy Assessments.................................................................69 
8.4.5 
Ophthalmologic Assessments...................................................................69 
8.4.6 
Pharmacokinetic Analysis........................................................................70 
8.4.7 
In Vivo Drug Dissolution Analysis of LYR-210......................................70 
8.4.8 
Pregnancy or Breast Feeding....................................................................70 

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8.4.9 
Adverse Events and Serious Adverse Events...........................................71 
8.4.9.1 
Adverse Event (AE)...........................................................71 
8.4.9.2 
Serious Adverse Event (SAE) ...........................................72 
8.4.9.3 
Relationship to Study Drug Product and 
Procedure...........................................................................72 
8.4.9.4 
Severity of Adverse Events ...............................................74 
8.4.9.5 
Expectedness of Serious Adverse Events..........................74 
8.4.9.6 
Reporting ...........................................................................74 
8.4.10 
Safety Monitoring.....................................................................................76 
9.
SAFETY INFORMATION OF STUDY DRUG PRODUCT...........................................77 
9.1 
Safety Rationale of Study Drug Doses and Polymers................................................77 
9.1.1 
Existing Non-clinical Safety Data............................................................77 
9.1.2 
Nonclinical Toxicology Assessment of LYR-210 ...................................77 
9.1.3 
Phase I Clinical Study of LYR-210 (2500 μg).........................................80 
9.1.4 
Systemic and Local Dose Safety of LYR-210 (7500 μg) ........................82 
9.1.4.1 
Systemic Safety .................................................................82 
9.1.4.2 
Local Safety.......................................................................84 
9.1.5 
Product Safety Rationale Conclusion.......................................................85 
9.2 
Anticipated Risks .......................................................................................................85 
9.2.1 
Expected ARs Associated with Endoscopic Procedures and 
LYR-210 Administration/Removal..........................................................85 
9.2.2 
Expected ARs Associated with Mometasone Furoate or Nasal 
Implant......................................................................................................86 
10. STATISTICAL ANALYSIS................................................................................................88 
10.1 
Analysis Populations..................................................................................................88 
10.2 
Disposition and Population Assignment ....................................................................88 
10.3 
Demographic and Other Baseline Characteristics......................................................89 
10.4 
Prior and Concomitant Medications...........................................................................89 
10.5 
Safety Analyses..........................................................................................................89 
10.6 
Efficacy Analyses.......................................................................................................90 
10.6.1 
Primary Efficacy Endpoint Analysis........................................................90 
10.6.1.1 
Handling of Missing Data..................................................91 
10.6.1.2 
Assessment of Treatment Effect Across Study 
Regions, Across Nasal Allergy Groups and 
Across Polyp Groups .........................................................92 
10.6.2 
Key Secondary Efficacy Endpoint Analysis ............................................92 
10.6.2.1 
CFBL in CS7DA4S at Week 24........................................92 
10.6.2.2 
Percentage of Subjects with Improved bilateral 
Zinreich score ....................................................................93 
10.6.2.3 
Time-to-Treatment Failure ................................................93 
10.6.3 
Non-Key Secondary Efficacy Endpoint Analysis....................................94 
10.6.4 
Exploratory Endpoint Analysis ................................................................94 
10.6.5 
Pharmacokinetic Analyses .......................................................................95 
10.6.5.1 
Pharmacokinetic Concentrations .......................................95 
10.6.5.2 
Pharmacokinetic Parameters..............................................95 
10.7 
Sample Size................................................................................................................95 
9.1.1
Existing Non-clinicalal Safafetety y y Da
Da
Datata............................................................77
9.1.2
No
Nonc
nclilininica
cal l To
Toxixicolology
gy Asssses
essm
smen
ent of
of LYR
YR-210 ...................................77
9.1.3
Phase I Clinical Study of LYR-210 (2500 μg).........................................80
80
9.1.4
Systemic and Local Dose Safety of LYR-210 (7500 μg) ........................82
82
9.1.4.1
Systemic Safety .................................................................82
9.1.4.2
Local Safety.......................................................................84
9.1.5
Product Safety Rationale Conclusion.......................................................85
9.2
Anticipated Risks .......................................................................................................85
9.2.1
Expected ARs Associated with Endoscopic Procedures and 
LYR-210 Administration/Removal..........................................................85
9.2.2
Expected ARs Associated with Mometasone Furoate or Nasalal 
Implant......................................................................................................86

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11. REGULATORY OBLIGATIONS......................................................................................97 
11.1 
Statements of Compliance..........................................................................................97 
11.2 
Site Selection and Training ........................................................................................97 
11.3 
Ethics Committee (EC) Approval ..............................................................................98 
11.4 
Informed Consent.......................................................................................................98 
11.5 
Protocol Amendments................................................................................................99 
11.6 
Protocol Deviations....................................................................................................99 
11.7 
Study Monitoring .....................................................................................................100 
11.8 
Data Quality Assurance............................................................................................100 
11.9 
Record Retention......................................................................................................101 
11.10 Auditing
101 
11.11 Use and Publication of Study Results ......................................................................102 
11.12 Confidentiality..........................................................................................................102 
11.13 Early Study Discontinuation ....................................................................................102 
12. CLINICAL RISK AND BENEFIT ANALYSIS..............................................................104 
13. LIST OF REFERENCES ..................................................................................................108 
14. APPENDICES ....................................................................................................................111 
14.1 
Daily Electronic Subject Reported Outcome (ePRO) ..............................................111 
14.2 
22-Item Sino-Nasal Outcome Test (SNOT-22)........................................................113
14.3 
LYR-210 Phase II End Of Treatment Questionnaire ...............................................114 
14.4 
36-item Short Form Health Survey version 2 (SF-36v2®) Questionnaire................116
14.5 
Summary and Outcome of Protocol Changes ..........................................................123 
14.5.1 
Summary of Protocol Changes from Version 4.0 (Applicable 
for New Zealand, Australia and Europe)................................................124 
14.5.2 
Summary of Protocol Changes from Version 7.0 (Applicable 
for United States)....................................................................................127 
14.1
Dailily Electronic Sub
ubjej ct Reporteted Ou
Outcom
ome (ePRO) ..............................................111
14
1 .2
22-Item Sino-Nasal Ou
Outcome Te
Test (SN
SNOT
OT-22
22)........................................................113
14.3
LYR-210 Phase II End Of Treatment Questionnaire ...............................................114
14.4
36-item Short Form Health Survey version 2 (SF-36v2®) Question
onnaire................11
116
14.5
Summary and Outcome of Protocol Changes ..........................................................123
14.5.1
Summary of Protocol Changes from Version 4.0 (Applicable 
for New Zealand, Australia and Europe)................................................124
14.5.2
Summary of Protocol Changes from Version 7.0 (Applicable 
for United States)....................................................................................127
y
y
CLINICAL RISK AND BENEFIT ANALYSIS..............................................................10
104

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LIST OF TABLES
Table 1: 
Schedule of Assessments for Subjects Randomized and Enrolled .............62 
Table 2: 
Categorized Survey Items for Separate Domains of the SNOT-22
Instrument ...................................................................................................66 
Table 3. 
SF-36v2® Health Survey Measurement Model...........................................66 
Table 4: 
Sinus Histological Score Summary of the 180-Day Rabbit Study .............78 
Table 5. 
Sinus Histological Score Summary of the 28-day Study............................79 
Table 6: 
Number of Subjects with Plasma MF Concentration < or ≥ 20 
pg/mL (ITT Population)..............................................................................80 
Table 7: 
Comparison of Systemic Exposure of LYR-210 (7500 μg) with 
Clinical Studies showing Systemic Safety of Chronic Use of MF 
Products.......................................................................................................83 
Table 8: 
Summary of Clinical Studies showing Local Tissue Safety of 
Chronic Intranasal use of Mometasone Furoate..........................................84 
Table 9: 
Summary of Expected ARs Associated with LYR-210
Administration or Removal Procedure........................................................85 
Table 10: 
Summary of Expected ARs Associated with Mometasone Furoate ...........86 
Table 4:4:
Sinus Histological Score Su
Summararary of the 180-Day Rabbitit Study .............78
Ta
Table 5.
Si
Sinu
nus Hi
Histstololog
ogicicalal Scorere Sum
umma
mary
ry of ththe 28
28-da
day St
St d
udy............................79
Table 6: 
Number of Subjects with Plasma MF Concentration < or ≥ 20
pg/mL (ITT Population)..............................................................................80
Table 7:
Comparison of Systemic Exposure of LYR-210 (7500 μg
μg) with 
Clinical Studies showing Systemic Safety of Chronic Use of MF 
Products.......................................................................................................83
Table 8: 
Summary of Clinical Studies showing Local Tissue Safety of 
Chronic Intranasal use of Mometasone Furoate..........................................84
Table 9: 
Summary of Expected ARs Associated with LYR-210
Administration or Removal Procedure........................................................85
85
Table 10: 
Summary of Expected ARs Associated with Mometasone Furoatete ...........86
86

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LIST OF FIGURES
Figure 1: 
Study Design Schematic .............................................................................40 
Figure 2: 
LYR-210 Images.........................................................................................56 
Figure 3: 
Chemical Structure of Mometasone Furoate...............................................57 
Figure 4: 
Chemical Structures of Inactive Ingredients...............................................57 
Figure 5: 
Applicator, Ready for LYR-210 Administration ........................................58 
Figure 6: 
Comparison of Plasma MF Concentration of LYR 210 and 
Nasonex® over 28 Days .............................................................................79 
Figure 7: 
In Vitro and In Vivo Percentage of Release of MF in LYR-210
(2500 μg) Over Time ..................................................................................81 
Figure 8: 
In vitro Cumulative Percentage of Release of MF from LYR-210
(7500 μg) Over Time ..................................................................................83 
Fi
Figu
g re 6:
Comparison
on of Plasma
ma MF Co
Co
Conc
nc
ncen
en
entrt ation of LYR 210 and
nd 
Nasonex® over 28 Days .............................................................................79
79
Figure 7:
In Vitro and In Vivo Percentage of Release of MF in LYR
YR-210
(2500 μg) Over Time ..................................................................................81
Figure 8:
In vitro Cumulative Percentage of Release of MF from LYR-210
(7500 μg) Over Time ..................................................................................83

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation / Term
Definition
AE
adverse event
AECS
acute exacerbation of chronic sinusitis
CS7DA4S
composite score of 7-day average scores of 4 CS cardinal symptoms
CFBL
change from baseline
CFR
code of federal regulations
COPD
chronic obstructive pulmonary disorder
CPmin
the minimum of the conditional power of the promising zone
CRF
case report form
CSsNP
chronic sinusitis without nasal polyps
CSwNP
chronic sinusitis with nasal polyps
CS
chronic sinusitis
CT
computed tomography
CTCAE
common terminology criteria for adverse events
CYP3A4
cytochrome P-450 3A4
DMC
data monitoring committee
EC
ethics committee
EOS
end-of-study
EOT
end-of-treatment
ePRO
electronic subject reported outcome
ESS
endoscopic sinus surgery
ET
early termination
FAS
full analysis set
FDA
food and drug administration
GCP
good clinical practice
GEE
generalized estimating equation
HEENT
head, ears, eyes, nose and throat 
HRS
Hours
IB
investigator brochure
ICF
informed consent form
ICH
international council for harmonization
IFU
instructions for use
IgA
immunoglobulin-a
IgG
immunoglobulin-g
INCS
intranasal corticosteroid spray
IOP
intraocular pressure
IRB
institutional review board
IRT
interactive response technology

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Abbreviation / Term
Definition
ITT
intention to treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
kg
Kilogram
LOCF
last observation carried forward
mcg
Microgram
MedDRA
medical dictionary for regulatory activities
MF
mometasone furoate
mg
Milligram
mL
Milliliter
mmHg
millimeters of mercury
mo
Month
NCI
national cancer institute
PAR
perennial allergic rhinitis
PAS
per-protocol analysis set
pg
Picogram
PK
Pharmacokinetics
PP
per protocol
SAE
serious adverse event
SAP
statistical analysis plan
SAR
seasonal allergic rhinitis
SD
standard deviation
SF-36v2
36-item short form health survey version 2
SNOT
sino-nasal outcome test
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
UADE
unexpected adverse device effect
UPSIT
University of Pennsylvania smell identification test
URTI
upper respiratory tract infection
US
United States
USP
united states pharmacopeia
WHO ATC
world health organization anatomical therapeutic classification

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1.
SYNOPSIS
Sponsor Lyra Therapeutics, Inc.
480 Arsenal Way
Watertown, MA 02472, USA
Protocol Title
A Randomized, Blinded, Sham Procedure-Controlled, 
Parallel-Group, Phase II Trial to Evaluate the Efficacy, 
Safety and Tolerability of LYR-210 in Adult Subjects with 
Chronic Sinusitis (CS) (LANTERN Study)
Protocol Number LYR-210-2018-002
Phase of Development
Phase II
Trial Location
Worldwide
Number of sites Up to 25 sites 
Study Population Adult CS subjects who have failed previous medical 
management and have not undergone endoscopic sinus 
surgery (ESS)
Estimated Number of Subjects
Approximately 70 subjects
Investigational Product
LYR-210 System, 2500 μg and 7500 μg
Active Ingredient
Mometasone Furoate (MF)
Study Objectives
Endpoints
Primary
To evaluate the efficacy of LYR-
210 in improving the composite 
score of 7-day average scores of
4 CS cardinal symptoms
(CS7DA4S) at Week 4
- Change from baseline (CFBL) in CS7DA4S score at
Week 4
The 4 CS cardinal symptoms include nasal
blockage/obstruction/congestion, facial pain/pressure,
reduction/loss of sense of smell, and anterior/posterior
nasal discharge. Each symptom is scored on a 0-3 scale
as follows: 0 = none, 1 = mild, 2 = moderate, and 3 =
severe.
Key Secondary
To evaluate the efficacy of LYR-
210 in improving CS7DA4S 
score at end of treatment 
- CFBL in CS7DA4S score at Week 24

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To evaluate the effect of LYR-
210 in reducing sinus 
inflammation as per magnetic 
resonance imaging (MRI)
- Percentage of subjects with at least 1-point decrease in
the bilateral Zinreich score in at least 1 pair of the
anterior ethmoid, maxillary, posterior ethmoid, frontal, or
sphenoid sinuses at Week 24
Each sinus is scored on a 0-5 scale per the Zinreich
modified Lund-Mackay scoring system and based on the
percentage of opacification as follows: 0 = 0%, 1 = 1%
to 25%, 2 = 26% to 50%, 3 = 51% to 75%, 4 = 76 % to
99%, and 5 = 100% or completely occluded.
To evaluate the
time to 
treatment failure 
- Time to treatment failure
A treatment failure is defined as, after subject
enrollment, subject being recommended by treating
physician for oral corticosteroid or ESS due to
worsening of CS symptoms, or the subject complaint of
persistent CS symptoms with an average CS7DA4S score
over the preceding 30 days greater than or equal to the
Baseline CS7DA4S score.
Other Secondary
To evaluate the safety and 
tolerability of LYR-210
- Severity and percentage of subjects reporting treatment-
emergent adverse events (TEAEs) and serious adverse
events (TESAEs) through Weeks 2, 4, 12, and 24
- Severity and percentage of subjects reporting Day 1
administration procedure and Week 24 removal
procedure related AEs and SAEs
- Severity and percentage of subjects reporting product
related AEs and SAEs on Day 1 and through Weeks 2, 4,
12, and 24
- Percentage of subjects with abnormal and clinically
significant abnormal laboratory values (hematology and
chemistry, vital signs) on Day 1 and at Weeks 4, 12, and
24
- Morning serum cortisol levels on Day 1 and at Weeks 4,
12, and 24
- Severity and percentage of subjects with adverse nasal
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findings requiring medical treatment in one or both 
nostrils on Day 1 and at Weeks 2, 4, 12, and 24
- Percentage of subjects with elevated intraocular pressure
(IOP) in one or both eyes at Weeks 4, 12, and 24
- Percentage of subjects with a clinically significant
increase of IOP at Weeks 4, 12, and 24
A clinically significant increase of IOP is defined as IOP
in one or both eyes > 28 mmHg or an increase of IOP
from Baseline in one or both eyes >= 10 mmHg.
- Percentage of subjects with newly identified or worsened
cataract in one or both eyes by slit-lamp examination at
Week 24
To evaluate the time to onset of 
action of LYR-210
- Time to onset of action
Time to onset of action is defined as, within the first 30
days, the time when all subsequent mean CFBL in the
CS7DA4S score of the LYR-210 is statistically
significantly greater than that for the sham procedure.
To evaluate the efficacy of LYR-
210 in improving CS7DA4S 
score and the 7-day average score 
of each of the 4 cardinal CS 
symptoms
- CFBL in the CS7DA4S score at Weeks 8, 12, 16, and 20
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, and anterior/posterior nasal
discharge at Weeks 1, 2, 3, 4, 8, 12, 16, 20, and 24
To evaluate the effect of LYR-
210 in improving CS disease-
specific quality of life as per 22-
item sino-nasal outcome test 
(SNOT-22) questionnaire 
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores at Weeks 2, 4, 8, 12, 16,
20, and 24
To evaluate the effect of LYR-
210 in reducing sinus 
inflammation as per magnetic 
resonance imaging (MRI)
- CFBL in bilateral Zinreich scores of posterior ethmoid,
frontal, sphenoid, maxillary, anterior ethmoid sinus and
OMC pairs at Week 24
- CFBL in total Zinreich score at Week 24
To evaluate the effect of LYR-
210 in reducing subjects’ needs 
- Percentage of subjects with use of oral antibiotics for CS
through Weeks 4, 8, 12, 16, 20, and 24

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for medical or surgical treatment 
for CS
- Percentage of subjects with use of oral corticosteroid for
CS through Weeks 4, 8, 12, 16, 20, and 24
- Percentage of subjects with use of intranasal
corticosteroid sprays for CS through Weeks 4, 8, 12, 16,
20, and 24
- Percentage of subjects being recommended by treating
physician for ESS through Weeks 4, 8, 12, 16, 20, and 24
To evaluate the pharmacokinetics 
of LYR-210
- Plasma MF concentrations at Days 3, 7, 14, 21 and
Weeks 4, 12, 24
Plasma PK samples at Days 3, 7, 14, 21 will only be
measured in approximately 15 randomized and
successfully enrolled subjects at US sites.
To evaluate the effect of LYR-
210 in improving subjects’
general quality of life as per 36-
item short form health survey 
version 2 (SF-36v2)
questionnaire
- CFBL in SF-36v2 physical health, mental health, and
domain scores at Week 24
To evaluate LYR-210 in 
improving smell function
assessed by the University of 
Pennsylvania Smell Identification 
Test (UPSITTM)
- CFBL in UPSIT score at Week 24
Exploratory 
To evaluate the percentage of
subjects experiencing acute 
exacerbations of CS (AECS) 
- Percentage of subjects experiencing AECS through
Weeks 4, 8, 12, 16, 20, and 24
AECS is defined as a sudden worsening of symptoms in a
subject resulting in the treating physician reporting an
escalation of treatment.
To assess effect of LYR-210 in 
reducing polyp severity within 
middle meatus in subgroup of CS 
subjects with nasal polyps 
(CSwNP)
- Percentage of subjects with improvement from Baseline
in nasal polyp severity within middle meatus in CSwNP
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To assess efficacy of LYR-210 in 
improving CS7DA4S score, the 
7-day average score of each of 4
CS cardinal symptoms, the
SNOT-22 total and subdomain
scores, and the SF-36v2 physical
health, mental health, and domain
scores in the subgroups of CS
subjects without nasal polyps
(CSsNP) and CSwNP subjects
- CFBL in the CS7DA4S score at Weeks 1, 2, 3, 4, 8, 12,
16, 20, and 24
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, anterior/posterior nasal
discharge in CSsNP and CSwNP subjects at Weeks 1, 2,
3, 4, 8, 12, 16, 20, and 24
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores in CSsNP and CSwNP
subjects at Weeks 2, 4, 8, 12, 16, 20, and 24
- CFBL in SF-36v2 physical health, mental health, and
each of the health domain scores in CSsNP and CSwNP
subjects at Week 24
To assess efficacy of LYR-210 in 
reducing sinus inflammation in 
CSsNP and CSwNP subjects 
- Percentage of subjects with at least 1-point decrease in
the bilateral Zinreich score in at least 1 pair of the
anterior ethmoid, maxillary, posterior ethmoid, frontal, or
sphenoid sinuses in CSsNP and CSwNP subjects at
Week 24
- CFBL in bilateral Zinreich scores of posterior ethmoid,
frontal, sphenoid, maxillary, anterior ethmoid sinus, and
OMC pairs in CSsNP and CSwNP subjects at Week 24
- CFBL in total Zinreich score at in CSsNP and CSwNP
subjects at Week 24
To assess effect of LYR-210 in 
improving smell function in 
CSsNP and CSwNP subjects 
- CFBL in UPSIT score in CSsNP and CSwNP subjects at
Week 24
To assess the safety of subjects 
post LYR-210 treatment
- Severity and percentage of subjects reporting AEs and
SAEs through Week 28 and Week 48
- Percentage of subjects with abnormal and clinically
significant abnormal laboratory values (hematology and
chemistry, vital signs) at Week 28
- Morning serum cortisol levels at Week 28
- Plasma MF concentrations at Week 28

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- Severity and percentage of subjects with adverse nasal
endoscopic findings and adverse nasal endoscopic
findings requiring medical treatment in one or both
nostrils at Week 28
- Percentage of subjects with elevated IOP in one or both
eyes at Week 48
- Percentage of subjects with a clinically significant
increase of IOP at Week 48
- Percentage of subjects with newly identified or worsened
cataract in one or both eyes by slit-lamp examination at
Week 48
To assess the durability of 
efficacy post LYR-210 treatment
- Percentage of subjects with improvement from Baseline
in nasal polyp severity within middle meatus in CSwNP
subjects at Week 28
- CFBL in the CS7DA4S score at Weeks 28, 32, 36, 40,
44, and 48
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, anterior/posterior nasal
discharge in CSsNP and CSwNP subjects at Weeks 28,
32, 36, 40, 44, and 48
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores at Weeks 28, 32, 36, 40,
44, and 48
- CFBL in SF-36v2 physical health, mental health, and
each of the health domain scores at Week 48
Study Design
This global, multicenter study will be conducted in a randomized, sham procedure-controlled, 
parallel-group, subject-blinded fashion in approximately 70 adult CS subjects who have failed 
previous medical management and have not undergone ESS. Subjects enrolled in the study will 
include patients who have not had ESS but their symptoms are not adequately controlled on 
medical management and are seeking further treatment. This may include subjects who are 
considering sinus surgery or those who have decided against it. The efficacy and safety of 
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assessed. Additionally, LYR-210 (2500 μg) and LYR-210 (7500 μg) will be compared to 
evaluate dose related responses.
The study will consist of three stages: 
x
Screening and Washout Stage: 2 -4 weeks
x
Treatment Stage: 24 weeks
x
Post-Treatment Follow-Up Stage: 24 weeks
Screening and Washout Stage
After providing written informed consent, subjects who are qualified to participate in this study 
will have an initial Screening visit. Immediately following the initial Screening visit, subjects 
will undergo a minimum of 2-week but a maximum of 4-week washout period. During this 
washout period, except for recommended twice daily saline irrigation, subjects will receive no 
active treatment for CS or any prohibited or rescue medications specified in the study protocol.
Beginning at least 7 days prior to LYR-210 administration/sham procedure on Day 1, subjects 
will record cardinal symptoms of CS on the electronic subject reported outcomes (ePRO) 
questionnaire.
Treatment Stage
The total duration of the Treatment Stage will be approximately 24 weeks. 
On Day 1, before any treatment, subjects will be randomized in a 1:1:1 ratio to one of the 
following study arms: 
x
Arm 1: bilateral administration of LYR-210 (2500 μg)
x
Arm 2: bilateral administration of LYR-210 (7500 μg)
x
Control Arm: bilateral sham procedure
Subjects will be stratified for treatment assignment according to the following criteria:
x
Nasal Allergy (Yes vs No)
x
Nasal polyps (Yes vs No)
Subjects who are assigned to the active treatment arms will have the LYR-210 administered 
bilaterally into the middle meatus on Day 1. Subjects who are assigned to the sham procedure 
arm, will undergo bilateral mock administration (i.e., sham procedure) on Day 1 consisting of 
bilateral insertion of an applicator (without LYR-210 loaded) into the middle meatus until the 
applicator tip touches the ethmoid bulla for a minimum of 20 seconds, followed by withdrawal 
of the applicator. 
Prior to LYR-210 administration/sham procedure, all subjects will receive topical anesthetic and 
decongestant sprays for endoscopic assessment. Subjects will also receive anesthetic and 

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decongestant soaked cottonoid or pledget in each nostril to prepare middle meatuses for the 
insertion procedure. To maintain the subject blind to treatment assignment, each subject will 
wear an eye mask (i.e., blindfold) at the time of the LYR-210 administration/sham procedure. 
The study clinic staff, including the Investigator and study coordinator, will be unblinded to 
LYR-210 treatment vs the sham procedure but will remain blinded as to the dose administered 
to subjects who receive LYR-210.
All subjects will return to clinic for the scheduled follow up assessments at Week 2, 4, 12 and 
24 visits and will remain blinded at these visits. Subjects will receive telephone follow-ups at
Weeks 8, 16, and 20 to record AEs and concomitant medications/procedures that they have had 
since their last follow-up assessment.
At the Week 24 visit, all subjects will return to clinic for the end-of-treatment (EOT) visit 
assessments. Subjects who receive LYR-210 will have bilateral depot removed using standard 
surgical tools. Sham control subjects will undergo a sham removal procedure to remain blinded.
If spontaneous dislodgement of LYR-210 occurs before the scheduled Week 24/EOT visit in 
subjects who receive either dose of LYR-210, subjects are required to call the study clinic 
immediately to report the event. If a subject experiences dislodgement of one of the two LYR-
210 depots, the subject will continue the study treatment unless an early treatment 
discontinuation is recommended by the treating physician or subject requests depot removal 
from the remaining side of the nose. If depots spontaneously dislodge from both sides of the 
nose, the subject will complete Week 24/EOT assessments and subsequently, the post-treatment 
follow-up stage.
If medically warranted per the treating physician’s discretion (for example, needing an ESS as 
rescue treatment), early depot removal may be performed at an Unscheduled early-termination 
(ET) visit (an Unscheduled EOT visit). Any subject who undergoes an ET visit is required to 
complete the assessments scheduled for the Week 24/EOT visit, and all safety follow up visits 
post treatment.
Post-treatment Follow-Up Stage
All subjects will undergo a Post-treatment Follow-up Stage that will be approximately 24 
weeks. Subjects will have 2 additional safety follow up visits during this stage, the Week 28 and
a final Week 48/end-of-study (EOS) safety visits. Subjects will receive telephone follow-ups at
Weeks 32, 36, 40, and 44 to record AEs and concomitant medications/procedures that they have 
had since their last follow-up assessment. Except for the cases of spontaneous depot 
dislodgement, subjects should remain blinded until the study database is locked.
Blinding
Except for the cases of spontaneous depot dislodgement, subjects should remain blinded to their 
treatment assignment (LYR-210 or sham) until the final study database is locked. The Sponsor 

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will be blinded to subjects’ study treatment assignments until database lock for the primary data 
analysis after all enrolled subjects have completed Week 28 visit or withdrawn from study, 
whichever comes first.
Assessments
Enrolled subjects will be asked to complete a daily ePRO questionnaire to assess the 
instantaneous morning scores of 4 CS cardinal symptoms including nasal 
blockage/obstruction/congestion, reduction/loss of sense of smell, facial pain/pressure, and 
anterior/posterior nasal discharge. In addition, the ePRO will capture use of daily saline 
irrigation by the subjects. Subjects will also complete a validated CS-specific quality of life 
questionnaire, the SNOT-22, on Day 1 before treatment, at Week 2 and every 4 weeks after the 
Day 1 visit. Subjects will complete a general quality of life questionnaire, the SF-36v2, on Day 
1 before the LYR-210 administration/sham procedure, and at Week 24/EOT and Week 48/EOS 
visits. At EOT visit, an end-of-treatment questionnaire will be administered. 
Subjects will be asked to complete the UPSITTM test for smell dysfunction at the Day 1 visit 
before the LYR-210 administration/sham procedure, and at Week 24/EOT and Week 28 visits.
Sinus inflammation will be assessed by MRI without contrast prior to the Day 1 visit and within 
7 days after the LYR-210 removal/sham removal at the Week 24/EOT visit, unless medically 
contraindicated. If a subject is experiencing or recovering from a cold, acute exacerbation of 
nasal allergy, or upper respiratory tract infection at the Week 24/EOT visit, the MRI assessment 
should be performed 4 weeks after resolution of the adverse event. If a subject requires oral 
corticosteroid as rescue during the 24-week treatment period, the follow-up MRI should be 
performed before receiving the rescue treatment instead of at Week 24/EOT visit. 
Nasal cavities will be assessed by endoscopy on Day 1 before the LYR-210
administration/sham procedure, and at Weeks 2, 4 and 12, Week 24/EOT, and Week 28 visits.
Subjects are required to wear a blindfold if any endoscopy examination is performed at these 
visits to remain blinded to treatment assignment. Local nasal safety evaluation will be 
performed at these visits to document presence of epistaxis, mucosal erosion or ulceration, 
perforation, infection, and any other local nasal adverse effects. For CSwNP subjects, real-time, 
qualitative endoscopic evaluation of change of polyp severity in the middle meatus will be 
performed by site Investigators at Week 24/EOT visit after LYR-210 removal/sham removal 
procedure and at Week 28 visit by comparing to that of the Day 1 visit. 
Ophthalmologic assessments will include IOP and slit-lamp examination during Screening, and 
within 7 days of Week 24/EOT and Week 48/EOS visits. IOP assessment will also be performed 
at Weeks 4 and 12 visits.
Plasma samples for PK will be collected from all subjects on Day 1 before the LYR-210
administration/sham procedure, and at Week 4, 12, 24/EOT, and 28 visits. Additional plasma 
PK samples will be collected at Days 3, 7, 14±1 (Week 2), 21±1 from approximately 15 

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randomized and successfully enrolled subjects at participating US sites for a minimum of 6 
subjects for each LYR-210 dose. The concentration of MF in plasma will be measured by a 
central laboratory.
Routine safety assessments will be performed during the study including vital signs and
physical exams. Samples for hematology, chemistry, and serum cortisol will be collected at 
Screening, Weeks 4, 12, 24/EOT, and 28 visits. An additional hematology, chemistry, and 
cortisol sample will be collected within 72 hours prior to LYR-210 administration/sham 
procedure for Baseline value. All post Screening serum cortisol samples will be evaluated by a 
central laboratory.
For female subjects of childbearing potential, a serum pregnancy test will be performed at 
Screening visit and a urine pregnancy test will be performed on Day 1 prior to randomization to 
confirm eligibility for participating in the study. A urine pregnancy test will be performed at 
every 4 weeks in clinic during the treatment stage in these female subjects.
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
events (AEs) or untoward findings. Any AEs observed by the Investigator or reported by the 
subjects, whether or not attributed to the investigational procedure or product, will be monitored 
and evaluated throughout the study. If AEs occur, the first concern will be the safety and 
welfare of the subject. Appropriate medical intervention will be undertaken per the treating 
physician’s discretion. 
Data Monitoring Committee (DMC)
An independent DMC will be formed by charter to assist in examining safety data periodically 
during the study. 
Concomitant Medications: Prohibited, Permitted, and Rescue
Subjects participating in the study are free to use any appropriate concomitant medications if
medically warranted per treating physician’s discretion. However, a standardized concomitant 
medications regimen is recommended during the washout and treatment stages to avoid 
confounding the efficacy or safety assessments of LYR-210.
Prohibited Concomitant Medications:
Use of the following medications is prohibited for the duration of the study: 
x
Oral/ocular/intramuscular/intravenous/intranasal corticosteroids (except for oral or
intranasal corticosteroids permitted as rescue medication only);
x
Anti-allergy medications, including: first generation antihistamines; leukotriene receptor
antagonists, nasal cromolyn sodium or sodium cromoglycate, nedocromil sodium,
atropine, ipratropium bromide, or guaifenesin;

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x
Oral decongestants;
x
Inhaled anti-cholinergic medications (except for a stable regimen for chronic obstructive
pulmonary disease (COPD) subjects);
x
Any potent cytochrome P-450 3A4 (CYP3A4) inhibitors (ketoconazole and ritonavir);
x
Any monoclonal antibody;
x
Any allergen immunotherapy (except for a stable dose and regimen);
x
Oral anti-fungal medication.
Subjects who received prohibited medications will be considered to have a protocol deviation
and may require withdrawal from the study.
Permitted Concomitant Medications:
At the discretion of the Investigator, the following concomitant medications may be used in 
accordance with the restrictions described for each treatment:
x
All subjects will be provided with saline and instructions for daily intranasal saline
irrigation twice a day starting from washout till Week 24/EOT.
x
If sinus infection is suspected at any time during the study, treatment with antibiotics
will be allowed after a clinic visit and per Investigator’s judgment.
x
Subjects who have been on a stable regimen of inhaled corticosteroids for asthma for a
minimum of 3 months prior to the Screening visit should remain on the same dosage
throughout the study. Inhaled corticosteroid use must be limited to a stable low- or
medium-dose as defined by guidelines established by the 2018 Global Initiative for
Asthma Management and Prevention [1].
x
Perennial allergic rhinitis (PAR) subjects who have been on a stable regimen of a non-
sedating oral antihistamine for a minimum of 3 months prior to the Screening visit
should remain on the same dosage throughout the study.
Rescue Medications and Treatment:
The following rescue medication is recommended for an acute exacerbation of the following 
conditions that result in the subject contacting the Investigator who determines an initiation of 
rescue therapy:
x
Any time during the 24-week treatment stage:
- After a clinic visit and per Investigator’s judgment, antibiotics for sinus infection.
- After a clinical visit and evaluation for worsening or uncontrolled severe CS
symptoms, the Investigator using his/her best judgement may give a course of oral
corticosteroids. Typical indications include persistent sinus infection after an initial

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course of antibiotics while starting another course of antibiotics, uncontrolled sinus 
inflammation not responding to an INCS, or a flare-up of asthma. The rationale for 
the use of oral corticosteroid must be recorded.  
x
After the Week 4 visit only:
- For acute allergic symptoms: Non-sedating oral antihistamine such as loratadine
(10 mg per day) or equivalent.
- For severe acute nasal blockage (score of 2 or more over the past 3 days): a course
of oxymetazoline spray for a maximum of 3 consecutive days and a total maximum
of 10 days during the treatment period. Oxymetazoline cannot be used within 24
hours before MRI assessments.
- For worsening CS symptoms: intranasal MF sprays with dose and duration per
Investigator’s recommendation.
- For worsening or uncontrolled severe CS symptoms: ESS as rescue treatment per
Investigator’s recommendation.
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria:
A subject must meet all of the following criteria to be eligible for this study:
1. Age ≥18.
2. A CS subject who
a.
has twelve weeks or longer of two or more of the following symptoms:
• nasal blockage/obstruction/congestion
• nasal discharge (anterior, posterior, or both)
• facial pain/pressure
• reduction/loss of sense of smell
and one or more of the following findings:
• evidence of inflammation within paranasal sinuses or ostiomeatal complex on
MRI
• evidence of purulence coming from paranasal sinuses or ostiomeatal complex
• nasal polyps
b.
has a composite score of 7-day average scores of 4 CS cardinal symptoms [2, 3]
(CS7DA4S) ≥7 (0-3 scale for each of the symptoms) at Day 1 visit, and

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c.
has had at least two trials of medical treatments in the past, one of which must
include intranasal corticosteroid sprays (INCS) for a minimum of 4 weeks.
3. Must be able to cease treatment with intranasal corticosteroid and decongestant sprays at
Screening.
4. Ability to tolerate topical anesthesia.
5. Has been informed of the nature of the study and has provided written informed consent
as approved by the Institutional Review Board (IRB)/Ethics Committee (EC) of the
respective clinical site or regulatory authority if applicable by national law.
6. Agrees to comply with all study requirements.
Exclusion Criteria:
A subject who meets any of the following criteria will be excluded from this study:
1. With previous balloon sinuplasty or any endo-nasal surgery (including sinus surgery),
except for septoplasty or surgical manipulation to nasal turbinates more than 6 months
prior to the Screening visit.
2. Seasonal allergic rhinitis (SAR) subjects with symptoms and/or, based on time of year,
would anticipate onset of symptoms within 4 weeks of randomization.
3. Perennial allergic rhinitis (PAR) subjects whose symptoms are well controlled by
regular use of intranasal corticosteroids.
4. With severe asthma or with one or more exacerbations of asthma requiring systemic
corticosteroid use within the 6 months prior to the Screening visit. Subjects with
moderate or severe asthma will also be excluded if they have not been on a stable
regimen of inhaled corticosteroids for asthma for a minimum of 3 months prior to the
Screening visit.
5. Endoscopic exclusion criteria:
a.
Complete/near complete middle meatal obstruction preventing proper placement
and/or visualization of LYR-210.
b. Evidence of mucosal erosion or ulceration.
c.
Ongoing nasal infection.
d. Evidence of nasal septal perforation.
6. MRI exclusion criteria:
a.
A bilateral Zinreich score < 4 in all 3 pairs of the posterior ethmoid, frontal, or
sphenoid sinuses (0-5 scale for each of sinuses) on Screening MRI.

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b. Anatomic variation which, in the opinion of the Investigator, would adversely
impact placement of LYR-210.
c.
Structural, non-inflammatory related CS (e.g., large concha bullosa, tumor).
d. Sinus disease extended into orbital or intracranial space.
e. Evidence of mycetoma/fungal ball, allergic fungal rhinosinusitis.
f.
Sinus mucocele.
7. History or clinical evidence or suspicion of invasive fungal sinusitis, allergic fungal
rhinosinusitis, or atrophic rhinitis.
8. Known history of hypersensitivity or intolerance to corticosteroids.
9. Oral-steroid or monoclonal antibody (Xolair, Nucala) dependent condition.
10. Having had systemic corticosteroids within 1 month prior to Screening visit.
11. Known history of hypothalamic pituitary adrenal axial dysfunction or having a clinically
significant out of normal range morning serum cortisol level at screening.
12. Previous pituitary or adrenal surgery.
13. Has had more than 1 episode of epistaxis with frank bleeding requiring medical attention
within 2 months of Screening visit or more than 1 episode of epistaxis with frank
bleeding within 1 month of Screening visit.
14. Has had acute exacerbation of nasal allergy or chronic sinusitis, upper respiratory tract
infection (URTI), or common cold within 4 weeks of the Screening visit.
15. Had dental procedure/implant on maxillary dentition within 4 weeks of the Screening
visit.
16. Has past or present acute or chronic intracranial or orbital complications of CS (e.g.,
brain abscess, related problems with eyes or central nervous system).
17. History or diagnosis (in either eye) of glaucoma or ocular hypertension
(IOP > 21 mmHg).
18. With prior cataract surgery or presence (in either eye) of posterior subcapsular cataract
of grade 2 or higher, nuclear sclerosis of grade 3 or higher, or cortical cataract of grade 2
or higher or involving a minimum of center optic zone of 3 mm diameter.
19. Past or present functional vision in only one eye.
20. Diagnosed with ongoing rhinitis medicamentosa.

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21. Known history of immune dysfunction including immune deficiency (IgG subclass
deficiency or IgA deficiency) or autoimmune disease (e.g., Wegener’s granulomatosis,
sarcoidosis).
22. Past, present, or planned organ transplant or chemotherapy with immunosuppression.
23. History or diagnosis of ciliary dysfunction (e.g., cystic fibrosis, primary ciliary
dyskinesia [Kartagener syndrome]).
24. Past or present systemic vasculitis (e.g., granulomatosis with polyangiitis).
25. Evidence of disease or condition expected to compromise survival or ability to complete
follow-up assessments.
26. Pregnant or breast feeding. Females of child-bearing potential must test negative for
pregnancy at the time of screening based on a serum pregnancy test and reverified at the
time of enrollment based on a urine pregnancy test. Both male and female subjects of
reproductive potential must agree to use highly effective methods of birth control,
throughout the study.
27. Previously participated in LYR-210 Phase I clinical study or received an experimental
treatment in another clinical study within 5 half-lives of Screening visit.
28. Currently participating in an investigational drug or device study.
29. Determined by the Investigator as not suitable to be enrolled for reasons not already
specified if the health of the subject or the validity of the study outcomes may be
compromised.
Investigational Product, Dosage and Mode of Administration: 
The LYR-210 System is a combination product comprised of a single-use applicator, pre-loaded 
with the LYR-210 drug depot, an anti-inflammatory drug depot. The LYR-210 drug depot 
contains mometasone furoate (MF), an FDA-approved drug indicated for therapeutic and 
prophylactic management of seasonal and perennial allergic rhinitis (AR), nasal polyps, a 
phenotype of CS disease, as well as asthma. The LYR-210 drug depot is designed to gradually 
soften over time and made of bioabsorbable polymers that have been used as components of 
approved pharmaceutical drugs and/or medical devices.
Each LYR-210 drug depot contains a total MF dose of 2500 μg or 7500 μg [referred to as LYR-
210 (2500 μg) or LYR-210 (7500 μg), or LYR-210 for either dose in this document]. LYR-210
is intended to be administered bilaterally into the ESS-naïve middle meatus by an 
otolaryngologist under endoscopic visualization via the provided single use applicator. Once 
administered, each LYR-210 is designed to gradually deliver sustained doses of MF to the 
inflamed mucosal tissue over a 24-week resident time. Bilateral placement of LYR-210 (2500
μg) is designed to deliver a total dose of 5,000 μg MF over the 24 weeks, or an average daily 

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dose of 30 μg MF per human subject (or 15 μg MF per nostril).  In the case of LYR-210 (7500
μg), a total dose of 15,000 μg MF will be delivered over the 24 weeks with an average daily 
dose of 89 μg MF per human subject (or 45 μg MF per nostril). LYR-210 can be removed at 
24-weeks or earlier at the physician’s discretion using standard instruments.
The LYR-210 drug depot has a tubular braid configuration with a uniform diamond pattern 
throughout and an uncompressed dimension of 13 mm in diameter and 10 mm in length in its 
unconstrained state. It is designed to be self-retaining against the mucosal tissue to allow 
effective drug transfer for up to 24 weeks. The depot is comprised of a base structure and a drug 
formulation matrix. The base structure is composed of poly(L-lactide-co-glycolide) and poly(L-
lactide-co-ε-caprolactone) elastomer to provide 3-dimensional structure and elasticity. The drug 
formulation matrix consists of an active ingredient, MF, embedded in the inactive ingredients 
containing poly(L-lactide-co-ε-caprolactone) and poly(L-lactide) to control the release rate of 
MF. 
Duration of Study: 
The total duration of the study, including the enrollment period, is approximately 22 months. 
Each enrolled subject is planned to participate in the study for a total duration of approximately 
12 months, which includes the Screening/Washout, Treatment, and Post-treatment Follow-up
stages. The active treatment period will be 24 weeks. The end of the trial is defined as the date 
of the last EOS visit of the last subject of the study.
Statistical Methods:
Analysis Sets:
x
Safety (SAF) analysis set: All randomized subjects who received the study treatment
(Sham procedure or a dose of LYR-210) or treatment attempt on Day 1. Subjects will be
analyzed according to the treatment received or attempted. This is the primary analysis
set for assessment of safety.
x
Intention-to-treat (ITT) analysis set: All randomized subjects who received the study
treatment (Sham procedure or a dose of LYR-210) or treatment attempt on Day 1 and
have post-Day 1 assessments available. This is the primary analysis set for assessment of
efficacy. Subjects will be analyzed according to the treatment they were assigned to at
randomization.
x
Per-Protocol (PP) analysis set: All randomized subjects who received the study
treatment, have specific post-Day 1 assessments, and are without major protocol
deviations at the time of the primary analysis.
x
Pharmacokinetic (PK) analysis set: All SAF patients with at least one evaluable drug
concentration post-Day 1.

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Data collected in this study will be presented using listings, as well as, summary tables and 
figures. Continuous data will be summarized by treatment group using the following descriptive 
statistics: the number of observations (n), mean, standard deviation, median, minimum and 
maximum). Categorical data will be summarized by treatment group as number and percentage 
of subjects in each category. Individual subject’s data will be presented in listings.
Subject Disposition and Demographic Characteristics:
Analysis set assignment will be summarized for all enrolled subjects by randomized treatment.
Subject disposition will be summarized for the ITT set. Demographics and other baseline 
characteristics and study drug exposure will be summarized for the SAF and ITT sets.
Safety Analyses:
Safety will be assessed through AEs and changes in laboratory tests, vital signs, morning serum 
cortisol levels, nasal endoscopy assessment, IOP and slit-lamp examination using the SAF set .
AEs will be coded by using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. 
The number and percentage of subjects with incidence of the safety endpoints will be presented 
by treatment group, where subjects will be classified according to the treatment received. There 
will be no formal statistical tests comparing treatments on safety endpoints and there will be no 
imputation of missing data. 
Efficacy Analyses:
All efficacy analyses will be carried out after the last subject completes the Week 28 visit or 
withdraws prematurely prior to Week 28.
All efficacy endpoints will be assessed using the ITT (primary analysis population) and PP
analysis sets with available data for the endpoint.
For the primary efficacy endpoint (CFBL in the CS7DA4S score at Week 4) analysis, 
descriptive statistics will be presented for each treatment group. The null and alternative 
hypotheses to be tested are:
H0: μL2500 = μC
H0: μL7500 = μC
vs.
vs.
H1: μL2500 < μC
H1: μL7500 < μC
where μL2500, μL7500 and μC are true mean value of, the CFBL in the CS7DA4S score at Week 4
for the LYR-210 (2500 μg), LYR-210 (7500 μg) and sham procedure (control) groups, 
respectively. An analysis of covariance (ANCOVA) model for CFBL in CS7DA4S score at 
Week 4 will be used to determine which of the two null hypotheses stated above can be rejected. 
This ANCOVA model will include terms for baseline CSD7A4S score as a covariate and the  
fixed  effects of treatment group (LYR-210 7500 μg, LYR-210 2500 μg, sham procedure) and 

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the randomization stratification variables, presence of nasal allergy and presence of nasal 
polyps. 
Secondary analyses of efficacy endpoints will also be performed in subjects in the PP analysis 
set with available data.
To assess consistency of treatment difference across study region, descriptive statistics of the 
primary endpoint will be presented by treatment group within each region. All subgroups to be 
assessed for treatment effect consistency on the primary endpoint will be detailed in the formal 
SAP.
The key secondary endpoints and other non-key secondary and exploratory efficacy endpoints 
that are continuous variables will be compared in the same manner as the primary endpoint. For 
dichotomous efficacy endpoints treatments will be compared at each time point measured using 
logistic regression adjusting for relevant baseline value and the randomization strata variables 
and other baseline covariates to be specified in the formal SAP. Each secondary endpoint will 
be compared between each LYR-210 dose and sham at a one-sided 0.05 level of significance. 
There will be no adjustment of the significance level adjusting for multiple comparisons.
As further exploratory analyses comparing treatments on all endpoints measured over time, 
generalized estimating equation (GEE) linear regression (for continuous outcomes) and GEE 
logistic regression (for dichotomous outcomes) will be used to compare treatments over time.
Sample Size:
Per the null and alternative hypotheses described above, and under the assumptions that μC = -
1.30 and μL2500 and/or μL7500 = -3.00 (approximately 130% larger decrease than the assumed 
control mean of -1.3) and that the true SD within each treatment group is at most 2.4, then an 
evaluable sample size of 63 patients (21 per treatment group) yields 73% power to reject at least 
one null hypothesis in favor of the alternative at a one-sided 0.05 level of significance. An 
additional 6-9 patients will be enrolled to account for potential subject dropout.
Handling of Missing Data:
The primary analysis on the efficacy endpoints will be performed based on subjects in the ITT 
analysis set with available data. Additional secondary analysis will be performed using the
above ANCOVA model for all subjects in the ITT analysis set. Two imputation approaches will 
be carried out: (a) Last observation carried forward (LOCF) single imputation method; and (b) 
multiple imputation. This will be carried out on the primary endpoint and the key secondary 
endpoint of CFBL in CS7DA4S score at Week 24.
For remaining secondary efficacy endpoints, sensitivity analyses of continuous variable will be 
conducted on all ITT subjects where missing data are first imputed by LOCF prior to carrying 
out the treatment comparisons.

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2.
INTRODUCTION
2.1
Chronic Sinusitis
Chronic sinusitis (CS), commonly referred as chronic rhinosinusitis (CRS) by the medical 
community, is a common condition defined by symptomatic inflammation of the paranasal 
sinuses lasting longer than 12 weeks. The cardinal symptoms of CS include nasal 
blockage/obstruction/congestion, facial pain/pressure, anterior/posterior nasal discharge, and 
reduction/loss of sense of smell [2, 3]. The underlying cause of CS-related symptoms is 
inflammation of mucosal tissue leading to impairment of mucociliary clearance. 
CS affects 10.9% European population [4] and 12.5% of the US population [5], and is the 5th most 
common condition in people under age 65 in the US [6]. CS results in 18 million annual office
visits [6], and the economic implications are at more than $9 billion each year in US alone [7]. The 
socioeconomic cost data outside of the US is limited, however, a 2002 randomized and 
controlled study by a university hospital in Netherland reported that, over a 24-week treatment 
period, the total direct and indirect treatment costs of a regular CS subject was €3661, and this 
number was as high as €8908 for a complicated CS subject [8].
Despite the high prevalence of the disease, no approved drug therapy for the treatment of CS is 
available. Evidence-based medical management supports the off-label use of an oral or topical 
corticosteroid therapy with or without antibiotics. The most common first-line therapy is topical 
intranasal corticosteroids (INCS) with adjunctive use of daily saline irrigation [9]. However, 
inefficient drug delivery to the inflamed mucosal tissues [10] and/or poor subject compliance limit 
the effectiveness of such therapy [11]. Second line medical therapy generally used for 
management of flare-ups and worsening inflammation or severe nasal polyps includes a short
course (1-3 weeks) of oral corticosteroids [2, 3]. While effective initially, improvements are not 
sustained for more than 3 months [12, 13]. Additionally, oral corticosteroids can lead to systemic 
side effects including mood disturbance, gastrointestinal issues, diabetes, cataracts, glaucoma, 
osteoporosis and rarely avascular necrosis of the hip and shoulder [14, 15]. Approximately half (40-
60%) of CS subjects do not benefit from this recommended medical regimen, and so become 
potential candidates for endoscopic sinus surgery (ESS) [16]. However, many surgical candidates 
opt out of surgical treatment [17].
2.2
Product Rationale
Mometasone furoate (MF) is a potent, topically active, anti-inflammatory corticosteroid drug 
indicated for both therapeutic and prophylactic management of seasonal and parenteral allergic 
rhinitis [18], nasal polyps [18], a phenotype of CS disease , as well as asthma [17]. Both rhinitis and 
sinusitis are characterized by an inflammation of the mucosal membrane of the sino-nasal
cavities. Despite the effectiveness of MF topical therapy in management of rhinitis and nasal 
polyposis, results from pharmacokinetic studies in adults and children suggest that systemic 
exposure to MF after intranasal administration is negligible, underscoring MF as an ideal choice 

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of safe drug for developing a new drug formulation for this group of underserved subject
population [19].
Drug-eluting drug delivery systems have demonstrated the ability to provide therapy directly at 
the local site of disease in a sustained fashion while eliminating systemic effects of the drug in 
many therapeutic areas[20, 21]. More recently, local drug delivery systems were approved by the 
FDA for CS subjects immediately following sinus surgery [22, 23] or subjects with recurrent 
polyposis post ESS procedure(s) [24, 25]. The American Rhinologic Society (ARS) endorsed the 
utilization of steroid-eluting drug delivery systems into the paranasal sinuses for their 
demonstrated improvement of subjects outcomes and limiting the need for oral steroids [26].
An ideal treatment for CS would provide local, sustained, anti-inflammatory drug delivery in 
subjects as an option, prior to sinus surgery. Such a therapy would be safe yet provide sustained 
drug delivery via a single administration. It would conform to irregularly shaped sino-nasal
cavities and maintain prolonged mucosal contact time with local drug absorption and minimal 
depletion. It would also allow easy removal at the end of treatment.
The LYR-210 System is a combination product comprised of a single-use applicator, pre-loaded 
with the LYR-210 drug depot, containing a total dose of 2500 μg or 7500 μg mometasone 
furoate [referred to as LYR-210 (2500 μg) or LYR-210 (7500 μg) or LYR-210 for either dose in 
this document]. LYR-210 is a miniaturized local drug delivery implant designed to fit within, 
and conform to, the confined space of a subject’s ESS-naïve middle meatus. LYR-210 consists 
of an active ingredient MF embedded in the inactive ingredients composed of bioabsorbable
polymers with a wide range of medical applications that aid in the controlled and sustained 
delivery of MF to the sino-nasal mucosal tissue from a single drug administration.
LYR-210 is intended to be administered bilaterally into the non-operated middle meatus by an 
otolaryngologist under endoscopic visualization via a provided single use applicator. The 
administration of LYR-210 is office-based and performed with topical anesthesia. Once 
administered, LYR-210 was designed to gradually release 2500 μg or 7500 μg of MF to the 
inflamed mucosal tissue over 24 weeks, from a single administration. Bilateral placement of 
LYR-210 (2500) μg is designed to deliver a total dose of 5000 μg MF over the 24 weeks, or an 
average daily dose of 30 μg MF per human subject (or 15 μg MF per nostril). In the case of 
LYR-210 (7500 μg), a total dose of 15000 μg MF will be delivered over the 24 weeks with an 
average daily dose of 89 μg MF per human subject (or 45 μg MF per nostril). LYR-210 can be 
removed at 24-weeks or earlier at the physician’s discretion using standard instruments.
2.3
Study Rationale
LYR-210 has undergone non-clinical safety assessments to demonstrate suitability for human 
study. A summary of non-clinical studies of LYR-210 is provided in Investigator Brochure (IB, 
Section 4.2). LYR-210 (2500 μg) was assessed in a multi-centered, prospective, open-label, 
single-arm study (clinicaltrials.gov ID: NCT02967731) in 20 adult CS subjects who had failed 

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previous medical management and have not undergone ESS. A summary of this Phase I study is 
provided in IB (Section 5).
The Phase I study concluded that LYR-210 (2500 μg) is safe and well-tolerated in ESS-naïve CS 
subjects and leads to sustained symptom improvement, measured by a CS disease specific 22-
item sino-nasal outcome test (SNOT-22) questionnaire [27], in subjects. These initial clinical 
experiences with LYR-210 (2500 μg) in CS subjects suggest encouraging clinical benefits 
without the need for surgery, while avoiding safety risks associated with prolonged oral steroid 
treatment. The main limitations in the Phase I study, however, include the small sample size and 
lack of a concurrent control group. Therefore, the potential contribution of a placebo effect is 
unknown. A larger clinical study which is randomized and blinded to a control will reduce the 
potential for treatment and assessment bias and will improve the veracity of detected safety and 
efficacy, particularly in the use of self-reported ePRO instruments for assessment of CS 
symptoms.
Additionally, CS subject symptom severity can be stratified with being “normal” defined on the 
SNOT-22 score as <8, “Mild” as 8-20 inclusive, “moderate” as >20-50 and “severe” as >50 [28].
After 24 weeks of treatment with LYR-210 (2500 μg), although 20% subject had achieved 
optimal “normal” symptom scores, some remained symptomatic (data on file with Lyra 
Therapeutics). These results indicate room for further symptom reduction in more subjects, 
possibly with more optimal drug dosing.
Lyra Therapeutics is conducting a global, multicenter study in a randomized, sham procedure-
controlled, parallel-group, subject-blinded fashion in approximately 70 adults CS subjects who 
have failed previous medical management and have not undergone ESS. Subjects enrolled in the 
study will include patients who have not had ESS but their symptoms are not adequately 
controlled on medical management and are seeking further treatment. This may include patients 
who are considering sinus surgery or those who have decided against it. The efficacy and safety 
of LYR-210 (2500 μg) and LYR-210 (7500 μg) versus a sham procedure control will be 
assessed. Additionally, LYR-210 (2500 μg) and LYR-210 (7500 μg) will be compared to 
evaluate dose related responses.

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3.
STUDY OBJECTIVES AND ENDPOINTS
The study objectives and endpoints are:
Study Objectives
Endpoints
Primary
To evaluate the efficacy of LYR-
210 in improving the composite 
score of 7-day average scores of 
4 CS cardinal symptoms 
(CS7DA4S) at Week 4
- Change from baseline (CFBL) in CS7DA4S score at
Week 4
The 4 CS cardinal symptoms include nasal
blockage/obstruction/congestion, facial pain/pressure,
reduction/loss of sense of smell, and anterior/posterior
nasal discharge. Each symptom is scored on a 0-3 scale
as follows: 0 = none, 1 = mild, 2 = moderate, and 3 =
severe.
Key Secondary
To evaluate the efficacy of LYR-
210 in improving CS7DA4S 
score at end of treatment 
- CFBL in CS7DA4S score at Week 24
To evaluate the effect of LYR-
210 in reducing sinus 
inflammation as per magnetic 
resonance imaging (MRI)
- Percentage of subjects with at least 1-point decrease in
the bilateral Zinreich score in at least 1 pair of the
anterior ethmoid, maxillary, posterior ethmoid, frontal, or
sphenoid sinuses at Week 24
Each sinus is scored on a 0-5 scale per the Zinreich
modified Lund-Mackay scoring system and based on the
percentage of opacification as follows: 0 = 0%, 1 = 1%
to 25%, 2 = 26% to 50%, 3 = 51% to 75%, 4 = 76 % to
99%, and 5 = 100% or completely occluded.
To evaluate the time to treatment 
failure 
- Time to treatment failure
A treatment failure is defined as, after subject
enrollment, subject being recommended by treating
physician for oral corticosteroid or ESS due to
worsening of CS symptoms, or the subject complaint of
persistent CS symptoms with an average CS7DA4S score
over the preceding 30 days greater than or equal to the
Baseline CS7DA4S score.
Other Secondary

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To evaluate the safety and 
tolerability of LYR-210
- Severity and percentage of subjects reporting treatment-
emergent adverse events (TEAEs) and serious adverse
events (TESAEs) through Weeks 2, 4, 12, and 24
- Severity and percentage of subjects reporting Day 1
administration procedure and Week 24 removal
procedure related AEs and SAEs
- Severity and percentage of subjects reporting product
related AEs and SAEs on Day 1 and through Weeks 2, 4,
12, and 24
- Percentage of subjects with clinically significant
abnormal and clinically significant abnormal laboratory
values (hematology and chemistry, vital signs) on Day 1
and at Weeks 4, 12, and 24
- Morning serum cortisol levels on Day 1 and at Weeks 4,
12, and 24
- Severity and percentage of subjects with adverse nasal
endoscopic findings and adverse nasal endoscopic
findings requiring medical treatment in one or both
nostrils on Day 1 and at Weeks 2, 4, 12, and 24
- Percentage of subjects with elevated intraocular pressure
(IOP) in one or both eyes at Weeks 4, 12, and 24
- Percentage of subjects with a clinically significant
increase of IOP at Weeks 4, 12, and 24
A clinically significant increase of IOP is defined as IOP
in one or both eyes > 28 mmHg or an increase of IOP
from Baseline in one or both eyes >= 10 mmHg.
- Percentage of subjects with newly identified or worsened
cataract in one or both eyes by slit-lamp examination at
Week 24
To evaluate the time to onset of 
action of LYR-210
- Time to onset of action
Time to onset of action is defined as, within the first 30
days, the time when all subsequent mean CFBL in the
CS7DA4S score of the LYR-210 is statistically
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To evaluate the efficacy of LYR-
210 in improving CS7DA4S 
score and the 7-day average score 
of each of the 4 cardinal CS 
symptoms
- CFBL in the CS7DA4S score at Weeks 8, 12, 16, and 20
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, and anterior/posterior nasal
discharge at Weeks 1, 2, 3, 4, 8, 12, 16, 20, and 24
To evaluate the effect of LYR-
210 in improving CS disease-
specific quality of life as per 22-
item sino-nasal outcome test 
(SNOT-22) questionnaire 
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores at Weeks 2, 4, 8, 12, 16,
20, and 24
To evaluate the effect of LYR-
210 in reducing sinus 
inflammation as per magnetic 
resonance imaging (MRI)
- CFBL in bilateral Zinreich scores of posterior ethmoid,
frontal, sphenoid, maxillary, anterior ethmoid sinus and
OMC pairs at Week 24
- CFBL in total Zinreich score at Week 24
To evaluate the effect of LYR-
210 in reducing subjects’ needs 
for medical or surgical treatment 
for CS
- Percentage of subjects with use of oral antibiotics for CS
through Weeks 4, 8, 12, 16, 20, and 24
- Percentage of subjects with use of oral corticosteroid for
CS through Weeks 4, 8, 12, 16, 20, and 24
- Percentage of subjects with use of intranasal
corticosteroid sprays for CS through Weeks 4, 8, 12, 16,
20, and 24
- Percentage of subjects being recommended by treating
physician for ESS through Weeks 4, 8, 12, 16, 20, and 24
To evaluate the pharmacokinetics 
of LYR-210
- Plasma MF concentrations at Days 3, 7, 14, 21 and
Weeks 4, 12, 24
Plasma PK samples at Days 3, 7, 14, 21 will only be
measured in approximately 15 randomized and
successfully enrolled subjects at US sites.
To evaluate the effect of LYR-
210 in improving subjects’
general quality of life as per 36-
item short form health survey 
version 2 (SF-36v2)
questionnaire
- CFBL in SF-36v2 physical health, mental health, and
domain scores at Week 24

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To evaluate LYR-210 in 
improving smell function
assessed by the University of 
Pennsylvania Smell Identification 
Test (UPSITTM)
- CFBL in UPSIT score at Week 24
Exploratory 
To evaluate the percentage of
subjects experiencing acute 
exacerbations of CS (AECS) 
- Percentage of subjects experiencing AECS through
Weeks 4, 8, 12, 16, 20, and 24
AECS is defined as a sudden worsening of symptoms in a
subject resulting in the treating physician reporting an
escalation of treatment.
To assess effect of LYR-210 in 
reducing polyp severity within 
middle meatus in subgroup of CS 
subjects with nasal polyps 
(CSwNP)
- Percentage of subjects with improvement from Baseline
in nasal polyp severity within middle meatus in CSwNP
subjects at Week 24
To assess efficacy of LYR-210 in 
improving CS7DA4S score, the 
7-day average score of each of 4
CS cardinal symptoms, the
SNOT-22 total and subdomain
scores, and the SF-36v2 physical
health, mental health, and domain
scores in the subgroups of CS
subjects without nasal polyps
(CSsNP) and CSwNP subjects
- CFBL in the CS7DA4S score at Weeks 1, 2, 3, 4, 8, 12,
16, 20, and 24
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, anterior/posterior nasal
discharge in CSsNP and CSwNP subjects at Weeks 1, 2,
3, 4, 8, 12, 16, 20, and 24
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores in CSsNP and CSwNP
subjects at Weeks 2, 4, 8, 12, 16, 20, and 24
- CFBL in SF-36v2 physical health, mental health, and
each of the health domain scores in CSsNP and CSwNP
subjects at Week 24
To assess efficacy of LYR-210 in 
reducing sinus inflammation in 
CSsNP and CSwNP subjects 
- Percentage of subjects with at least 1 point of decrease in
the bilateral Zinreich score in at least 1 pair of the
posterior ethmoid, frontal, or sphenoid sinuses in CSsNP
and CSwNP subjects at Week 24

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- CFBL in bilateral Zinreich scores of posterior ethmoid,
frontal, sphenoid, maxillary, anterior ethmoid sinus, and
OMC pairs in CSsNP and CSwNP subjects at Week 24
- CFBL in total Zinreich score at in CSsNP and CSwNP
subjects Week 24
To assess effect of LYR-210 in 
improving smell function in 
CSsNP and CSwNP subjects 
- CFBL in UPSIT score in CSsNP and CSwNP subjects at
Week 24
To assess the safety of subjects 
post LYR-210 treatment
- Severity and percentage of subjects reporting AEs and
SAEs through Week 28 and Week 48
- Percentage of subjects with abnormal and clinically
significant abnormal laboratory values (hematology and
chemistry, vital signs) at Week 28
- Morning serum cortisol levels at Week 28
- Plasma MF concentration at Week 28
- Severity and percentage of subjects with adverse nasal
endoscopic findings and adverse nasal endoscopic
findings requiring medical treatment in one or both
nostrils at Week 28
- Percentage of subjects with elevated IOP in one or both
eyes at Week 48
- Percentage of subjects with a clinically significant
increase of IOP at Week 48
- Percentage of subjects with newly identified or worsened
cataract in one or both eyes by slit-lamp examination at
Week 48
To assess the durability of 
efficacy post LYR-210 treatment
- Percentage of subjects with improvement from Baseline
in nasal polyp severity within middle meatus in CSwNP
subjects at Week 28
- CFBL in the CS7DA4S score at Weeks 28, 32, 36, 40,
44, and 48
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, anterior/posterior nasal

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discharge in CSsNP and CSwNP subjects at Weeks 28, 
32, 36, 40, 44, and 48    
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores at Weeks 28, 32, 36, 40,
44, and 48
- CFBL in SF-36v2 physical health, mental health, and
each of the health domain scores at Week 48

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4.
INVESTIGATIONAL PLAN
4.1
Overall Study Design
This global, multicenter study will be conducted in a randomized, sham procedure-controlled, 
parallel-group, subject-blinded fashion in approximately 70 adults CS subjects who have failed 
previous medical management and have not undergone ESS. Subjects enrolled in the study will 
include patients who have not had ESS but their symptoms are not adequately controlled on 
medical management and are seeking further treatment. This may include patients who are 
considering sinus surgery or those who have decided against it. The efficacy and safety of LYR 
210 (2500 μg) and LYR-210 (7500 μg) versus a sham procedure only control will be assessed. 
Additionally, the study results of LYR-210 (2500 μg) and LYR-210 (7500 μg) will be compared 
to evaluate dose related responses.
The study will consist of three stages: 
x
Screening and Washout Stage: 2 - 4 weeks
x
Randomized and Blinded Treatment Stage: 24 weeks
x
Blinded Post-Treatment Follow-Up Stage: 24 weeks
The overall flow diagram of subject enrollment and follow up schedule is shown in Figure 1.
Figure 1:
Study Design Schematic

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4.1.1
Screening Stage
After providing written informed consent, subjects who are qualified to participate in this study 
will have an initial Screening visit. Immediately following the initial Screening visit, subjects
will undergo a minimum of 2-week but a maximum of 4-week washout period. During this 
washout period, subjects will receive no active treatment for CS but are recommended to start 
daily saline irrigation twice a day. Subjects will be provided with saline and instructions for daily 
intranasal saline irrigations while participating in the study.
Medications that are prohibited during the washout period (and during the study) are listed in 
Section 6.4.2. Beginning at least 7 days prior to Day 1 visit, subjects will record the severity of 
the 4 cardinal symptoms of CS and the use of saline irrigation each day in the morning on the 
electronic subject reported outcomes (ePRO) questionnaire.
4.1.2
Treatment Stage
The total duration of the Treatment Stage will be 24 weeks. Subjects who complete the study 
Screening assessments and the washout period and meet all eligibility criteria on Day 1 will be 
stratified according to the presence or absence of nasal allergy and nasal polyps and, then, 
randomized in a 1:1:1 ratio to receive LYR-210 (2500 μg), LYR-210 (7500 μg), or sham 
procedure. Subjects who are assigned to the experimental arms will have the LYR-210
administered bilaterally into the middle meatus (Section 6.2) and, then, removed at Week 24
(Section 6.5). Subjects who are assigned to the sham procedure arm, will undergo bilateral mock 
administration (i.e., sham procedure) on Day 1. Enrolled subjects will undergo scheduled study 
visits at Weeks 2, 4, 12, and 24 during the treatment duration. Subjects will receive phone 
follow-ups at Weeks 8, 16, and 20 to record AEs and concomitant medications/procedures that 
they have had since last follow-up assessment. [NOTE: Female subjects of childbearing potential 
will be asked to return to the clinic for urine pregnancy test at Weeks 8, 16, and 20.] All subjects
will remain blinded and undergo the assessments and procedures scheduled for these visits 
(Section 8.1).
At the Week 24 visit, all subjects will return to clinic for the end-of-treatment (EOT) visit 
assessments. Subjects who receive LYR-210 will have bilateral depot removed using standard 
surgical tools. Sham control subjects will undergo a sham removal procedure to remain blinded.
If medically warranted per the treating physician’s discretion (for example, needing an ESS as 
rescue treatment), early depot removal before the schedule EOT visit at Week 24 may be 
performed at an unscheduled early-termination (ET) visit (an unscheduled EOT visit). Any 
subject who undergoes an ET visit is required to complete the assessments scheduled for the 
Week 24/EOT visit, and all safety follow up visits post treatment.
If spontaneous dislodgement of LYR-210 occurs before Week 24 in subjects who receive either 
dose of LYR-210, subjects are required to call the study clinic immediately to report the event. If

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a subject experiences a dislodgement of one of the two LYR-210 depots, the subject will 
continue the study treatment unless an early treatment discontinuation is recommended by the 
treating physician or subject requests depot removal from the remaining side of the nose. If 
depots spontaneously dislodge from both sides of the nose, subject will complete Week 24/EOT 
assessments and subsequently, the post-treatment follow-up stage.
4.1.3
Post-Treatment Follow-Up Stage
After the Week 24/EOT visit, all enrolled subjects will undergo a blinded Post-treatment Follow-
up Stage that will be approximately 24 weeks. Subjects will have 2 additional scheduled safety 
follow up visits, the Week 28 and a final Week 48/EOS visit. Subjects will receive phone follow-
ups at Weeks 32, 36, 40, and 44 to record AE and concomitant medications/procedures that they 
have had since last follow-up assessment. Except for the cases of depot dislodgement, subjects
should remain blinded until the study database is locked.
4.1.4
End of the Trial
The end of the trial is defined as the date of the last EOS visit of the last subject of the study.
4.2
Rationale for Study Design
The goal of treatment is to reduce the symptoms of adult CS with a well-tolerated product. The 
study design and endpoints are adequate for assessment of safety and efficacy of LYR-210 in the 
context of a Phase II study of subjects with CS. Blinding and randomization will reduce the 
potential for treatment and assessment bias and will improve the veracity of detected safety and 
efficacy, particularly in the use of self-reported ePRO instruments for assessment of CS
symptoms. The parallel arm study design and 1:1:1 randomization scheme of LYR-210
(2500 μg): LYR-210 (7500 μg): sham procedure permits adequate statistical comparison of 
groups for efficacy assessment and safety signal detection. The ePRO of daily morning cardinal 
symptoms and the SNOT-22 subject reporting instruments have been selected because they are 
specific to the subject population to be enrolled in this study. Other efficacy endpoints involving 
objective changes in the sino-nasal cavities (i.e., inflammation and polyps), smell dysfunction 
improvement, and general quality of life improvement are appropriate for development and 
further refinement of study endpoints in the clinical program. Although MF is well-characterized 
as a treatment in other indications, chronic assessments of local nasal and ophthalmologic 
parameters in this study’s CS population and in the context of in situ delivery via drug-depot are 
appropriate for associating safety results with local MF levels. Summarized in Section 9.1 is the 
safety rationale for the selection of drug doses and polymers in LYR-210 in this Phase II study.
4.3
Discontinuation of Study Subjects
Subjects will be encouraged to complete the study through the treatment and post-treatment 
follow up periods. Each subject is free to discontinue from the study at any time, for any reason, 
and without penalty or loss of benefit. Participation in the study treatment may be discontinued 
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x
Occurrence of any medical condition or circumstance that exposes the subject to
substantial risk and/or does not allow the subject to adhere to the requirements of the
protocol, including early removal of LYR-210 (Section 6.5).
x
Any serious AE (SAE, Section 8.4.9.2), clinically significant AE, severe laboratory
abnormality, intercurrent illness, or other medical condition that indicates to the
Investigator that continued participation is not in the best interest of the subject.
x
Subject’s decision to withdraw.
x
Requiring ESS as rescue treatment.
x
If deviations to the use of prohibited medications occur after randomization and study
treatment, the Investigator in consultation with the Sponsor and Sponsor’s medical
monitor will decide on a case-by-case basis whether the subject may continue in the
study based on the time the prohibited medication was administered and its
pharmacology.
x
Subject’s failure to comply with protocol requirements or study related procedures.
x
Termination of the study by the Sponsor or a regulatory authority that has provided
approval to proceed.
Subjects who withdraw or are withdrawn from the study treatment will be requested to return to 
the clinic for the assessments and procedures scheduled for the EOT visit and the safety follow 
up visits post EOT (Section 8.1).
The Investigator or study staff will document the reason(s) for subject discontinuation on the 
Case Report form (CRF), notify the IRB/EC as required by their Institution’s procedures, and 
notify the Sponsor the reason for discontinuation.
4.4
Criteria for Study Termination
If the Sponsor, the Investigator, the medical monitor, the data monitoring committee (DMC), 
Institutional Review Board (IRB)/Ethics Committee (EC), and/or appropriate regulatory officials 
discover conditions arising during the study that indicate the study should be halted or that the 
study center should be terminated, appropriate action may be taken after consultation among (at 
a minimum) the Sponsor, the IRB/EC, and the medical monitor. Refer to Section 11.13 for
additional information.
4.5
Data Monitoring Committee (DMC)
An independent DMC will be formed by charter to assist in examining safety data periodically 
during the study and will include independent physicians with appropriate experience of clinical 
trials but who are not participating in this study. The DMC will:
x
Review the safety and tolerability data at predefined time points. The first study level
safety review will occur after the 30th subject has completed 4 weeks of treatment or
early terminated from the study, whichever occurs first. A second safety review will
occur after all enrolled subjects have completed the Week 4 follow-up. The timing
and details of subsequent data review will be detailed in the DMC charter.

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x
Review the safety data at ad hoc time points if significant safety concerns are
identified during the study.
x
Review events that may impact subject continuation and make recommendations
regarding study progression.
x
Review any other data, as appropriate.
The membership, responsibilities and operating procedures of the DMC will be described in a
DMC Charter.

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5.
SELECTION OF SUBJECTS
5.1
Subject Screening
All subjects evaluated for participation in this study will be screened for study eligibility. A 
delegated member of the Institution’s research team will review the subject’s medical history to 
screen for study eligibility. All subjects who meet initial eligibility requirements will be asked to 
participate in the study. Each subject will indicate his or her willingness to participate in the 
study by signing an IRB/EC-approved informed consent form (ICF).
Each subject will be assigned a unique subject identification number upon signing informed 
consent. Subjects who are assigned a subject ID but do not meet the eligibility criteria will be 
considered Screen Failures. 
If the Investigator believes rescreening is warranted, a subject can be rescreened upon 
consultation with the study Medical Monitor or study Sponsor. Subject numbers assigned to 
subjects who fail screening should not be reused. Investigators must account for all subjects who 
sign an ICF. If the subject is found to be not eligible at this visit, the investigator/designee should 
still complete the applicable electronic case report forms (eCRF).
5.2
Subject Informed Consent
Prior to enrollment in the study, all subjects must review and complete an IRB/EC-approved 
ICF. All potential subjects must complete the consent process prior to undergoing procedures 
performed specifically for this study that are outside the standard of care for the institution. 
Failure to obtain a signed ICF renders the subject ineligible for the study. Sites will comply with 
ICH Guidelines for obtaining informed consent.
5.3
Inclusion Criteria
A subject must meet all of the following criteria to be eligible for this study:
1. Age ≥18.
2. A CS subject who
a.
has twelve weeks or longer of two or more of the following symptoms:
• nasal blockage/obstruction/congestion
• nasal discharge (anterior, posterior, or both)
• facial pain/pressure
• reduction/loss of sense of smell
and one or more of the following findings:
• evidence of inflammation within paranasal sinuses or ostiomeatal complex
on MRI

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• evidence of purulence coming from paranasal sinuses or ostiomeatal
complex
• nasal polyps
b.
has a composite score of 7-day average scores of 4 CS cardinal symptoms [2, 3]
(CS7DA4S) ≥7 (0-3 scale for each of the symptoms) at Day 1 visit, and
c.
has had at least two trials of medical treatments in the past, one of which must
include intranasal corticosteroid sprays (INCS) for a minimum of 4 weeks.
3. Must be able to cease treatment with intranasal corticosteroid and decongestant
sprays at Screening.
4. Ability to tolerate topical anesthesia.
5. Has been informed of the nature of the study and has provided written informed
consent as approved by the IRB/ EC of the respective clinical site or regulatory
authority if applicable by national law.
6. Agrees to comply with all study requirements.
5.4
Exclusion Criteria
A subject who meets any of the following criteria will be excluded from this study:
1. With previous balloon sinuplasty or any endo-nasal surgery (including sinus surgery),
except for septoplasty or surgical manipulation to nasal turbinates more than 6
months prior to the Screening visit.
2. Seasonal allergic rhinitis (SAR) subjects with symptoms and/or, based on time of
year, would anticipate onset of symptoms within 4 weeks of randomization.
3. Perennial allergic rhinitis (PAR) subjects whose symptoms are well controlled by
regular use of intranasal corticosteroids.
4. With severe asthma or with one or more exacerbations of asthma requiring systemic
corticosteroid use within the 6 months prior to the Screening visit. Subjects with
moderate or severe asthma will also be excluded if they have not been on a stable
regimen of inhaled corticosteroids for asthma for a minimum of 3 months prior to the
Screening visit.
5.
Endoscopic exclusion criteria:
a. Complete/near complete middle meatal obstruction preventing proper placement
and/or visualization of LYR-210.
b. Evidence of mucosal erosion or ulceration.
c. Ongoing nasal infection.
d. Evidence of nasal septal perforation.
6. MRI exclusion criteria:
a.
A bilateral Zinreich score < 4 in all 3 pairs of the posterior ethmoid, frontal, or
sphenoid sinuses (0-5 scale for each of the sinuses) on Screening MRI.

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b. Anatomic variation which, in the opinion of the Investigator, would adversely
impact placement of LYR-210.
c.
Structural, non-inflammatory related CS (e.g., large concha bullosa, tumor).
d. Sinus disease extended into orbital or intracranial space.
e.
Evidence of mycetoma/fungal ball, allergic fungal rhinosinusitis.
f.
Sinus mucocele.
7. History or clinical evidence or suspicion of invasive fungal sinusitis, allergic fungal
rhinosinusitis, or atrophic rhinitis.
8. Known history of hypersensitivity or intolerance to corticosteroids.
9. Oral-steroid or monoclonal antibody (Xolair, Nucala) dependent condition.
10. Having had systemic corticosteroids within 1 month prior to Screening visit.
11. Known history of hypothalamic pituitary adrenal axial dysfunction or having a
clinically significant out of normal range morning serum cortisol level at screening.
12. Previous pituitary or adrenal surgery.
13. Has had more than 1 episode of epistaxis with frank bleeding requiring medical
attention within 2 months of Screening visit or more than 1 episode of epistaxis with
frank bleeding within 1 month of Screening visit.
14. Has had acute exacerbation of nasal allergy or chronic sinusitis, upper respiratory
tract infection (URTI), or common cold within 4 weeks of the Screening visit.
15. Had dental procedure/implant on maxillary dentition within 4 weeks of the Screening
visit.
16. Has past or present acute or chronic intracranial or orbital complications of CS (e.g.,
brain abscess, related problems with eyes or central nervous system).
17. History or diagnosis (in either eye) of glaucoma or ocular hypertension (IOP > 21
mmHg).
18. With prior cataract surgery or presence (in either eye) of posterior subcapsular
cataract of grade 2 or higher, nuclear sclerosis of grade 3 or higher, or cortical
cataract of grade 2 or higher or involving a minimum of center optic zone of 3 mm
diameter.
19. Past or present functional vision in only one eye.
20. Diagnosed with ongoing rhinitis medicamentosa.
21. Known history of immune dysfunction including immune deficiency (IgG subclass
deficiency or IgA deficiency) or autoimmune disease (e.g., Wegener’s
granulomatosis, sarcoidosis).
22. Past, present, or planned organ transplant or chemotherapy with immunosuppression.
23. History or diagnosis of ciliary dysfunction (e.g., cystic fibrosis, primary ciliary
dyskinesia [Kartagener syndrome]).
24. Past or present systemic vasculitis (e.g., granulomatosis with polyangiitis).

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25. Evidence of disease or condition expected to compromise survival or ability to
complete follow-up assessments.
26. Pregnant or breast feeding. Females of child-bearing potential must test negative for
pregnancy at the time of screening based on a serum pregnancy test and reverified at
the time of enrollment based on a urine pregnancy test. Both male and female
subjects of reproductive potential must agree to use highly effective methods of birth
control, throughout the study.
27. Previously participated in LYR-210 Phase I clinical study or received an
experimental treatment in another clinical study within 5 half-lives of Screening visit.
28. Currently participating in an investigational drug or device study.
29. Determined by the Investigator as not suitable to be enrolled for reasons not already
specified if the health of the subject or the validity of the study outcomes may be
compromised.

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6.
TREATMENT OF SUBJECTS
6.1
Randomization
Subjects who complete the study Screening assessments and the washout period, and meet all
eligibility criteria on Day 1 will be, before any treatment, randomized in a 1:1:1 ratio to one of 
the following study arms: 
x
Arm 1: bilateral administration of LYR-210 (2500 μg)
x
Arm 2: bilateral administration of LYR-210 (7500 μg)
x
Control Arm: bilateral sham procedure
Subjects will be stratified for treatment assignment according to the following criteria:
x
Nasal allergy (Yes vs No)
x
Nasal polyps (Yes vs No)
For any reason, if the Investigator is unable to successfully administer LYR-210 or perform 
sham procedure into both middle meatuses in a subject (as described in Section 6.2), this subject 
will be considered as an Enrollment Failure.
Randomization will be conducted using Interactive Response Technology (IRT) and treatment 
will be assigned according to a randomization scheme generated by the Sponsor’s unblinded 
biostatistician. The person generating the randomization scheme will not be involved in the 
collection, review, and/or analysis of study data before database lock and unblinding.
6.2
Study Product Administration
6.2.1
Pre-procedure Medication
Prior to LYR-210 administration or the sham procedure, all subjects will receive topical 
anesthetic and decongestant sprays for endoscopic assessment. Subjects will further receive 
anesthetic and decongestant soaked cottonoids or pledgets in each nostril to prepare the middle 
meatus for the study product insertion procedure.
6.2.2
Study Product Preparation
LYR-210 and the sham procedure article will be provided to the study site as described in 
Section 7.2.1. Preparation of LYR-210 or the sham procedure article should be performed in 
accordance with the instructions of use (IFU) provided in a separate document and should not 
start until the subject has been prepared and is ready for the administration procedure.
6.2.3
Study Product Administration
LYR-210 is designed to be administered intranasally under endoscopy visualization. Subjects 
who are assigned to either dose of LYR-210 will have LYR-210 administered bilaterally into the 
middle meatus. Subjects who are assigned to the sham procedure arm, will undergo bilateral 
mock administration (i.e., sham procedure), consisting of a bilateral insertion of an applicator 

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(without LYR-210 loaded) into the middle meatus until the applicator tip touches the ethmoid 
bulla for a minimum of 20 seconds, followed by withdrawal of the applicator. To maintain 
subject blinding to the treatment assignment, each subject will wear an eye mask (i.e., blindfold) 
at the time of the LYR-210 administration/sham procedure. An independent, unblinded case 
manager may be present during day 1 visit to assist product administration.
Following administration procedure, all enrolled subjects will rest for at least 1 hour and be 
monitored to ensure there is no epistaxis that requires medical attention.
6.2.4
Enrollment Failure
The Investigator will be allowed up to two attempts at LYR-210 administration or at the sham 
procedure per side. A treatment attempt is defined as that an applicator of a LYR-210 or sham
article is inserted to a subject’s left or right nostril for an attempt of investigational product
administration. If the Investigator is unable to administer LYR-210 bilaterally or perform sham 
procedure successfully into both middle meatuses of a subject, the Investigator will remove any
LYR-210 already administered and treat the subject with any appropriate therapy, if necessary. 
The subject will be considered as an Enrollment Failure as described in Section 6.1. Subjects
will be followed within 7 (± 2) days via telephone for AE and concomitant medication 
assessment.
6.2.5
End of Day 1 Visit
Prior to discharge at Day 1 visit, all enrolled subjects will be provided with clear instructions and 
the following reminders:
x
That they are currently enrolled in an investigational study for up to 12 months.
x
To avoid nose blowing for the rest of the day post-procedure.
x
To wipe or gently blow their nose during the treatment stage.
x
To sneeze with mouth open to avoid over-pressurization to the nose.
x
To call the study clinic if they have any unexpected epistaxis.
x
To call the study clinic immediately should the subject experience severe discomfort
or if LYR-210 falls out of the nose.  If this occurs - instruct subject to retain the depot
(place in a plastic bag/vial and store in a freezer if possible) and return to the clinic at
the next clinic visit.
6.3
Blinding
Except for the cases of spontaneous depot dislodgement, subjects should remain blinded to their 
treatment assignment (LYR-210 or sham) until the final study database is locked. To maintain 
subject blinded (LYR-210 or sham), each subject will wear an eye mask (i.e., blindfold) at the 
time of the LYR-210 administration/sham procedure and at all post Day 1 visits (scheduled or 
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The investigational site staff will be blinded regarding the impending treatment assignment until 
after a study subject has completed all baseline assessments required on Day 1 visit (Section 8.1)
prior to randomization assignment. After randomization assignment, the investigational site staff, 
including the Investigator and study coordinator, will be unblinded as to whether the subjects 
receive LYR-210 administration or sham procedure. The study clinic staff, including the 
Investigator and study coordinator, will be blinded as to the dose administered to subjects 
receiving LYR-210.
The Sponsor will be blinded to subjects’ study treatment assignments until database lock for the 
primary data analysis after all enrolled subjects have completed Week 28 visit or withdrawn 
from study, whichever comes first.
6.3.1
Procedures for Breaking the Blind Prior to Study Completion
Breaking the blind is expressly forbidden except in the event of spontaneous dislodgment of
LYR-210, or a medical emergency where the identity of the treatment assignment must be 
known in order to properly treat the subject. If breaking the blind is required because of a 
medical emergency, decision to unblind lies solely with the investigator.
In all cases where the code is broken, the Investigator must record the date and reason for code 
breaking. The unblinding should be noted in the subject’s eCRF. 
6.3.2
Revealing Randomization
In the absence of a medical emergency or inadvertent unblinding due to depot dislodgement, the 
blinded randomization for this study will not be revealed until all data are entered in the 
database, edit checks are performed, queries are closed, CRFs are signed by the Investigator at
each site, and the database is officially locked per study unblinding plan.
6.4
Prior and Concomitant Medications
Subjects participating in the study are free to use any appropriate concomitant medications if 
medically warranted per treating physician’s discretion. However, a standardized concomitant 
medications regimen is recommended during the washout and treatment stages to avoid 
confounding the efficacy or safety assessments of LYR-210.
All medications taken by subjects during the course of the study will be recorded. 
6.4.1
Prior Medications
Beginning at Screening, all medications and other treatments taken by subjects will be recorded 
on the CRF. In addition, all subjects will be required to refrain from use of prohibited 
medications (Section 6.4.2) beginning at Screening.
Subjects may be permitted to continue medications that do not meet exclusionary criteria (see 
also Section 6.4.3). If any additional concomitant medications are to be administered during the 
study, or a dose adjustment is required for any existing concomitant medication, the Investigator 

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should contact the Sponsor’s medical monitor for approval prior to administration, provided the 
safety of the subject would not be compromised.
6.4.2
Prohibited Concomitant Medications
The following medication that could potentially affect symptoms of CS or the safety assessment 
of LYR-210 will not be allowed during the Screening and washout period or during the treatment 
stage:
x
Oral/ocular/intramuscular/intravenous/intranasal corticosteroids (except for oral or
intranasal corticosteroids permitted as rescue medication only);
x
Anti-allergy medications, including: first generation antihistamines; leukotriene receptor
antagonists, nasal cromolyn sodium or sodium cromoglycate, nedocromil sodium,
atropine, ipratropium bromide, or guaifenesin;
x
Oral decongestants;
x
Inhaled anti-cholinergic medications (except for a stable regimen for chronic obstructive
pulmonary disease (COPD) subjects);
x
Any monoclonal antibody;
x
Any potent cytochrome P-450 3A4 (CYP3A4) inhibitors (ketoconazole and ritonavir);
x
Any allergen immunotherapy (except for a stable dose and regimen);
x
Oral anti-fungal medication.
Subjects who received prohibited medications will be considered a protocol deviation and may 
require withdrawal from the study as detailed in Section 4.3.
6.4.3
Permitted Concomitant Medications
At the discretion of the Investigator, the following concomitant medications may be used in 
accordance with the restrictions described for each treatment:
x
All subjects will be provided with saline and instructions for daily intranasal saline
irrigation twice a day starting from washout till Week 24/EOT.
x
If a sinus infection is suspected at any time during the study, treatment with antibiotics
will be allowed after a clinic visit and per Investigator’s judgment.
x
Subjects who have been on a stable regimen of inhaled corticosteroids for asthma for a
minimum of 3 months prior to the Screening visit should remain on the same dosage
throughout the study. Inhaled corticosteroid use must be limited to a stable low- or
medium-dose as defined by guidelines established by the 2018 Global Initiative for
Asthma Management and Prevention [1].
x
Perennial allergic rhinitis (PAR) subjects who have been on a stable regimen of a
non-sedating oral antihistamine for a minimum of 3 months prior to the Screening visit
should remain on the same dosage throughout the study.

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6.4.4
Rescue Concomitant Medications and Treatment
The following rescue medications are recommended in the event of an acute exacerbation of the 
following conditions that result in the subject contacting the Investigator who determines an 
initiation of rescue therapy:
x
Any time during the 24-week treatment stage:
- After a clinic visit and per Investigator’s judgment, antibiotics for sinus infection.
- After a clinical visit and evaluation for worsening or uncontrolled severe CS
symptoms, the Investigator using his/her best judgement may give a course of oral
corticosteroids. Typical indications include persistent sinus infection after an initial
course of antibiotics while starting another course of antibiotics, uncontrolled sinus
inflammation not responding to an INCS, or a flare-up of asthma. The rationale for
the use of oral corticosteroid must be recorded.
x
After the Week 4 visit only:
- For acute allergic symptoms: non-sedating oral antihistamine such as loratadine
(10 mg per day) or equivalent.
- For severe acute nasal blockage (score of 2 or more over the past 3 days): a course of
oxymetazoline spray for a maximum of 3 consecutive days and a total maximum of
10 days during the treatment period. Oxymetazoline cannot be used within 24 hours
before MRI assessments.
- For worsening CS symptoms: intranasal MF sprays with dose and duration per
Investigator’s recommendation.
- For worsening or uncontrolled severe CS symptoms: ESS as rescue treatment per
Investigator’s recommendation.
6.5
Removal Procedure
Subjects who receive LYR-210 will have the bilateral drug depots removed at the Week 24/EOT
visit or earlier in an Unscheduled early termination (ET) visit if medically warranted per the 
treating physician’s discretion (for example, requiring an ESS as rescue treatment). The removal 
procedure will be performed under endoscopic visualization after topical anesthetic and 
decongestant sprays applied to each nostril.  Standard surgical tools are used to remove LYR-
210. LYR-210 is made of polymers designed to gradually soften over time. Care should be taken
to remove LYR-210 in one piece or in sections should any disintegration of LYR-210 occur.
To keep the subjects enrolled in the sham procedure group fully blinded in the post-treatment 
safety follow up stage, all sham control subjects will undergo a sham removal procedure either at 
the scheduled Week 24 visit or earlier in an unscheduled early termination (ET) visit if the 
subjects request early depot removal.

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6.6
Treatment Compliance
Administration and removal of LYR-210 and the sham procedure article will be performed in a 
clinical setting by trained personnel who will be responsible for ensuring and recording 
compliance with all treatment procedures.

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7.
DRUG PRODUCT MATERIALS AND MANAGEMENT
7.1
Investigational Product
7.1.1
Product Description
The LYR-210 System is a combination product comprised of a single-use applicator, pre-loaded 
with the LYR-210 drug depot, containing mometasone furoate (MF), an FDA-approved drug 
indicated for therapeutic and prophylactic management of seasonal and perennial allergic rhinitis 
(AR), nasal polyps, a phenotype of CS disease, as well as asthma. The LYR-210 drug depot is 
made of bioabsorbable polymers designed to gradually soften over time. It has a tubular braid 
configuration with a uniform diamond pattern throughout and dimensions of 13 mm in diameter 
and 10 mm in length in the unconstrained state (Figure 2). It is designed to be self-retaining 
against the mucosal tissue to allow effective drug transfer for up to 24 weeks. The depot is 
comprised of a base structure and a drug formulation matrix. The base structure is composed of 
poly(L-lactide-co-glycolide) and poly(L-lactide-co-ε-caprolactone) elastomer to provide a 3-
dimensional structure and elasticity. The drug formulation matrix consists of the active 
ingredient, MF, embedded in the inactive ingredients containing poly(L-lactide-co-ε-
caprolactone) and poly(L-lactide) to control the release rate of MF. All these polymers are 
currently being used as components of approved pharmaceutical drugs and/or medical devices.
Figure 2:
LYR-210 Images 
7.1.2
Dosage and Administration
Each LYR-210 drug depot contains either 2500 μg or 7500 μg MF. LYR-210 is intended to be 
administered bilaterally into the ESS-naive middle meatus by an otolaryngologist under 
endoscopic visualization via a provided single use applicator. Once administered, each LYR-210
is designed to gradually deliver MF to the inflamed mucosal tissue over 24 weeks with a single 
drug administration. Bilateral placement of LYR-210 (2500 μg) is designed to deliver a total 
dose of 5,000 μg MF over the 24 weeks, or an average daily dose of 30 μg MF per human 
subject (or 15 μg MF per nostril).  In the case of LYR-210 (7500 μg), a total dose of 15,000 μg 
MF will be delivered over the 24 weeks with an average daily dose of 89 μg MF per human 
subject (or 45 μg MF per nostril). 

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7.1.3
Active Ingredient: Mometasone Furoate
Mometasone furoate, USP, is the active pharmaceutical ingredient. It is a potent, topically active, 
anti-inflammatory corticosteroid, having the chemical name of 9α,21-dichloro-11ꞵ,17α-
dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 17-(2-furoate), with an empirical formula of 
C27H30Cl2O6 and a molecular weight of 521.43 g/mol. It has the chemical structure shown in 
Figure 3.
Figure 3:
Chemical Structure of Mometasone Furoate
7.1.4
Inactive Ingredients
The inactive ingredients are poly(L-lactide-co-ε-caprolactone) (L-PLCL) and poly(L-lactide) (L-
PLA), shown in Figure 4A and Figure 4B, respectively.
Figure 4:
Chemical Structures of Inactive Ingredients
7.1.5
Applicator
LYR-210 is designed to be administered intranasally under endoscopy visualization via a single 
use applicator that contains the drug depot (Figure 5). The applicator compresses LYR-210 just 
prior to use, accesses the treatment site, and administers the drug depot. The applicator is 
constructed from materials commonly used in medical devices with well-established 
biocompatibility: polycarbonate, polytetra-fluoroethylene, Pebax® (comprised of polyamide and 
polyether), polyethylene, nylon, and stainless steel. 

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Figure 5:
Applicator, Ready for LYR-210 Administration
7.2
Drug Product Management
7.2.1
Packaging and Labeling
LYR-210 will be packaged and labeled appropriately for the blinded clinical study, as required 
by regional legislation and industry guidelines.
The Sponsor or designee will ship study products to the sites as needed. Specific instructions for 
ordering product will be provided to the sites.
7.2.2
Storage
It is recommended that LYR-210 be stored at 15 °C to 25 °C (59 °F to 77 °F) and in the original 
packaging to protect from moisture and light. The labeled expiry dates of LYR-210 are specified 
on the label. The location of drug product storage must be locked, and access must only be 
allowed to the study team or a designated person involved with the study team.
7.2.3
Product Traceability
Traceability of LYR-210 or the sham procedure articles shall be achieved by assigning each 
depot and applicator a unique serial number, designated next to the “SN” symbol on the label. 
7.2.4
Product Accountability
The Sponsor will supply sufficient quantities of LYR-210 and the sham procedure articles to 
allow completion of the study. The Investigator or designee must maintain accurate records to 
document the disposition of all product received by the clinical site. Required information 
includes the date received, date used, lot number, product description, expiry date, and a subject 
identifier for product that has been administered. Investigational sites will use a form to 
document product disposition which will be reviewed by the study monitor during routine 
monitoring visits. When enrollment in the Clinical Study is complete, any unused investigational 
product will be returned to Sponsor or discarded per Sponsor authorization along with a final 

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Accountability Log. The Accountability Log must document the disposition of all investigational 
product including those that have been returned to the Sponsor.
7.2.5
Product Return
All products that are not administered into a subject must be returned to the Sponsor or designee
or discarded per Sponsor authorization. Applicators successfully used for administration may be 
disposed on site after the study procedure is complete. For all investigational product that are 
associated with a malfunction, the product and all ancillary components (e.g., applicator) 
remaining from the index procedure should be returned to the Sponsor. The Investigator will 
inform the Sponsor of any complaints or malfunctions during the study. The Sponsor will 
investigate all product complaints and malfunctions. Instructions for returning product will be 
provided to the sites by the Sponsor.

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8.
STUDY ASSESSMENTS
8.1
Study Schedule of Assessment
The schedule of study assessments for subjects is summarized in Table 1 below and detailed in 
Sections 8.2, 8.3, and 8.4.
Enrolled subjects will be asked to complete an ePRO questionnaire daily in the morning to assess 
the 4 cardinal symptoms of CS including nasal blockage/obstruction/congestion, reduction/loss 
of sense of smell, facial pain/pressure, and anterior/posterior nasal discharge. In addition, the 
ePRO will capture the recommended daily use of nasal saline irrigation by the subject. Subjects 
will also complete a validated CS-specific quality of life questionnaire, the SNOT-22, throughout 
the study; and a general quality of life questionnaire, the SF-36v2, on Day 1 and at Week 
24/EOT and Week 48/EOS visits. At the Week 24/EOT visit, an end-of-treatment questionnaire 
will be administered. 
Subjects will be asked to complete the UPSITTM for smell dysfunction on Day 1 before the LYR-
210 administration/sham procedure, and at Week 24/EOT and Week 28 visits.
Sinus inflammation will be assessed by MRI without contrast before the LYR-210
administration/sham procedure during Screening and at the Week 24/EOT visit, unless medically 
contraindicated. If a subject is experiencing or recovering from a cold, acute exacerbation of 
nasal allergy, or upper respiratory tract infection at this visit, perform assessment 4 weeks after 
resolution of the adverse event. If a subject requires oral corticosteroid as rescue during the 24-
week treatment period, the follow-up MRI should be performed before receiving the rescue 
treatment instead of at Week 24/EOT visit.
Nasal cavities will be assessed by endoscopy before the LYR-210 administration/sham 
procedure on Day 1, at Weeks 2, 4 and 12, Week 24/EOT, and Week 28 visits. Subjects are 
required to wear a blindfold if endoscopy examination is performed at these visits to remain 
blinded to treatment assignment. Local nasal safety evaluation will be performed at these visits 
to document presence of epistaxis, mucosal erosion or ulceration, perforation, infection, and any 
other local nasal adverse effects. For CSwNP subjects, real-time, qualitative endoscopic 
evaluation of change of polyp severity within middle meatus will be performed by site 
Investigators at the Week 24/EOT visit after LYR-210 removal/sham removal procedure and at
Week 28 visit by comparing to that of the Day 1 visit.
Ophthalmologic assessments will include IOP and slit-lamp examination for cataract 
development at Screening, Week 24/EOT and Week 48/EOS visits. IOP assessment will be also 
performed at Week 4 and Week 12 visits.
Plasma samples for PK will be collected from all subjects on Day 1 before the LYR-210
administration/sham procedure, and at Weeks 4 and 12, Week 24/EOT, and Week 28 visits.

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Additional plasma PK samples will be collected at Days 3, 7, 14 (Week 2), 21 from
approximately 15 randomized and successfully enrolled subjects at participating US sites. The 
concentration of MF in plasma will be measured by a central laboratory.
Routine safety assessments will be performed during the study including vital signs and physical 
exams at all clinic visits. Samples for hematology, blood chemistry, and cortisol will be collected 
during Screening, at Weeks 4 and 12, Week 24/EOT, and Week 28 visits. An additional 
hematology, chemistry, and serum cortisol sample will be collected within 72 hours prior to 
LYR-210 administration/sham procedure for Baseline value. All post-Screening serum cortisol 
samples will be evaluated by a central laboratory. 
For female subjects of childbearing potential, a serum pregnancy test will be performed at 
Screening visit and a urine pregnancy test will be performed on Day 1 prior to randomization to 
confirm eligibility for participating in the study. A urine pregnancy test will be performed every 
4 weeks in clinic during the treatment stage in these female subjects.
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
events (AEs) or untoward findings. Any AEs observed by the Investigator or reported by the 
subjects, whether or not attributed to the investigational procedure or product, will be monitored 
and evaluated throughout the study. If AEs occur, the first concern will be the safety and welfare 
of the subject. Appropriate medical intervention will be undertaken at the treating physician’s 
discretion. 
Additional visits may occur as clinically warranted.  At these Unscheduled Visits, any of these 
assessments may be performed per the treating physician’s discretion. 

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Table 1:
Schedule of Assessments for Subjects Randomized and Enrolled
Evaluation
Screening
Procedure 
Day a
Treatment Stage a
(24 weeks)
Post-Treatment Stage a
(24 weeks)
Visits #
1
2 b
3 b
4 b
5 b
6 b
7 b
8
Study Day/Week
DAY 
-28 to -14
DAY 1
WK 2
(±1
day)
WK 4
(±3 
days)
WK 8
(±3 
days) r
WK 12
(±3 
days)
WK 16
(±3 
days) r
WK 20
(±3 
days) r
WK 24 /
EOT
(±3 
days)
WK 28
(±7 
days)
WK 32 
(±7
days) r
WK 36 
(±7
days) r
WK 40 
(±7
days) r
WK 44 
(±7
days) r
WK 48 /
EOS 
(±7 
days)
Informed Consent
X c
Demographics
X
Medical History 
X
Vital Signs
X
X d
X
X
X
X d
X
X
Physical Exam 
X
X d
X
X
X d
X
X
Pregnancy Test f
X e
X d,e,t
X e
X e
X e
X e
X e
X e
Hematology/Chemistry f
X
X d,t
X
X
X d
X
Morning Serum Cortisol f,g
X
X d,t
X
X
X d
X
Magnetic Resonance Imaging
X h
X p,q
Ophthalmology Assessment i
X h
X j
X j
X p
X
UPSIT TM
X d
X d
X
Endoscopy
X
X k, m
X
X
X
X k,m
X k
Eligibility Assessment
X
X d
Washout Period
X l
Randomization
X d
Baseline LYR-210/Sham Procedure
X
Plasma Pharmacokinetics s
X d
X
X
X d
X
LYR-210/Sham Removal Procedure
X
Daily ePRO 
X n
SNOT-22 Questionnaire
X
X d
X
X
X
X
X
X
X d
X
X
X
X
X
X
SF-36v2 Questionnaire
X d
X d
X
End-of-Treatment Questionnaire
X
Concomitant Medications/Procedures
X
Adverse Events o
X

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Abbreviations: UPSIT = university of pennsylvania smell identification test; CS = chronic sinusitis; ePRO = electronic patient reported outcomes; EOT = end of-
treatment; EOS = end-of-study; SF-36v2 = short form health survey version 2; SNOT = sino-nasal outcome test; WK=week
a:
Subjects remain blinded starting from the time of randomization
b:
Subjects will wear a blindfold during any endoscopy procedure or endoscopy imaging.
c:
To be obtained before any study related assessments occur.
d:
Occurs before the LYR-210 or sham administration and removal procedures. 
e: 
Complete a serum pregnancy test at initial Screening visit and a urine pregnancy test in clinic at all subsequent visits during the treatment stage for female 
subjects of childbearing potential.
f: 
Investigators must document their review of each laboratory report.
g:
Blood samples will be collected during the morning hours before 10:00 AM (i.e., before 1000 HRS). Screening cortisol samples will be performed locally 
at the study site. Cortisol samples collected at all post-Screening visits will be sent to a central laboratory for testing. 
h:
Performed anytime between Screening and Day 1 visits.
i: 
Performed by a blinded ophthalmologist/optometrist. 
j: 
IOP assessment only.
k:
For CSwNP subjects, endoscopic evaluation of severity of polyps within middle meatus will be performed by the site Investigator at the time of imaging 
recording.  Polyp severity evaluation should occur after topical anesthetic and decongestant sprays are administered, but before anesthetic and decongestant 
soaked pledgets or cottonoids are applied. 
l: 
For a minimum of 2 weeks on all prohibited medications before the Day 1 visit. Subjects will start daily saline irrigation twice a day during washout.
m: 
Local nasal safety and polyp assessments to be performed before LYR-210/sham insertion on Day 1 or after LYR-210/sham removal at EOT visit.
n:
Daily instantaneous morning (between 06:00:00AM and 11:59:59AM) CS symptoms to be recorded by the subject on ePRO questionnaire beginning at 
least in the preceding 7 days prior to Day 1 visit.
o:
All adverse events shall be reported after subject signs informed consent.
p:
To be performed within 7 days after removal procedure. 
q:
If a subject is experiencing or recovering from a cold, acute exacerbation of nasal allergy, or upper respiratory tract infection at EOT visit, perform 
assessment 4 weeks after resolution of the adverse event. If a subject requires oral corticosteroid as a rescue treatment, perform follow-up MRI before 
receiving the rescue treatment instead of at EOT visit.
r:
Phone follow up to collect any potential AEs and use of concomitant medications/procedures.
s:
Additional plasma PK samples will be collected at Days 3, 7, 14±1 (Week 2), and 21±1 in approximately 15 randomized and successfully enrolled subjects 
at participating US sites.
t:
Samples can be collected within 72 hours prior to LYR-210 administration/sham procedure.

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8.2
Assessment of Subject Characteristics
8.2.1
Demographics
Demographic information (age, sex, ethnicity, and race) will be obtained during Screening as 
specified in the Study Schedule of Assessments (Section 8.1).
8.2.2
Medical and Surgical History
Medical and surgical history information will be obtained during Screening as specified in the Study 
Schedule of Assessments (Section 8.1).
A general medical history will be collected. In addition, the medical history will document 
conditions, focusing specifically on the following body systems: Head, Eyes, Ears, Nose, Throat 
(HEENT). The medical history will also include an assessment of the subject’s lifetime history of the 
following: 
x
Chronic sinusitis
x
Asthma
x
Chronic obstructive pulmonary disease (COPD)
x
Perennial allergic rhinitis (PAR)
x
Seasonal allergic rhinitis (SAR)
x
Sensitivity to Non-steroidal anti-inflammatory drugs (NSAIDs)
x
Smoking
Subjects will also be assessed if they had the following history of surgery or injury in the past:
x
Endoscopic sinus surgery (ESS)
x
Septoplasty
x
Sinuplasty
x
Polypectomy
x
Nasal surgery involving nasal turbinates
x
Facial trauma
8.3
Assessment of Efficacy
8.3.1
Subject Reported Outcomes
Subject symptom improvement, use of saline irrigation, and the overall experience of study will be 
captured using an ePRO system. Subjects will be instructed on the method for completing the ePRO.
At all clinic visits, the ePRO will be completed prior to any intranasal procedure or clinic 
assessments.

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8.3.1.1
Chronic Sinusitis Cardinal Symptom Assessment
For assessment of the 4 cardinal symptoms of CS, the ePRO will be completed by subjects on a daily 
basis as specified in the Schedule of Events (Section 8.1). Subjects will start recording their 
symptoms on the ePRO at least 7 days preceding the Day 1 visit. A minimum of 5 daily entries are 
required for composite score calculation over the preceding 7 days prior to Day 1 (not including Day 
1) for assessing subject’s eligibility for participating in the study.
The 4 cardinal symptoms of CS, as defined in the 2012 European position paper on rhinosinusitis 
and nasal polyps (EPOS-2012) [2] and the 2016 international consensus statement on allergy and 
rhinology: rhinosinusitis (ICAR:RS-2016) guidelines [3], include nasal 
blockage/obstruction/congestion, reduction/loss of sense of smell, facial pain/pressure, and nasal 
discharge (anterior/posterior nasal drip). 
Subjects will score the severity of their morning (between 06:00:00AM to 11:59:59AM)
instantaneous symptoms of CS on a 4-point scale (Section14.1):
x
0 = absent symptoms (no sign/symptom evident)
x
1 = mild symptoms (sign/symptom present but minimal awareness; easily tolerated)
x
2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but
tolerable)
x
3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with
activities of daily living and/or sleeping)
8.3.1.2
22-Item Sino-Nasal Outcome Test (SNOT-22) Questionnaire
The ePRO will also be used to collect responses to the SNOT-22 questionnaire at the time points 
specified in the Schedule of Events (Section 8.1).
The SNOT-22 questionnaire is a 22-item disease-specific quality of life instrument validated for use 
in CS [27] (Section 14.2). Subjects score the severity of their symptoms and social/emotional 
consequences of CS on a 6-point scale: 
x
0 = no problem
x
1 = very mild problem
x
2 = mild or slight problem
x
3 = moderate problem
x
4 = severe problem
x
5 = problem as bad as it can be
The scores are summed; higher scores on the SNOT-22 instrument total score or subdomain scores 
as defined in Table 2 [29] indicate higher severity of symptoms or social/emotional consequences of 
CS.

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Table 2:
Categorized Survey Items for Separate Domains of the SNOT-22 Instrument
SNOT-22 Domains
Survey Items
Score Range
Rhinologic Symptoms
#1, #2, #3, #4, #7, #12
0–30
Extra-Nasal Rhinologic Symptoms
#5, #6, #7
0–15
Ear/Facial Symptoms
#3, #8, #9, #10, #11
0–25
Psychological Dysfunction
#16, #17, #18, #19, #20, #21, #22
0–35
Sleep Dysfunction
#13, #14, #15, #16, #17
0–25
SNOT-22 = 22-item Sino-nasal Outcome Test
8.3.1.3
Saline Irrigation Use
The ePRO will also be used to collect the frequency of daily saline irrigation by the subjects. 
8.3.1.4
36-item Short Form Health Survey version 2 (SF-36v2®) Questionnaire 
At Day-1, Week 24/EOT, and Week 48/EOS visits, subjects will complete the SF-36v2®
questionnaire by ePRO. SF-36v2® is a generic health survey that asks 36 questions to measure 
functional health and well-being of a subject (Section 14.4). It is a valid measure of physical and 
mental health and the most frequently used PRO instrument in clinical trials today [30]. Additionally, 
the SF-36v2® provides scores for each of the eight health domains and psychometrically based 
physical component summary (PCS) and mental component summary (MCS) scores (Table 3) [31].
The items of the SF-36v2 are transformed and summed to a norm-based scores (Mean = 50, SD = 
10) scale for each PCS and MCS domain in which higher scores indicate a better health-related QoL.
Table 3.
SF-36v2® Health Survey Measurement Model
SF-36v2 Components and Domains
Survey Items
Physical Component Summary (PCS)
Physical Functioning (PF)
#3a, #3b, #3c, #3d, #3e, #3f, #3g, #3h, #3i, #3j
Role -Physical (RP)
#4a, #4b, #4c, #4d
Bodily Pain (BP)
#7, #8
General Health (GH)
#1, #11a, #11b, #11c, #11d 
Mental Component Summary (MCS)
Vitality (VT)
#9a, #9e, #9g, #9i
Social Functioning (SF)
#6, #10
Role-Emotional (RE)
#5a, #5b, #5c
Mental Health (MH)
#9b, #9c, #9d, #9f, #9h

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8.3.1.5
End-of-Treatment Questionnaire
At Week 24/EOT visit, subjects will complete an end-of-treatment questionnaire by ePRO 
(Section 14.3). The questionnaire will query subjects about their general experience and satisfaction 
with their assigned study treatment. Subjects will describe their experiences by answering multi-
choice questions or providing narrative responses.
8.3.2
Sinus Inflammation Imaging
Sinus inflammation will be assessed by MRI without contrast at the time points specified in the 
Schedule of Events (Section 8.1), unless medically contraindicated. The Screening MRI should be 
performed anytime between the Screening and Day 1 visits. The follow up MRI will be conducted 
within 7 days after the LYR-210 removal/sham procedure at Week 24/EOT visit. If a subject is 
experiencing or recovering from a cold, acute exacerbation of nasal allergy, or upper respiratory tract 
infection at the EOT visit, the MRI will be performed 4 weeks after resolution of the adverse event. 
If a subject requires oral corticosteroid as rescue during the 24-week treatment period, the follow-up
MRI should be performed before receiving the rescue treatment instead of at Week 24/EOT visit.
The sinus inflammation will be assessed using the Zinreich modified Lund-Mackay scoring system
(referred herein as the Zinreich scores)[32] where each sinus is assigned a score based on the 
percentage of opacification as follows: 
x
0 = 0%
x
1 = 1% to 25%
x
2 = 26% to 50%
x
3 = 51% to 75%
x
4 = 76 % to 99%
x
5 = 100% or completely occluded
The ostiomeatal complex (OMC) is given a score of 0 to 2 as follows:
x
0 = completely patent
x
1 = partially occluded
x
2 = completely occluded
Each sinus pair has a bilateral Zinreich score in the range of 0 to 10, and the OMC pair in the range 
of 0 to 4, and the total sum of all sinuses and OMCs in the range of 0-54.
8.3.3
Nasal Polyp Assessment
Visualization and assessment of nasal polyps will be conducted using endoscopy at the time points 
specified in the Schedule of Events (Section 8.1). At the Day 1 visit, prior to the LYR-210
administration/sham procedure, an endoscopic assessment of nasal passageway for eligibility will be 
conducted after topical anesthetic and decongestant sprays are administered, but before any 

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anesthetic and decongestant soaked pledget or cottonoid is applied for the LYR-210
administration/sham procedure. The follow up endoscopic assessment of the nasal passageway will 
be conducted at Weeks 2, 4 and 12, Week 24/EOT, and Week 28 visits.
Investigators will evaluate the severity of nasal polyps in the middle meatus at the Week 24/EOT 
and Week 28 visits by grading polyp severity as “better,” “worse,” or “the same” in comparison to 
the Baseline severity evaluated at Day 1 visit before the insertion procedure.
8.3.4
The University of Pennsylvania Smell Identification Test (UPSITTM)
The UPSIT will be conducted at 3 time points during the study as specified in the Schedule of 
Events (Section 8.1). At Day 1 and Week 24/EOT visits, the UPSITTM will be conducted prior to the 
LYR-210 administration/sham procedure and prior to the LYR-210 removal/sham procedure
endoscopy assessment.
The UPSITTM is composed of 40 odorants embedded on scent strips that are released when scratched 
with a sharply tipped object [33]. The UPSIT is comprised of 4 booklets, each containing 10 
microencapsulated (scratch & sniff) odors. The UPSIT is a forced-choice test, and subjects will be 
instructed to identify each odorant with alternatives accompany each test item. The total olfaction 
score using the UPSIT is defined as the number of odorants correctly identified out of the 40 odors 
tested, with higher scores designating better olfactory performance. 
8.4
Assessment of Safety
8.4.1
Physical Examination
A physical examination including a careful assessment of all body systems, including the skin, eyes, 
ears, nose and throat, respiratory will be performed at all clinic visits as specified in the Schedule of 
Events (Section 8.1). Height (cm) will only be measured at Screening visit. Weight (kg) and body 
mass index (BMI) will be measured at all visits.
8.4.2
Vital Signs
Vital signs will be measured at all clinic visits as specified in the Schedule of Events (Section 8.1).
Vital sign measurements will include blood pressure (systolic and diastolic, mmHg), and pulse rate
(beats per minute), aural/oral temperature (°C), and respiration rate (breaths per minute). All 
measurements will be obtained after the subject has been resting supine for at least 5 minutes.
8.4.3
Laboratory Assessments
Laboratory testing will be performed at clinic visits as specified in the Schedule of Events 
(Section 8.1). Any unused duplicated samples collected for the purpose of this study will be 
destroyed after the completion of the study.

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8.4.3.1
Hematology
Samples for hematology assessments will be obtained during Screening, within 72 hours prior to 
LYR-210 administration/sham procedure, and at Weeks 4 and 12, Week 24/EOT, and Week 28
visits as specified in the Schedule of Events (Section 8.1).
Hematology assessments will include a leukocyte count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, and basophils), erythrocytes, hematocrit, hemoglobin, and platelet count.
Testing will be performed according to the standard of care at the investigational site.
8.4.3.2
Blood Chemistry
Samples for blood chemistry assessments will be obtained during Screening, within 72 hours prior to 
LYR-210 administration/sham procedure, and at Weeks 4 and 12, Week 24/EOT, and Week 28
visits as specified in the Schedule of Events (Section 8.1).
Clinical blood chemistry laboratory analytes will include electrolytes (sodium, potassium, chloride, 
and bicarbonate), blood urea nitrogen, serum creatinine, glucose, total bilirubin, aspartate 
aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, uric acid, 
total protein, albumin, calcium, magnesium, and phosphate. 
Testing will be performed according to the standard of care at the investigational site unless 
otherwise noted in the Lab Manual.
8.4.3.3
Morning Serum Cortisol
Samples for serum cortisol will be collected during the morning hours before 10:00 (i.e., before 
1000 HRS) during Screening, within 72 hours prior to LYR-210 administration/sham procedure, and 
at Weeks 4 and 12, Week 24/EOT, and Week 28 visits as specified in the Schedule of Events 
(Section 8.1).
All serum cortisol samples, except for Screening, will be sent to a central laboratory for testing.  
8.4.4
Nasal Endoscopy Assessments
Nasal cavities will be assessed by endoscopy on Day 1 before the LYR-210 administration/sham 
procedure, and at Weeks 2, 4 and 12, Week 24/EOT, and Week 28 visits as specified in the Schedule 
of Events (Section 8.1). Local nasal safety evaluation will be performed at these visits to document 
presence of epistaxis, mucosal erosion or ulceration, perforation, infection, and any other adverse 
local nasal observations. 
8.4.5
Ophthalmologic Assessments
The ophthalmologic assessment of IOP and slit-lamp examination to identify cataract development 
will be conducted at Screening, Week 24/EOT, and Week 48/EOS visits as specified in the Schedule 
of Events (Section 8.1). IOP assessment will also be performed at Weeks 4 and 12 visits.

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Assessments will be conducted by a blinded ophthalmologist/optometrist. 
8.4.6
Pharmacokinetic Analysis
Blood samples for assessment of plasma PK will be at Day 1, Weeks 4 and 12, Week 24/EOT, and 
Week 28 visits as specified in the Schedule of Events (Section 8.1). Additional plasma PK samples 
will be collected at Days 3, 7, 14 (Week 2), 21 from approximately 15 randomized and successfully 
enrolled subjects at participating US sites for a minimum of 6 subjects for each LYR-210 dose.
At the Day 1 visit, the blood sample for plasma PK analysis will be collected prior to the LYR-210
administration/sham procedure. Subsequent blood samples may be collected at any time of the day 
during the scheduled study visits.
The concentration of MF in plasma will be measured at a central core lab.
8.4.7
In Vivo Drug Dissolution Analysis of LYR-210
All removed or spontaneously dislodged LYR-210 will be collected and returned to Lyra 
Therapeutics if allowed by the individual hospital standard operating procedures (SOPs).
Instructions for the processing and return of removed LYR-210 will be provided. 
The mass of remaining MF in LYR-210 will be measured at Lyra Therapeutics.
8.4.8
Pregnancy or Breast Feeding
Females of child-bearing potential must test negative for pregnancy at the time of Screening visit
based on a serum pregnancy test and re-verified prior to randomization at Day 1 visit based on a 
urine pregnancy test. Females who can confirm that they are surgically sterile or have been 
postmenopausal for at least 1 year prior to signing the ICF do not need to undergo a pregnancy test.
Urine pregnancy test will be performed to successfully enrolled female subjects of child-bearing 
potential every 4 weeks during the treatment stage.
Female subjects who are of childbearing potential are required to practice a highly effective form of 
birth control to continue in the study and for 4 weeks after the removal procedure. Male subjects of 
reproductive potential who are having intercourse with female partners of childbearing potential 
must agree to use 2 forms of contraception, 1 of which must be a barrier method, during the study 
and for 4 weeks after the removal procedure. Acceptable barrier methods include a condom and 
diaphragm. 
Definition of Childbearing Potential and Highly Effective Contraceptive Methods:
A woman is considered of childbearing potential (i.e., fertile), following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
A
w

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A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. 
A high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to 
confirm a post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
For women of childbearing potential, the following methods of contraception, when used 
consistently and correctly, are considered reliable for participation in the study: 
x
Combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation: oral, intravaginal, or transdermal
x
Progestogen-only hormonal contraception associated with inhibition of ovulation: oral,
injectable or implantable
x
Intrauterine device (IUD)
x
Intrauterine hormone-releasing system (IUS)
x
Bilateral tubal; occlusion
x
Vasectomized partner (provided that partner is the sole sexual partner and that
vasectomized partner has received medical assessment of the surgical success)
x
Sexual abstinence (refraining from heterosexual intercourse during the entire study
period; the reliability of sexual abstinence needs to be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the subject).
If a female subject who has successfully received bilateral placement of either dose of the LYR-210
becomes pregnant during the treatment stage, the Investigator must notify the Sponsor within 24 
hours of becoming aware of the event on a Pregnancy Report Form. The Investigator must continue 
to follow the pregnancy until the completion of the pregnancy, including the outcome and the 
condition of the newborn at 8 weeks post-partum (if applicable). If not all information on the 
Pregnancy Report Form is available at the time of the initial report, follow-up reports should be 
provided to the Sponsor in a timely manner. Additional subsequent follow-up is not needed when a 
newborn baby is healthy.
8.4.9
Adverse Events and Serious Adverse Events
8.4.9.1
Adverse Event (AE)
Throughout the course of the study, all efforts will be made to remain alert to possible AEs or 
untoward findings. If AEs occur, the first concern will be the safety and welfare of the subject.
Appropriate medical intervention will be undertaken. Any AE observed by the Investigator or 
reported by the subjects, whether or not ascribed to the investigational procedure or product, will be 
recorded on the subject’s AE Case Report Form. A new AE Case Report Form will be used for each 
AE. All on-going AEs that result in early termination from the study or are deemed to be study 

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product or procedure related by the Site Investigator will be followed up until resolution or 
stabilization of the AE.
Documentation regarding the AE should be made as to the nature, date of onset, end date, severity, 
and relationship to study drug, action(s) taken, seriousness, and outcome of any sign or symptom 
observed by the physician or reported by the subject upon indirect questioning.
An AE is any untoward medical occurrence (signs, symptoms, abnormal laboratory findings) in a 
subject regardless of relationship to the investigational product or procedure. Each adverse event is 
considered to be either expected or unexpected as described below. The site is required to report AEs 
that occur in the study. These events shall also be classified according to the suspected causality by 
the study Investigator. 
A Treatment Emergent AE (TEAE) is an AE that occurs or worsens on or after initiation of the 
LYR-210 administration/sham procedure.
8.4.9.2
Serious Adverse Event (SAE)
An SAE is any untoward medical occurrence that:
x
Results in, leads to, or contributes to, a death;
x
Is life-threatening (“Life-threatening” refers to an event in which the subject was at risk
of death at the time of the event. It does not refer to an event which hypothetically might
have caused death if it were more severe);
x
Results in subject hospitalization or prolongation of existing hospitalization;
x
Results in persistent or significant disability/incapacity (i.e., permanent impairment of a
body function or permanent damage to a body structure);
x
Results in fetal distress, fetal death or a congenital anomaly/birth defect;
x
Is an important medical event which may jeopardize the subject and may require medical
or surgical intervention to prevent one of the above outcomes.
The Investigator will assess each AE for its seriousness. Please note the term “serious” AE is not 
synonymous with a “severe” AE, which may be used to describe the intensity of an event 
experienced by the subject (Section 8.4.9.4). Any treatment related SAE (Section 8.4.9.5) will be 
followed until resolution of the event, or until the subjects withdraw from the study.
8.4.9.3
Relationship to Study Drug Product and Procedure
The Investigator should initially classify the causality of an AE and determine the relationship 
between an AE and the study product or procedure.

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8.4.9.3.1
Relationship to Study Drug Product 
The relationship between an AE and the LYR-210 study drug product will be determined by the 
Investigator on the basis of his or her clinical judgment and the following definitions: 
x
Definitely Related: The AE follows a reasonable temporal sequence from administration
of the investigational product; the AE follows a known or expected response pattern to
the investigational product.
x
Possibly Related:The AE follows a reasonable temporal sequence from administration
of the investigational product; the AE follows a known or expected response pattern to
the investigational product but could readily have been produced by a number of other
factors.
x
Not Related: An AE for which sufficient information exists to indicate that the etiology
is unrelated to the investigational product. One or more of the following variables apply:
o The AE does not follow a reasonable temporal sequence following administration of
the investigational product;
o The AE is readily explained by the subject’s clinical state or other therapies.
For events that are determined to be definitely or possibly related, additional information on the 
timing of the event in relation to the LYR-210 study drug product administration will be captured.
8.4.9.3.2
Relationship to Study Procedure
The Relationship between an AE and the LYR-210 administration/sham procedure (within 24 hours) 
will be determined by the Investigator on the basis of his or her clinical judgment and the following 
definitions: 
x
Definitely Related: The AE follows a reasonable temporal sequence from performance
of the study procedure; the AE follows a known or expected response pattern to the study
procedure.
x
Possibly Related:The AE follows a reasonable temporal sequence from performance of
the study procedure; the AE follows a known or expected response pattern to the study
procedure but could readily have been produced by a number of other factors.
x
Not Related: An AE for which sufficient information exists to indicate that the etiology
is unrelated to the study procedure. One or more of the following variables apply:
o The AE does not follow a reasonable temporal sequence following the study
procedure;
o The AE is readily explained by the subject’s clinical state or other therapies.

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For events that are determined to be definitely or possibly related to the study LYR-210
administration/sham procedure, additional information on the timing of the event in relation to the 
study procedure will be captured.
8.4.9.4
Severity of Adverse Events
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an adverse 
event as determined by the Investigator or reported to him/her by the subject. The assessment of 
severity is made irrespective of relationship to study procedure or product or seriousness of the event 
and should be evaluated according to the following scale:
x
Mild: Event is noticeable to the subject but is easily tolerated and does not interfere with
the subject’s daily activities.
x
Moderate:Event is bothersome, possibly requiring additional therapy, and may interfere
with the subject’s daily activities.
x
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and
interferes with the subject’s daily activities.
8.4.9.5
Expectedness of Serious Adverse Events
The expectedness of a product or procedure related SAE should be determined by Sponsor based 
upon existing safety information about the investigation product or study procedure using these 
explanations:
x
Unexpected: An SAE that is not listed in the study protocol, Investigator’s brochure, or
prescribing information for the registered formulation of MF or is not listed at the
specificity or severity that has been observed.
x
Expected: An SAE that is listed in the Investigator’s Brochure (IB) or prescribing
information for the registered formulation of MF or is listed at the specificity and severity
that has been observed.
8.4.9.6
Reporting
8.4.9.6.1
Adverse Event Reporting
Adverse events are to be collected from the time a subject signs informed consent until the 
completion of all follow-up visits. At each office visit during the study, AEs that have occurred since 
the previous office visit must be recorded. All subjects will be evaluated for AEs or complications 
associated with the study procedure or the investigational product. The Investigator will determine 
the severity and relationship of each event, as defined above.
AEs observed during the course of this study, regardless of severity or relationship to the study 
procedure or investigational product will be recorded on the appropriate CRF. 

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Documentation of all new AEs or changes in previously reported AEs will be recorded. Pre-existing 
diseases or conditions will not be reported as AEs unless there has been a substantial increase in 
severity or frequency of the problem which cannot be attributed to the expected progression of the 
disease or condition.
The Investigator will review the results of all clinical and laboratory tests as they become available.
For each laboratory test result, the Investigator will ascertain whether the result represents an 
abnormal (e.g., clinically significant) change from Baseline for that individual subject. If this 
laboratory test result is determined to be an abnormal change from Baseline for that subject, the 
value will be considered to be an AE.
The description of the AE will include the date of onset, date of resolution (ongoing), severity, 
seriousness, relationship of the event to the investigational product and to the study procedure, and 
any procedure required. Specific procedures implemented in response to the AE will also be 
recorded. For all AEs, the Investigator is required to supply any additional data that may be deemed 
necessary by the Sponsor or designee.
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) throughout the study (Version 21.1 will be used at the start of the study).
8.4.9.6.2
Serious Adverse Event Reporting
The Investigator will be required to report all SAEs that occur throughout the course of the study. 
Information such as the Investigator name, study name/protocol number, subject identification 
number, the description of the SAE, the Investigator’s assessment as to the relationship to the 
investigational product and the study procedure, and the reporting source should be included in the 
initial report. Any additional supporting documentation may be requested by the Sponsor or designee
as necessary. This also includes forwarding pertinent follow-up information (e.g., clinic discharge 
summary) as it becomes available. A completed SAE form needs to be submitted with each follow-
up. Reports relating to the subject’s subsequent medical course must be submitted to the Sponsor 
until the event has resolved or, in case of permanent impairment, until the event stabilizes, and the 
overall clinical outcome has been ascertained.
Each SAE should be reported to the Sponsor or designee within 24 hours of knowledge of the event. 
The Sponsor will ensure that all SAEs are reported to the relevant authorities and Investigators, as 
required by local regulations. 
8.4.9.6.3
Expedited Reporting
Any serious and unexpected suspected adverse reactions (SUSARs) and unexpected adverse device 
effect (UADE) will be reported by the Sponsor or designee to the appropriate Regulatory Authorities 
in accordance with applicable local guidelines. 
The SUSARs meet all the following criteria:

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x
Suspected adverse reaction
x
Serious
x
Unexpected
x
Assessed as related to study treatment
A UADE is any serious adverse effect on health or safety, any life-threatening problem or death 
caused by, or associated with a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the application; or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects.
8.4.10
Safety Monitoring
Subject will be closely monitored throughout the trial with high priority for subject safety. The 
sponsor will establish Safety/Medical Monitoring team early in the study. The team will be 
responsible for developing a Safety/Medical Monitoring Plan (MMP) which will define in detail the 
objectives, scope and roles and responsibilities of each team member involved. 
Subject safety monitoring encompasses, but is not limited to, providing advice to sites and the 
project team for protocol-related issues, providing input into decisions requiring medical advice and 
routine safety monitoring of the study, review of serious and non-serious AEs, various data listings, 
lab results, vital signs, and other clinical data may be undertaken. Reviews of blinded aggregate data 
as well as individual subject data may be undertaken to identify outliers and trends that may impact 
safety of the subject and consistency of data.

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9.
SAFETY INFORMATION OF STUDY DRUG PRODUCT
9.1
Safety Rationale of Study Drug Doses and Polymers
LYR-210 is designed to be administered intranasally under endoscopy visualization via a single use
applicator that contains the drug depot. Bilateral placement of LYR-210 (2500 μg) is designed to 
deliver a total dose of 5000 μg MF over the 24 weeks with an average daily dose of 30 μg MF per 
subject (or 15 μg MF per nostril).  In the case of LYR-210 (7500 μg), a total dose of 15000 μg MF 
will be delivered over the 24 weeks with an average daily dose of 89 μg MF per subject (or 45 μg 
MF per nostril). The safety of LYR-210 (2500 μg) and LYR-210 (7500 μg) are supported by the 
extensive clinical and nonclinical data from existing marketed MF containing pharmaceutical 
products and medical devices, the non-clinical toxicology assessment of LYR-210, and the Phase I 
clinical study of LYR-210 (2500 μg) in adult CS subjects. 
9.1.1
Existing Non-clinical Safety Data
A significant amount of non-clinical data exists in the public domain to support the use of MF doses 
at the daily exposure levels expected from LYR-210 at either the 2500 μg or 7500 μg strength
dosage unit.  Non-clinical studies conducted to support Nasonex® (mometasone furoate monohydrate 
Nasal Spray 50 mcg) [18] and Asmanex® Twisthaler® (mometasone furoate Inhalation Powder, 110 
mcg, 220 mcg, Merck & Co., Inc) [17] are particularly relevant.  In both rats and dogs, observed 
effects were associated with well-defined pharmacological effects of glucocorticoids, with some 
progestational-like effects seen at the highest doses evaluated.  Carcinogenicity studies (mice and 
rats) were reported using nose-only inhalation with the no human risk of carcinogenicity identified 
for the therapeutic dose of MF.
Additionally, a comprehensive literature review was conducted for each of the polymers used as the 
inactive ingredients and the base structure in LYR-210.  All of these polymers are currently being 
used as components of approved pharmaceutical drugs and/or medical devices. A detailed summary 
of these studies is provided in the IB (Section 4.1 for more detail).
9.1.2
Nonclinical Toxicology Assessment of LYR-210
LYR-210 was placed in the maxillary sinus cavity of New Zealand White rabbits to evaluate in vivo 
drug release kinetics, and local and systemic toxicity. During the development of LYR-210,
preclinical drug matrices with various configurations and drug doses were tested in more than 110 
rabbits over various duration for up to 6 months.  Two studies that were most relevant to LYR-210
(2500 μg) and LYR-210 (7500 μg) human drug matrices are described below and a detailed 
summary of these studies is provided in the Investigator Brochure (IB, Section 4.2).
x
Study 1 is a 180-day non-GLP rabbit study in which a 3-months drug formulation
representative of the LYR-210 (2500 μg) in the first 3 months was assessed. The in vivo drug
release profile of LYR-210 was compared to that of in vitro. Local safety assessments were
performed at 28, 90 and 180 days compared to a drug-free depot (a “placebo” drug depot
without MF) by endoscopy and histopathology.
9.1.1
Existing Non-clinical Safety Da
D ta
A significant amount of non-clininical data ex
exisi ts in n the public domain to support the use of MF doses 
at the
h  daily exposure levels exp
xpected frfrom
om LYR-21
210 atat eitither ththe 2500 μg or
or 7500 μg strength
do
d sage unit.  Non- lclinic lal studidies
es conducted
ed to su
supp
ppor
ort t Na
Nasonex® (mometasone furoate monohydrate 
Nasal Spray 50 mcg) [18] and Asmanex® Tw
T isthaler® (mometasone furoate Inhalation Powder, 110 
mcg, 220 mcg, Merck & Co., Inc) [17] are particularly relevant.  In both rats and dogs, observed 
effects were associated with well-defined pharmacological effects of glucocorticoids, with some
progestational-like effects seen at the highest doses evaluated.  Carcinogenicityty studies (mice and 
rats) were reported using nose-only inhalation with the no human risk of carcinogenicity identified
ed 
for the therapeutic dose of MF.
Additionally, a comprehensive literature review was conducted for each of the polymers used as the
inactive ingredients and the base structure in LYR-210.  All of these polymers are currently being
used as components of approved pharmaceutical drugs and/or medical devices. A detailed summary 
of these studies is provided in the IB (Section 4.1 for more detail).
9.1.2
Nonclinical Toxicology Assessment of LYR-210
LYR-210 was placed in the maxillary sinus cavity of New Zealand White rabbits to evaluate in vivo 
drug release kinetics, and local and systemic toxicity. During the development of LYR-210,
preclinical drug matrices with various configurations and drug doses were tested in more than 110 
rabbits over various duration for up to 6 months.  Two studies that were most relevant to LYR-210
(2500 μg) and LYR-210 (7500 μg) human drug matrices are described below and a detailed 
summary of these studies is provided in the Investigator Brochure (IB, Section 4.2).
x
Study 1 is a 180-day non-GLP rabbit study in which a 3-months drug formulation
representative of the LYR-210 (2500 μg) in the first 3 months was assessed. The in vivo dr
drug
release profile of LYR-210 was compared to that of in vitro. Local safety asses
essm
smen
entst  werere
performed at 28, 90 and 180 days compared to a drug-free depot (a “placeb
e o”
o” drug depo
p t
without MF) by endoscopy and histopathology.

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x
Study 2 is a 28-day non-GLP rabbit study in which a 24-week drug release formulation fully
representative of the LYR 210 (7500 μg) human drug depot was assessed. The primary
purposes of the study were to compare the MF pharmacokinetics with Nasonex® over 28
days and assess the local and systemic toxicology of LYR 210 by a weekly nasal
examination and at the end of the 28 days for a change in intraocular pressure, a slit-lamp
examination for cataract, an endoscopy and histopathologic evaluation of sinus cavity, as
well as change of serum cortisol level.
The 180-day rabbit study assessed the rabbit drug depot with a control drug-free depot.
Histopathological sections were scored for inflammation, epithelial injury, and bone remodelling at 
days 28, 90, and 180.  The scoring system used ranged from 0 to 4, with 0 designating no findings 
while a value of 4 designated severe changes. 
Average scores for inflammation, epithelial injury and bone remodelling across days 28, 90 and 180 
are summarized in Table 4. All variables scores indicated minimal to mild changes with average 
values ranging between 1 and 2. At each time period where the drug or the drug-free matrices 
physically contacted the mucosa, there was evidence of focal attenuation or flattening of the 
respiratory epithelial layer, but the epithelium remained intact.  Focal bone remodelling at the 
depot/mucosal layer contact points was observed in some sinuses, but bone loss was not observed in 
either group.   
Table 4:
Sinus Histological Score Summary of the 180-Day Rabbit Study
Time 
Points
Testing Group (n)
Inflammation 
Score
(0-4 scale)
Epithelial Ulceration 
Score
(0-4 scale)
Bone Remodelling 
Score
(0-4 scale)
Day 28
Drug Free Depot (n=4)
1.50 ± 0.58
1.50 ± 0.58
1.75 ± 0.50
Drug Depot (n=4)
1.25 ± 0.50
1.50 ± 0.58
1.00 ± 0.00
Day 90
Drug Free Depot (n=5)
1.80 ± 0.84
1.40 ± 0.55
1.80 ± 0.45
Drug Depot (n=4)
1.00 ± 0.00
1.25 ± 0.50
2.00 ± 0.82
Day 180
Drug Free Depot (n=4)
2.00 ± 0.00
1.75 ± 0.50
1.00 ± 0.00
Drug Depot (n=4)
2.00 ± 0.00
1.25 ± 0.50
1.25 ± 0.50
n represents number of matrices; values are shown as mean ± standard deviation.
In the 28-day rabbit study, plasma MF concentrations measured over 28 days from both LYR-210
and NASONEX treated rabbits are shown in Figure 6. After LYR-210 placement, the mean MF 
concentrations measured from 6 rabbits peaked initially within the first 24 hours to be 105.6±25.5 
pg/mL and gradually decreased to 82.6±10.1 pg/mL by 48 hours. Beyond this time point, MF 
concentrations remained stable over the remaining duration of study with an average plasma drug 
concentration of 73 pg/mL from Day 1 to Day 28. These pharmacokinetics results confirmed a 
controlled and sustained release kinetics from LYR-210. Importantly, the plasma MF concentrations 
measured from this rabbit study closely match with the predicted values under steady-state using a 
one-compartment pharmacokinetic model and the in vitro drug release data. 
x
Study 2 is a 28-day non-GLP rabbit stutudy in which a 24-week drug release formulation fully
rerepr
pres
esen
entative of the LYR 210 (7500 μg
μg) huma
man drug depot was assessssed
ed. The primary
purposes of the study we
were to comparare ththe e MF
MF pharmacokinetics with Nasonex® over 28
days and assess the loca
c l and systemic toxicology y of LYR 210 by a weekly nasal
examination and at the end of the 28 days for a ch
change
ge in intraocular pressure, a slit-lamp
examination for cataractct, an
an endoscop
opy an
and hihiststop
opathologic evaluation of sinus cavity, as
well as change of serum cortisol lev
evel.
The 180-day rabbit study assessed the rabbit drug depot with a control drug-free depot.
Histopathological sections were scored for inflammation, epithelial injury, and bone remodelling at
days 28, 90, and 180.  The scoring system used ranged from 0 to 4, with 0 designating no findings
while a value of 4 designated severe changes.
Average scores for inflammation, epithelial injury and bone remodelling across days 28, 90 and 180 
are summarized in Table 4. All variables scores indicated minimal to mild changes with average 
values ranging between 1 and 2. At each time period where the drug or the dr
drug
ug-free matrices
physically contacted the mucosa, there was evidence of focal attenuation or flattening of the 
respiratory epithelial layer, but the epithelium remained intact.  Focal bone remodelling at the 
depot/mucosal layer contact points was observed in some sinuses, but bone loss was not observed in 
either group.   
Table 4:
Sinus Histological Score Summary of the 180-Day Rabbit Study
Time 
Points
Testing Group (n)
Inflammation 
Score
(0-4 scale)
Epithelial Ulceration
Score
(0-4 scale)
Bone Remodelling 
Score
(0-4 scale)
Day 28
Drug Free Depot (n=4)
1.50 ± 0.58
1.50 ± 0.58
1.75 ± 0.50
Drug Depot (n=4)
1.25 ± 0.50
1.50 ± 0.58
1.00 ± 0.00
Day 90
Drug Free Depot (n=5)
1.80 ± 0.84
1.40 ± 0.55
1.80 ± 0.45
Drug Depot (n=4)
1.00 ± 0.00
1.25 ± 0.50
2.00 ± 0.82
Day 180
Drug Free Depot (n=4)
2.00 ± 0.00
1.75 ± 0.50
1.00 ± 0.00
Drug Depot (n=4)
2.00 ± 0.00
1.25 ± 0.50
1.25 ± 0.50
n represents number of matrices; values are shown as mean ± standard deviation.
In the 28-day rabbit study, plasma MF concentrations measured over 28 days from both LYR-210
and NASONEX treated rabbits are shown in Figure 6. After LYR-210 placement, the mean MF 
concentrations measured from 6 rabbits peaked initially within the first 24 hours to be 105.6±25.5 
pg/mL and gradually decreased to 82.6±10.1 pg/mL by 48 hours. Beyond this time point, MF
concentrations remained stable over the remaining duration of study with an average plasma drug 
concentration of 73 pg/mL from Day 1 to Day 28. These pharmacokinetics results confirmed a
controlled and sustained release kinetics from LYR-210. Importantly, the plasma MF concentratioions 
measured from this rabbit study closely match with the predicted values under steady-state using a
one-compartment pharmacokinetic model and the in vitro drug release data. 

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Figure 6:
Comparison of Plasma MF Concentration of LYR 210 and Nasonex® over 28 
Days
N=6 animals for all data points representing LYR 210, except for N = 3 animals for time points between baseline and the first 24 
hours. N=6 animals at baseline and N=3 animals for all other data points representing Nasonex. Data represents mean ± standard
deviation.
Safety assessments of potential local and systemic effects of LYR-210 indicated the drug matrices
were well tolerated. As expected, LYR-210 affected some clinical pathology parameters (e.g., 
cholesterol, triglycerides, and creatinine) and serum cortisol concentrations with these changes 
associated with the initial release of MF into the systemic circulation. However, it is also possible 
that stress associated with surgery could have contributed to some of the observed systemic changes. 
The nasal and ophthalmological examination results indicated that LYR-210 did not cause local
adverse effects to the nasal passages and the eyes. Similar to the 180-day study, histopathology 
evaluation of the maxillary sinuses indicated no concern of local sinus tissue toxicity (Table 5).
Table 5.
Sinus Histological Score Summary of the 28-day Study
Description (n)
Day
Inflammation Score
(0-4 scale)
Epithelial Ulceration 
Score
(0-4 scale)
Bone Remodelling 
Score
(0-4 scale)
Rabbit Drug Depot
(n = 12)
28
0.67 ± 0.49
0.33 ± 0.65
1.42 ± 0.90
n represents number of drug matrices; values are presented as mean ± standard deviation.
Figure 6:
Comparison of Plasma MF Co
C ncentrtration of LYR 210 and Nasonex® over 28
Days
N=6 animals for all data points representing LYR 210, except for N = 3 animals for time points between baseline and the first 24 
hours. N=6 animals at baseline and N=3 animals for all other data points representing Nasonex. Data represents mean ± standard
deviation.
Safety assessments of potential local and systemic effects of LYR-210 indicated the drug matrices
were well tolerated. As expected, LYR-210 affected some clinical pathology parameters (e.g., 
cholesterol, triglycerides, and creatinine) and serum cortisol concentrations with these changes 
associated with the initial release of MF into the systemic circulation. However, it is also possible 
that stress associated with surgery could have contributed to some of the observed systemic changes. 
The nasal and ophthalmological examination results indicated that LYR-210 did not cause local
adverse effects to the nasal passages and the eyes. Similar to the 180-day study, histopathology
evaluation of the maxillary sinuses indicated no concern of local sinus tissue toxicity (Table 5).
Table 5.
Sinus Histological Score Summary of the 28-day Study
Description (n)
Day
Inflammation Score
(0-4 scale)
Epithelial Ulceration
Score
(0-4 scale)
Bone Remodelling 
Score
(0
(0-4 sc
scala e)
Rabbit Drug Depot
(n = 12)
28
0.67 ± 0.49
0.33 ± 0.65
1.42 ± 0.90
n rerepresents number of drug matrices; values are presented as mean ± standard deviation.

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9.1.3
Phase I Clinical Study of LYR-210 (2500 μg) 
LYR-210 (2500 μg) was evaluated in an open-label Phase I clinical study (clinicaltrials.gov ID: 
NCT02967731) in 20 adult CS subjects who had failed medical management and were deemed 
candidates for ESS. Each subject received bilateral placement of LYR-210 (2500 μg) for up to 24 
weeks. The study results published in January 2019 in Int Forum Allergy Rhinol. [34]. A brief 
summary of the Phase I clinical study is provided here, and more details can be found in Section 5 of 
the IB.
The Phase I study concluded that LYR-210 (2500 μg) is safe and well-tolerated in ESS-naïve CS 
subjects and leads to sustained symptom improvement in subjects. Specifically, there was no product 
related serious adverse event reported. No local nasal adverse events (AEs), including epistaxis, 
nasal burning, nasal dryness, nasal irritation, and nasal septal perforation, were reported.  No subject 
had intraocular hypertension (IOP >21 mmHg) and no AEs indicative of high IOP were reported.  
Mean changes from baseline over time in morning serum cortisol levels were minimal and not 
statistically significant. No AEs indicative of adrenal insufficiency were reported.  These results 
indicated low level of systemically circulated steroid from LYR-210 (2500 μg).  
The MF plasma concentrations were monitored in all 20 subjects at baseline (before administration) 
and 1 hour, 1 week, 4 weeks, and 12 weeks post bilateral administration of LYR-210 (2500 μg).  The 
plasma concentrations of MF were undetectable in about 50% subjects and near the lower limit of 
quantification (LLOQ, 20 pg/mL) in the other 50% subjects through a period of 12 weeks post LYR-
210 (2500 μg) administration (Table 6).
Table 6:
Number of Subjects with Plasma MF Concentration < or ≥ 20 pg/mL (ITT 
Population)
MF plasma concentration
Number of subjects
Baseline
1 hour
1 week
4 weeks
12 weeks
< 20 pg/mL (LLOQ)
20
11
10
16
10
t 20 but < 35 pg/mL
0
9
10
4
10
LLOQ=lower limit of quantification.
Thirty-five drug matrices were collected after removal or dislodgement and tested for remaining MF 
in the depot. Shown in Figure 7 is the percentage of MF released at the time of LYR-210
dislodgement or removal. This result confirmed controlled and sustained drug release of the MF over 
the 24 weeks of treatment duration that is characterized by a near linear drug release kinetics.
9.1.3
Phase I Clinical Study of LYR-210 (2
(2500 μg) 
LYR-210 (2500 μg) was evalua
uated in an op
open
en-lalabe
be
b l Ph
Phase
s I clinical study (clinicaltrials.gov ID: 
NC
NCT02967731) in 20 adult CS subjectsts who
ho had f iailed d medical manageme tnt and were deemed 
candidates for ESS. Each subjectct received d bibilateraral l plplac
acem
ement of LYR-210 (2500 μg) for up to 24 
we
weeks. The study results publblisished in Janua
u ry 2019 in In
Int Forum Allergy Rhinol. [34]. A brief 
summary of the Phase I clinical study is provided here, and more details can be found in Section 5 of 
the IB.
The Phase I study concluded that LYR-210 (2500 μg) is safe and well-tolerated in ESS-naïve CS 
subjects and leads to sustained symptom improvement in subjects. Specifically, there was no product
related serious adverse event reported. No local nasal adverse events (AEs), including epistaxis, 
nasal burning, nasal dryness, nasal irritation, and nasal septal perforation, were reported.  No subject 
had intraocular hypertension (IOP >21 mmHg) and no AEs indicative of high IOP were reported.  
Mean changes from baseline over time in morning serum cortisol levels were minimal and not 
statistically significant. No AEs indicative of adrenal insufficiency were reported.  These results
indicated low level of systemically circulated steroid from LYR-210 (2500 μg).  
The MF plasma concentrations were monitored in all 20 subjects at baseline (before administration) 
and 1 hour, 1 week, 4 weeks, and 12 weeks post bilateral administration of LYR-210 (2500 μg).  The 
plasma concentrations of MF were undetectable in about 50% subjects and near the lower limit of 
quantification (LLOQ, 20 pg/mL) in the other 50% subjects through a period of 12 weeks post LYR-
210 (2500 μg) administration (Table 6).
Table 6:
Number of Subjects with Plasma MF Concentration < or ≥ 20 pg/mL (ITT
Population)
MF plasma concentration
Number of subjects
Baseline
1 hour
1 week
4 weeks
12 weeks
< 20 pg/mL (LLOQ)
20
11
10
16
10
t 20 but < 35 pg/mL
0
9
10
4
10
LLOQ=lower limit of quantification.
Thirty-five drug matrices were collected after removal or dislodgement and tested for remaining MF
MF
in the depot. Shown in Figure 7 is the percentage of MF released at the time of LYR-21
210
did sls odgement or removal. This result confirmed controlled and sustained drug relea
e se
se of the MF
M over 
ththt e e 24 weeks of treatment duration that is characterized by a near linear drug relea
ease kininetics.

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Figure 7:
In Vitro and In Vivo Percentage of Release of MF in LYR-210 (2500 μg) Over 
Time
In vitro data represents mean ± standard deviation. N=3 samples at each time point for in vitro data. Dashed lines 
represent linear regression fitting to guide the eyes.
The in vitro drug dissolution studies were conducted by submerging the drug matrices in a pH 7.4 
PBS with 2% SDS solution at 37 qC that provided infinite drug sink conditions.  The in vitro drug
dissolution profile (also shown in Figure 7) indicates that, although the in vitro drug release rate is 
faster than that of in vivo, the MF release from LYR-210 (2500 μg) follows near linear kinetics, 
which is in line with the Phase I clinical results. The in vitro drug release rate is approximately twice 
the rate of the in vivo drug release rate measured from the Phase I clinical study. This is expected, as 
in the Phase I clinical study, LYR-210 (2500 μg) was placed in the middle meatus of nasal cavity 
and only exposed to a moderately humid environment with a surrounding temperature up to 34 qC
[35]. The established in vitro-in vivo correlation enables the projection of an in vivo drug release 
profile from an in vitro profile.
Based on the in vivo drug release profile, bilateral placement of LYR-210 (2500 μg) delivers 
approximately an average of 30 μg MF per day over a period of 24 weeks.  While LYR-210 (2500 
μg) follows a substantially linear drug release profile, the corresponding in vitro cumulative drug 
release can be described as a combination of zero-order and first-order release kinetics using 
Equation (1).
ܯܨ ܴ݈݁݁ܽݏ݁݀% = ቂݔ
௞బ
஽బݐ+ (1 −ݔ)(1 −݁ି௞ೌ௧)ቃ× 100%
(1)
Figure 7:
In Vitro and In Vivo Percentage of Re
Release of MF in LYR-210 (2500 μg) Over 
Time
In vitro data represents mean ± standard deviation. N=3 samples at each time point for in vitro data. Dashed lines 
represent linear regression fitting to guide the eyes.
The in vitro drug dissolution studies were conducted by submerging the drug matrices in a pH 7.4
PBS with 2% SDS solution at 37 qC that provided infinite drug sink conditions.  The in vitro drug
dissolution profile (also shown in Figure 7) indicates that, although the in vitro drug release rate is 
faster than that of in vivo, the MF release from LYR-210 (2500 μg) follows near linear kinetics, 
which is in line with the Phase I clinical results. The in vitro drug release rate is approximately twice 
the rate of the in vivo drug release rate measured from the Phase I clinical study. This is expected, as 
in the Phase I clinical study, LYR-210 (2500 μg) was placed in the middle meatus of nasal cavity
and only exposed to a moderately humid environment with a surrounding temperature up to 34 qC
[35]. The established in vitro-in vivo correlation enables the projection of an in vivo drug release 
profile from an in vitro profile.
Based on the in vivo drug release profile, bilateral placement of LYR-210 (2500 μg) delivers 
approximately an average of 30 μg MF per day over a period of 24 weeks.  While LYR-210 (2500
μg) follows a substantially linear drug release profile, the corresponding in vitro cumulative drug
release can be described as a combination of zero-order and first-order release kinetics using 
Equation (1).
ܯܨܴ݈݁݁ܽݏ݁݀% = ቂݔ
௞బ
஽బݐ+ (1 −ݔ)(1 −݁ି௞ೌ௧)ቃ× 100%
(1)

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Where ܦ଴ is the total drug dose in the depot (i.e. 2500 μg herein), ݇଴ the zero-order drug release rate
constant, ݇௔ the first-order drug release rate constant, ݔ the fractional factor of zero-order drug
release.
The drug concentration in plasma can therefore be estimated using a simple one-compartment 
pharmacokinetic model shown below (Equation (2)):
݈ܲܽݏ݉ܽ ܯܨ ܿ݋݊ܿ݁݊ݐݎܽݐ݅݋݊=
ଶ௫௞బᇲி
௞௏ವ(1 −݁ି௞௧) +
ଶ(ଵି௫)௞ೌᇲ஽బி
(௞ೌᇲି௞)௏ವ൫݁ି௞௧−݁ି௞ೌᇲ௧൯
(2)
where ݇଴
ᇱ(0.505 μg/h for LYR-210 (2500 μg)) and ݇௔ᇱ(3.71x10-3 h-1 for LYR-210 (2500 μg)) are
respectively the projected in vivo zero-order and first-order drug release rate constants, ݔthe 
fractional factor of zero-order drug release (0.919 for LYR-210 (2500 μg)), ܨthe fraction of drug 
absorption (0.8 herein), ݇the elimination rate constant (0.1195 h-1, estimated from reference [18]), ܸ஽
the volume of distribution at the steady state (418 L h-1, estimated from reference [36]), ܦ଴the dose of
a single depot (2500 μg herein), ݐthe time.  Based on this pharmacokinetic model, it can be 
estimated that the systemic MF concentration of LYR-210 (2500 μg) under steady state is 
approximately 15.2 pg/mL, which closely matches the Phase I clinical study result as shown in Table
6 and validated the pharmacokinetics modeling.
9.1.4
Systemic and Local Dose Safety of LYR-210 (7500 μg) 
9.1.4.1
Systemic Safety
Lyra Therapeutics has conducted drug dissolution studies to assess the in vitro drug release profile of 
LYR-210 (7500 μg) and modeled its pharmacokinetics as described above. LYR-210 (7500 Pg) has 
a comparable in vitro drug dissolution profile to LYR-210 (2500 μg) (i.e. combination of zero-order
and first-order drug release kinetics but with more contribution from the latter, Figure 8).  Bilateral 
placement of LYR-210 (7500 μg) will deliver an average of 89 μg MF per day per subject over a 
period of 24 weeks.  Using the same pharmacokinetic model (Equation (2)) and a ݇଴
ᇱof 1.200 μg/h ,  
݇௔ᇱof 1.23x10-3 h-1, and ݔof 0.738 that are derived from curve-fitting in Figure 8, it is estimated that 
the bilateral administration of LYR-210 (7500 μg) would result in a plasma MF concentration of 
approximately 38.4 pg/mL at the steady state. 
Where ܦ଴is the total drug dose in the depot (i.e. 2500
00 μg herein), ݇଴the zero-order drug release rate
constant, ݇௔the first
f
-order drug
ug release ratate cons
nstatant, ݔthe fractional
f
factor of zero-order drug
release.
Th
The drug concentration in plasma can therefefore be
be estim
imatated using a simple one-compartment 
pharmacokinetic model shown below (Equation (2)):
݈ܲܽݏ݉ܽܯܨܿ݋݊ܿ݁݊ݐݎܽݐ݅݋݊=
ଶ௫௞బᇲி
௞௏ವ(1 −݁ି௞௧) +
ଶ(ଵି௫)௞ೌᇲ஽బி
(௞ೌᇲି௞)௏ವ൫݁ି௞௧−݁ି௞ೌᇲ௧൯
(2)
where ݇଴
ᇱ(0.505 μg/h for LYR-210 (2500 μg)) and ݇௔ᇱ(3.71x10-3 h-1 for LYR-210 (2500 μg)) are
respectively the projected in vivo zero-order and first-order drug release rate constants, ݔthe
fractional factor of zero-order drug release (0.919 for LYR-210 (2500 μg)), ܨthe fraction of drug
absorption (0.8 herein), ݇the elimination rate constant (0.1195 h-1, estimated from reference [18]), ܸ஽
ܸ
the volume of distribution at the steady state (418 L h-1, estimated from reference [36]), ܦ଴the dose of
a single depot (2500 μg herein), ݐthe time.  Based on this pharmacokinetic model, it can be 
estimated that the systemic MF concentration of LYR-210 (2500 μg) under steady state is
approximately 15.2 pg/mL, which closely matches the Phase I clinical study result as shown in Table
6 and validated the pharmacokinetics modeling.
9.1.4
Systemic and Local Dose Safety of LYR-210 (7500 μg) 
9.1.4.1
Systemic Safety
Lyra Therapeutics has conducted drug dissolution studies to assess the in vitro drug release profile of 
LYR-210 (7500 μg) and modeled its pharmacokinetics as described above. LYR-210 (7500 Pg) has
a comparable in vitro drug dissolution profile to LYR-210 (2500 μg) (i.e. combination of zero-order
and first-order drug release kinetics but with more contribution from the latter, Figure 8).  Bilateral
placement of LYR-210 (7500 μg) will deliver an average of 89 μg MF per day per subject over a
period of 24 weeks.  Using the same pharmacokinetic model (Equation (2)) and a ݇଴
ᇱof 1.200 μg/h h , 
݇௔ᇱof 1.23x10-3 h-1, and ݔof 0.738 that are derived from curve-fitting in Figure 8, it is estimated that
the bilateral administration of LYR-210 (7500 μg) would result in a plasma MF concentration of 
ap
approximately 38.4 pg/mL at the steady state. 

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Figure 8:
In vitro Cumulative Percentage of Release of MF from LYR-210 (7500 μg) Over 
Time
In vitro data represents mean ± standard deviation. N=9 samples at each time point. Hollow symbols represent the best 
fitting of in vitro release data using Equation (1).
This estimated systemic exposure of LYR-210 (7500 μg) is higher than that of Nasonex®, expected 
due to the low bioavailability of the latter (< 1%).  However, the Cmax value of LYR-210 (7500 μg) 
is estimated to be significantly lower than that of the approved dose of Asmanex® Twisthaler® (400
μg, BID); and the AUC24h is comparable to that of Asmanex® Twisthaler® (400 μg, BID).  
Moreover, a 5-day clinical study on a higher dose of Asmanex® Twisthaler® (800 μg, BID) indicated 
that this dose of MF was also safe and well-tolerated and did not cause clinically significant effects 
on clinical laboratory test results or on vital signs [37], although its systemic exposure is 4-fold higher 
than the projected average exposure of LYR-210 (7500 μg).  These data further support the systemic 
safety of LYR-210 (7500 μg).
Table 7:
Comparison of Systemic Exposure of LYR-210 (7500 μg) with Clinical Studies 
showing Systemic Safety of Chronic Use of MF Products
Drug product
Dose (Pg)
Cmax
(pg/mL)
AUC (Duration) 
(pg h/mL)
AUC24h
(pg h/mL)*
References
Nasonex
200 QD
5.77
29.6 (12 h)
29.6
Nasonex [18]
800 TID
25.5
64 (8 h)
192
Daley-Yates 2004 [38]
Asmanex
Twisthaler
400 BID
114
634 (12 h)
1268
Asmanex Twisthaler [39]
400 BID
90.2
646 (12 h)
1292
Kosoglou 2013 [40]
800 BID
383
2820 (12 h)
5640
Kosoglou 2014 [37]
LYR-210
15000 / 24 
95
175518 (168 d)
1045
Lyra Therapeutics 
Figure 8:
In vitro Cumulative Percentage
g  of Re
Relelease of MF from LYR-210 (7500 μg) Over 
Time
In vitro data represents mean ± standarard deviation. N=
N=9 samples at each time point. Hollow symbols represent the best 
fitting of in vitro release data using Equation (1).
Th
This estimated syste i
mic exposure of LY
LYR-210 (750
5 0 μg
μg) is higher ththan that of Nasonex®, expected 
due to the low bioavailability of the latter (< 1%).  Howeve
ver, the Cmax value of LYR-210 (7500 μg) 
is estimated to be significantly lower than that of the approved dose of Asmanex® Twisthaler® (400
μg, BID); and the AUC24h is comparable to that of Asmanex® Twisthaler® (400 μg, BID).  
Moreover, a 5-day clinical study on a higher dose of Asmanex® Twisthaler® (800 μg, BID) indicated d 
that this dose of MF was also safe and well-tolerated and did not cause clinically significant effects
on clinical laboratory test results or on vital signs [37], although its systemic expo
p sure is 4-fold higher 
than the projected average exposure of LYR-210 (7500 μg).  These data further support the systemic 
safety of LYR-210 (7500 μg).
Table 7:
Comparison of Systemic Exposure of LYR-210 (7500 μg) with
th Clinical Studies
showing Systemic Safety of Chronic Use of MF Products
Drug product
Dose (Pg)
Cmax
(pg/mL)
AUC (Duration) 
(pg h/mL)
AUC24h
(pg h/mL)*
References
Nasonex
200 QD
5.77
29.6 (12 h)
29.6
Nasonex [18]
800 TID
25.5
64 (8 h)
192
Daley-Yates 2004 [38]
Asmanex
Twisthaler
400 BID
114
634 (12 h)
1268
Asmanex Twisisththalalerer [39
[39]
400 BID
90.2
646 (12 h)
1292
Kosoglou 2013 [40]
800 BID
383
2820 (12 h)
5640
Kosoglglou 201
0 4 [37]
LYR-210
15000 / 24 
95
175518 (168 d)
d
1045
Lyra Therapeutics

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(7500 μg)
weeks
estimated value
QD=once a day, BID= twice a day, TID = three times a day, h = hour, PI=prescription information.
* AUC24h was obtained by normalizing the literature reported AUC to the respective dosing schedule.
9.1.4.2
Local Safety 
Topical administration of LYR-210 (7500 μg) over a treatment duration of 24 weeks is also 
anticipated to be safe to local nasal tissue supported by the long-term clinical use of Nasonex®.
Summarized in Table 8 are clinical studies showing local tissue safety of high dose and/or long-term 
intranasal use of MF in the form of nasal sprays or nasal implants. Based on these data, it can be 
expected that bilateral placement of LYR-210 (7500 μg) with 15,000 Pg MF delivered over 24 
weeks, with an average daily dose of approximately 89 Pg MF per human subject, or 45 Pg MF per 
nostril, is not expected to cause adverse effects on the nasal mucosa or an elevation of intraocular 
pressure. 
Table 8:
Summary of Clinical Studies showing Local Tissue Safety of Chronic Intranasal 
use of Mometasone Furoate
References
Study Design
Condition & 
Number of 
Subjects in MF 
Treatment 
Group
MF Drug Form, Dose, 
and Duration
Safety Outcome
Local Tissue safety -Nasal Mucosa
Minshall, 
1998 [41]
Multicenter, 
open label study
Adult subject
diagnosed with 
PAR, N=52
MFNS 100 mcg QD in 
each nostril for 12 
months
No adverse tissue changes 
in nasal mucosa in nasal 
biopsies.
Fokkens, 
2012 [2]
Randomized, 
active-
controlled, open 
label study 
Adult subjects
diagnosed with 
PAR, N=42
MFNS 100 mcg QD in 
each nostril for 12 
months
No appreciable change in 
epithelial thickness, the 
percentage of goblet cells 
in nasal biopsies.
Local Tissue safety -Eyes
Bross-
Soriano, 
2004 [42]
Double-blind, 
placebo and 
active-controlled
Adult subjects
diagnosed with 
rhinitis regardless 
of its etiology, 
N=90 
MFNS 100 mcg QD in 
each nostril for 12 
months
No clinically significant 
change to intraocular 
pressure.
Forwith 
2011 [22]
Multicenter, 
open-label
CS subject
underwent 
bilateral ESS, 
N=50
PROPEL implant (MF 
370 mcg) in each 
ethmoid sinus over 30 
days
No clinically significant 
change from baseline to 
intraocular pressure and 
lens opacity.
Marple, 
2012 [23]
Multicenter, 
intra-subject
placebo-
controlled
CS subject
underwent 
bilateral ESS, 
N=105
PROPEL implant (MF 
370 mcg) in one ethmoid 
sinus and a non-drug-
releasing depot in the 
other ethmoid sinus over 
30 days
No clinically significant 
change from baseline to 
intraocular pressure.
(7500 μg)
weeks
estimated value
QD=onc
nce a da
day, BID= twice a day, TID = three times
es a day, h = hour, PI=prescription informatatioion.
* AUC24h was obtained by normalizining the literaturere repor
orteted AU
AU
AUC to the respective dosing schedule.
9.1.
1 4.2
Local Safety 
Topical administration of LYR-21
210 (7500 μg
μg) overer a trereatatme
m nt duration of 24 weeks is also
an
anticipated to be safe to local na
nasal tissue sup
u ported by the long-term clinical use of Nasonex®.
Summarized in Table 8 are clinical studies showing local tissue safety of high dose and/or long-term
intranasal use of MF in the form of nasal sprays or nasal implants. Based on these data, it can be
expected that bilateral placement of LYR-210 (7500 μg) with 15,000 Pg MF delivered over 24
weeks, with an average daily dose of approximately 89 Pg MF per human subject, or 45 Pg MF per 
nostril, is not expected to cause adverse effects on the nasal mucosa or an elevation of intraocular 
pressure. 
Table 8:
Summary of Clinical Studies showing Local Tissue Safety of Chronic Intranasal 
use of Mometasone Furoate
References
Study Design
Condition & 
Number of 
Subjects in MF 
Treatment 
Group
MF Drug Form, Dose,
and Duration
Safety Outcome
Local Tissue safety -Nasal Mucosa
Minshall, 
1998 [41]
Multicenter,
open label study
Adult subject
diagnosed with 
PAR, N=52
MFNS 100 mcg QD in 
each nostril for 12 
months
No adverse tissue changes
in nasal mucosa in nasal 
biopsies.
Fokkens, 
2012 [2]
Randomized, 
active-
controlled, open 
label study 
Adult subjects
diagnosed with 
PAR, N=42
MFNS 100 mcg QD in 
each nostril for 12 
months
No appreciable change in
epithelial thickness, the
percentage of goblet cells
in nasal biopsies.
Local Tissue safety -Eyes
Bross-
Soriano,
2004 [42]
Double-blind, 
placebo and 
active-controlled
Adult subjects
diagnosed with 
rhinitis regardless
of its etiology, 
N=90 
MFNS 100 mcg QD in 
each nostril for 12 
months
No clinically significant 
change to intraocular 
pressure.
Forwith 
2011 [22]
Multicenter,
open-label
CS subject
underwent 
bilateral ESS, 
N=50
PROPEL implant (MF
370 mcg) in each 
ethmoid sinus over 30 
days
No clinically significant 
change from baseline to 
intraocular pressure and 
lens opacity.
Marple, 
2012 [23]
Multicenter,
intra-subject
placebo-
controlled
CS subject
underwent 
bilateral ESS, 
N=105
PROPEL implant (MF
370 mcg) in one ethmoid 
sinus and a non-drug-
releasing depot in the 
other ethmoid sinus over 
30 days
No clinically significant 
change from baseline to 
intraocular pressurere.

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Han, 2014 
[24]
Randomized, 
sham-controlled, 
subject blinded
CRSwNP subject
with prior ESS, 
N=100
One SINUVA implant
(MF 1350 mcg) for 60 
days in conjunction with 
MFNS 100 mcg QD in 
each nostril for 90 days
No clinically significant 
increases in intraocular 
pressure or cataract 
formation.
MFNS=mometasone furoate nasal spray, QD=once a day, SAR= seasonal allergic rhinitis, PAR= perennial 
allergic rhinitis, ESS= ethmoid sinus surgery, CS=chronic sinusitis, CRSwNP=chronic rhinosinusitis with nasal 
polyps
9.1.5
Product Safety Rationale Conclusion
In summary, both LYR-210 (2500 μg) and LYR-210 (7500 μg) release the drug in zero-order 
kinetics over 24 weeks in vivo.  Bilateral placement of LYR-210 (2500 μg) and LYR-210 (7500 μg) 
will deliver an average daily dose of 30 μg and 89 μg MF per human subject, or 15 μg and 45 μg 
MF per nostril, respectively.  Based on literature review and Lyra Therapeutics’ non-clinical
toxicology assessments and Phase I clinical results, these two doses of LYR-210 are expected to be 
safe regarding both local and systemic safety in the proposed Phase II clinical study.
9.2
Anticipated Risks
Lyra Therapeutics has completed a risk analysis and all identified risks have been mitigated to the 
fullest extent possible. Potential expected adverse reactions (ARs) to the subject are similar to those 
associated with endoscopy procedures and current therapies using local or systemic delivery of MF 
that is utilized in several commercially approved MF drug products (Nasonex® [18], Asmanex®
Twisthaler® [39], and Sinuva™ [43]) to treat chronic sinusitis with nasal polyps and respiratory 
diseases. 
9.2.1
Expected ARs Associated with Endoscopic Procedures and LYR-210
Administration/Removal
LYR-210 is inserted into the middle meatus at the drug administration and removed from the middle 
meatus at the end of treatment using minimally invasive endoscopic techniques. The risks associated 
with any general endoscopic procedures (within 24 hours of procedure) are relevant to the 
administration or removal of the LYR-210. The possible expected ARs and the highest incidence 
rates reported in clinical studies of similar products and/or LYR-210 Phase I study that are related to 
endoscopic procedures are summarized in Table 9.
Table 9:
Summary of Expected ARs Associated with LYR-210 Administration or 
Removal Procedure
Incidence rate >5% and ≤ 10%
Procedural headache
Incidence rate >0% and ≤ 5%
Han, 2014 
[24]
Randomized, 
sh
s am-controlled, 
subject blinded
CRSwNP subjec
ect
with prior ESS, 
N=
N 100
One SI
SINU
NUVA implant
(MF 13
1350 mcg) for 60 
da
days in n conjunction with 
MF
M NS 100
00 mcg QD in 
each nostril for 90 days
No clinically significant 
increases inin intraocular 
pressure or cataract 
formation.
MFNS=mometasone furoate nasal spray, QD=once a day, SAR=
R= seasonal allergic rhinitis, PAR= perennial
allergic rhinitis, ESS= ethmoid sinus surgery, CS=chronic sinusitis,s, CRSwNP=chronic rhinosinusitis with nasal 
polyps
9.1.5
Product Safety Rationale Conclusion
In summary, both LYR-210 (2500 μg) and LYR-210 (7500 μg) release the drug in zero-order 
kinetics over 24 weeks in vivo.  Bilateral placement of LYR-210 (2500 μg) and d LY
LYR-210 (7500 μg) 
will deliver an average daily dose of 30 μg and 89 μg MF per human subject, or 15 μg and 45 μg 
MF per nostril, respectively.  Based on literature review and Lyra Therapeutics’ non-clinical
toxicology assessments and Phase I clinical results, these two doses of LYR-210 are expected to be
safe regarding both local and systemic safety in the proposed Phase II clinical study.
9.2
Anticipated Risks
Lyra Therapeutics has completed a risk analysis and all identified risks have been mitigated to the
fullest extent possible. Potential expected adverse reactions (ARs) to the subject are similar to those 
associated with endoscopy procedures and current therapies using local or systemic delivery of MF 
that is utilized in several commercially approved MF drug products (Nasonex® [18], Asmanex®
Twisthaler® [39], and Sinuva™ [43]) to treat chronic sinusitis with nasal polyps and respiratory 
diseases. 
9.2.1
Expected ARs Associated with Endoscopic Procedures and LYR-210
Administration/Removal
LYR-210 is inserted into the middle meatus at the drug administration and removed from the middle
meatus at the end of treatment using minimally invasive endoscopic techniques. The risks associated 
with any general endoscopic procedures (within 24 hours of procedure) are relevant to the
administration or removal of the LYR-210. The possible expected ARs and the highest incidence 
rates reported in clinical studies of similar products and/or LYR-210 Phase I study that are related to 
endoscopic procedures are summarized in Table 9.
Table 9:
Summary of Expected ARs Associated with LYR-210 Administration or
Removal Procedure
Incidence rate >5% and ≤ 10%
Procedural headache
Incidence rate >0% and ≤ 5%

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Dizziness
Epistaxis (moderate)
Facial pain
Nasal congestion
Nasal discomfort
Parosmia
Post procedural discomfort
Presyncope
Rare events without incidence rates reported but potential to endoscopy procedure
Nasopharyngitis
Pharyngitis
9.2.2
Expected ARs Associated with Mometasone Furoate or Nasal Implant
The possible expected ARs and the highest incidence rates reported in clinical studies of MF drug 
products (Nasonex® [18], Asmanex® Twisthaler® [39], and Sinuva™ [44]) and/or LYR-210 Phase I 
study are summarized in Table 10.
Table 10:
Summary of Expected ARs Associated with Mometasone Furoate
Incidence rate > 40% and ≤ 60%
Headache
Rhinitis 
Upper respiratory tract infection
Viral Infection
Incidence rate > 20% and ≤ 40%
Candidiasis
Epistaxis/blood-tinged mucus
Musculoskeletal pain
Pharyngitis
Incidence rate > 10% and ≤ 20%
Alteration of HPA axis (endocrine)
Arthralgia (joint pain)
Back pain
Coughing
Dysmenorrhea
Dyspepsia (indigestion)
Dysphonia
Earache
Fatigue
Flu-like symptoms
Nasal congestion
Nasal odor
Nasal Pharyngitis
Sinusitis 
Incidence rate > 5% and ≤ 10%
Abdominal pain
Diarrhea
Dizziness
Epista ixis (m
(moderate)
Facial pain
Nasal congestion
Nasal discomfort
Parosmia
Post procedural discomfort
Presyncope
Rare events without incidence rates reported but potential to endoscopy procedure
Nasopharyngitis
Pharyngitis
9.2.2
Expected ARs Associated with Mometasone Furoate or Nasal Implant
The possible expected ARs and the highest incidence rates reported in clinical studies of MF drug
products (Nasonex® [18], Asmanex® Twisthaler® [39], and Sinuva™[44]) and/or LYR-210 Phase I 
study are summarized in Table 10.
Table 10:
Summary of Expected ARs Associated with Mometasone Furoate
Incidence rate > 40% and ≤ 60%
Headache
Rhinitis 
Upper respiratory tract infection
Viral Infection
Incidence rate > 20% and ≤ 40%
Candidiasis
Epistaxis/blood-tinged mucus
Musculoskeletal pain
Pharyngitis
Incidence rate > 10% and ≤ 20%
Alteration of HPA axis (endocrine)
Arthralgia (joint pain)
Back pain
Coughing
Dysmenorrhea
Dyspepsia (indigestion)
Dysphonia
Earache
Fatigue
Flu-like symptoms
Nasal congestion
Nasal odor
Nasal Pharyngitis
Sinusitis
Incidence rate > 5% and ≤ 10%
Abdominal pain
Diarrhea

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Facial Pain
Flatulence
Lower respiratory tract infection
Menstrual disorder
Myalgia (muscle pain)
Nasal discomfort
Nausea
Pain
Rhinorrhea
Sinus congestion
Sneezing
Incidence rate >0% and ≤ 5%
Abnormal hepatic function
Adverse drug reaction (rash)
Catarrh
Chest pain
Conjunctivitis
Dizziness
Dry throat
Ear infection
Edema
Gastroenteritis
Hypertension
Insomnia
Nasal burning
Nasal dryness
Nasal irritation
Parosmia
Presyncope
Pruritus
Pyrexia (fever)
Rhinalgia (nose pain)
Tooth ache
Urinary tract infection
Vomiting
Rare events without incidence rates reported but potential to corticosteroids or 
biodegradable implants
Cataract
Glaucoma
Impaired local wound healing
Nasal ulcer (mucosal erosion, ulceration, perforation)
Reduced bone mineral density
Septum perforation
Sinus perforation
Susceptibility to infection
Swallowing or aspiration of implant or fragments 
Facial Pain
Flatatululen
ence
ce
Lower respiratory tract infection
Menstrual disorder
Myalgia (muscle pain)
Nasal discomfort
Nausea
Pain
Rhinorrhea
Sinus congestion
Sneezing
Incidence rate >0% and ≤ 5%
Abnormal hepatic function
Adverse drug reaction (rash)
Catarrh
Chest pain
Conjunctivitis
Dizziness
Dry throat
Ear infection
Edema
Gastroenteritis
Hypertension
Insomnia
Nasal burning
Nasal dryness
Nasal irritation
Parosmia
Presyncope
Pruritus
Pyrexia (fever)
Rhinalgia (nose pain)
Tooth ache
Urinary tract infection
Vomiting
Rare events without incidence rates reported but potential to corticosteroids or 
biodegradable implants
Cataract
Glaucoma
Impaired local wound healing
Nasal ulcer (mucosal erosion, ulceration, perforation)
Reduced bone mineral density
Septum perforation
Sinus perforation
Susceptibility to infection
Swallowing or aspiration of implant or fragments 

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10.
STATISTICAL ANALYSIS
A Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will 
describe the subject analysis sets to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  Analyses will be carried out using SAS Version 9.4 or higher.
10.1
Analysis Populations
The following analysis sets are defined for analysis purposes:
x
Safety (SAF) analysis set: The SAF analysis set will consist of all randomized subjects
who received the study treatment (Sham procedure or a dose of LYR-210) or treatment
attempt on Day 1. Subjects will be analyzed according to the treatment actually received
or attempted. This is the primary analysis set for safety analyses.
x
Intention-to-treat (ITT) set: The ITT analysis will consist of all randomized subjects who
received the study treatment (Sham procedure or a dose of LYR-210) or treatment
attempt and have post-Day 1 assessments available. Subjects will be analyzed according
to the treatment they were assigned to at randomization. This is the primary analysis set
for efficacy analyses.
x
Per-Protocol (PP) analysis set: The PP analysis set will include all randomized subjects
who received the study treatment, have specific post-Day 1 assessments (i.e., non-
missing data for the assessment being analyzed), and are without major protocol
deviations at the time of the primary analysis. This is a secondary analysis set for the
primary, key secondary, and remaining secondary efficacy analyses. Major protocol
deviations and the definition of the PP analysis set will be identified and finalized based
on blinded review of the data, prior to the data extraction for the primary analysis and
unblinding of the treatment code.
x
Pharmacokinetic (PK) analysis set: The PK analysis set will include all SAF subjects
with at least one evaluable drug concentration post-Day 1. Subjects will be analyzed
according to the successful bilateral treatment received (“actual treatment”). As
concentration data is required to assign the PK analysis set, this can only be done at study
unblinding, at the time of the primary analysis.
10.2
Disposition and Population Assignment
Analysis set assignment will be summarized for all enrolled subjects by randomized treatment.
Subject disposition will be summarized for the ITT set by randomized treatment group and will 
include the total number and percentage of subjects randomized into the study, treated, completed 
the study treatment and the study. The number and percentage of subjects prematurely discontinuing 
from the study treatment and the study will be presented for each treatment group.  Subjects who 
discontinued are categorized into reason for discontinuation; the number and percentage of subjects 
in each category will also be summarized for each treatment group.

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10.3
Demographic and Other Baseline Characteristics
All demographic (age, race, ethnicity, height, weight and BMI) and baseline disease characteristics 
recorded at screening and prior to LYR-210 administration/sham procedure will be summarized, by 
treatment group, for the SAF and ITT analysis sets.  Summaries will include n, mean, standard 
deviation, median, quartiles, and minimum and maximum for continuous variables, and number and 
percentage of subjects in each category for categorial variables.
Medical history, serology, and pregnancy test results will only be listed by subject.
10.4
Prior and Concomitant Medications
Prior medications are those medications that were stopped prior to investigational product 
administration. Concomitant medications are medications that are taken at least once after 
investigational product administration. Medications stopping on the same day as investigational 
product administration will be considered as concomitant medications.
All prior and concomitant medications will be listed. In addition, for each treatment group, the 
number and percentage of subjects taking at least one concomitant medication will be presented.
10.5
Safety Analyses
All safety analyses will be performed using the SAF analysis set. There will be no formal statistical 
tests comparing treatments on safety endpoints and there will be no imputation of missing data.
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened in 
severity during and after the administration of study treatment.
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). For each study treatment, numbers of TEAEs and incidence rates (number 
and percentage of subjects with at least one TEAE) will be tabulated by preferred term and system 
organ class. 
TEAEs by maximum severity, TEAEs by highest relationship to study procedure and product, 
TESAEs, TEAEs leading to death, and TEAEs leading to discontinuation of study treatment will be 
tabulated as (a) total number of such TEAEs occurring across all subjects; and (b) number and 
percentage of subjects with at least one such TEAE for each treatment group overall and by 
preferred term and system organ class.   Note that subjects experiencing >1 event within the same 
system organ class will be tabulated only under the maximum severity and highest relationship 
experienced for that system organ class; similarly, subjects experiencing >1 event within the same 
preferred term will be tabulated only under the maximum severity and highest relationship 
experienced for that preferred term.
All laboratory test results, vital signs measurements, morning serum cortisol levels and IOP will be 
summarized for each treatment group using descriptive statistics by visit for actual value and for 
percentage change from baseline. The incidence of treatment-emergent abnormal and clinically 

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significantly abnormal laboratory, vital sign, morning serum cortisol levels, IOP values and slit-lamp 
examination findings will be summarized by visit for each treatment group using frequency counts 
and percentages of subjects.
10.6
Efficacy Analyses
All efficacy analyses will be carried out after the last subject completes the Week 28 visit or 
withdraws study prematurely prior to Week 28. Each efficacy analysis will be performed based on 
both the ITT and PP analysis sets.
10.6.1
Primary Efficacy Endpoint Analysis
The primary endpoint is CFBL in the composite score of 7-day average scores of the 4 CS cardinal 
symptoms (CS7DA4S) at Week 4. The 4 cardinal symptoms include nasal blockage 
/obstruction/congestion score facial pain/pressure, reduction/loss of sense of smell, and 
anterior/posterior nasal discharge. Specifically, the score for each of the 4 individual components (on
a scale of 0-3) of this composite score will be collected each day by daily electronic patient reported 
outcome (ePRO). The total score across these 4 components will then be calculated each day to 
create a total composite score for each day. At each of Day 1 (prior to procedure) and Week 4 visits,
the average of the total composite score across the preceding 7 days prior to the visit will be 
calculated for each subject. This 7-day per-subject average total composite score is hereafter referred 
to as CS7DA4S. The null and alternative hypotheses to be tested are:
H0: μL2500 = μC
H0: μL7500 = μC
vs.
vs.
H1: μL2500 < μC
H1: μL7500 < μC
where μL2500, μL7500 and μC are true mean primary endpoint for the LYR-210 (2500 μg) treatment, 
the LYR-210 (7500 μg) treatment, and the control (Sham) treatment, respectively. Descriptive 
statistics (number of observations[n], mean, standard deviation, median, minimum and maximum) of 
the Baseline CS7DA4S score, the Week 4 CS7DA4S score, and the CFBL to Week 4 CS7DA4S
score will be presented for each treatment group. 
The primary efficacy analysis will be performed based on subjects in the ITT analysis set with 
available baseline and Week 4 CS7DA4S score. An analysis of covariance (ANCOVA) model for 
CFBL in CS7DA4S score at Week 4 will be used to determine which of the two null hypotheses
stated above can be rejected. This ANCOVA model will include terms for baseline CSD7A4S score 
as a covariate and the fixed  effects of treatment group (LYR-210 7500 μg, LYR-210 2500 μg, sham 
procedure) and the randomization stratification variables, presence of nasal allergy and presence of 
nasal polyps. 
Additional secondary analyses of the primary efficacy endpoint will be performed using this 
ANCOVA model for the following:

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x
Secondary analyses of the endpoint will also be performed in subjects in the PP analysis set
with available data.
x
All subjects in the ITT analysis set. Missing Week 4 CS7DA4S data will be imputed as
described in Section 10.6.1.1.
x
Assessment of treatment effect across study regions, across nasal allergy groups and across
polyp groups will be performed as described in Section 10.6.1.2.
10.6.1.1
Handling of Missing Data
The primary efficacy endpoint analysis will be performed based on subjects in the ITT analysis set
with available CS7DA4S data at Baseline and Week 4 visit. At each of these visits, a subject is 
considered as having an available (NON-missing) CS7DA4S score if the daily ePRO score is 
available (NON-missing) for at least 5 of the preceding 7 days prior to the time point.
For the secondary analyses based on all subjects in the ITT analysis set regardless of available data 
status, two imputation approaches will be carried out for subjects who have missing Week 4 
CS7DA4S data: (a) Last observation carried forward (LOCF) single imputation method; and (b) 
multiple imputation. 
LOCF will be carried out as follows: the CS7DA4S score at each visit will be calculated in a similar 
manner as described above for the Baseline and Week 4 visits (i.e., 7-day average scores of the 4 CS 
cardinal symptoms at that visit).   If Week 4 CS7DA4S is missing, then the last available CS7DA4S 
calculated at a post-baseline visit prior to Week 4 will be carried forward and be used as the Week 4 
CS7DA4S.
The multiple imputation approach will be carried out as follows:
A. Assuming the missing CS7DA4S pattern at Baseline, Weeks 1, 2, 3 and 4 will not be exactly
monotone across visits through Week 4, then a non-monotone missing pattern in CS7DA4S will
be imputed 50 times to make 50 copies of a dataset with a monotone missing CS7DA4S data
pattern; the Monte Carlo Markov Chain approach will be used for this imputation.
B. For each of these 50 imputed datasets, missing CS7DA4S at Week 4 will be imputed using the
monotone linear regression approach: the imputation regression model will include treatment
group, study center/region, randomization strata variables, CS7DA4S measured at Baseline and
Weeks 1, 2, and 3 scores, and Baseline subject and demographic characteristics that will be
fully specified in the SAP.
C. The above-mentioned analysis of covariance comparing treatments on the mean primary
endpoint will be carried out on each of the 50 imputed datasets. The estimate of the treatment
differences in least square means vs. Sham and their standard errors from each imputed dataset
will be combined across the imputed datasets using PROC MIANALYZE in SAS in order to

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calculate one overall estimate of treatment effect vs. Sham and its standard error for each Lyra 
dose group. From these overall estimates, one t-test statistic and its p-value for each LYR-210
dose vs. Sham, assessing whether the above null hypotheses can be rejected, will be calculated 
and presented.
10.6.1.2
Assessment of Treatment Effect Across Study Regions, Across Nasal Allergy 
Groups and Across Polyp Groups
To assess consistency of treatment difference across study region, descriptive statistics of the 
primary endpoint will be presented by treatment group within each region. An exploratory analysis 
of covariance on the primary endpoint, with independent variables of treatment group, region,
baseline CS7DA4S score, and treatment by region interaction, will be carried out on the ITT analysis 
set with available data.
Similar analyses will be presented to assess consistency of treatment effect across nasal allergy 
groups (yes/no) and polyp groups (yes/no). Assessment of consistency across subgroups such as 
baseline CS7DA4S (below median, at or above median), sex and age (below median, at or above 
median) will be conducted as well. All subgroups to be assessed for treatment effect consistency on 
the primary endpoint will be detailed in the statistical analysis plan. These analyses will be carried 
out on the ITT analysis set with available data.
10.6.2
Key Secondary Efficacy Endpoint Analysis
The key secondary endpoints are:
x
CFBL in CS7DA4S score at Week 24
x
Percentage of subjects with at least 1-point decrease in bilateral Zinreich score in at least
one pair of the anterior ethmoid, maxillary, posterior ethmoid, frontal, or sphenoid
sinuses at Week 24
x
Time to treatment failure:  A treatment failure is defined as, after subject enrollment, the
subject being recommended by treating physician for oral corticosteroid or ESS due to
worsening of CS symptoms, or the subject complaint of persistent CS symptoms with an
average CS7DA4S score over the preceding 30 days greater than or equal to the Baseline
CS7DA4S score.
For each key secondary endpoint, each LYR-210 dose will be compared to sham at a one-sided 0.05 
level of significance. There will be no adjustment of the significance level for multiple comparisons 
across the secondary endpoints. 
10.6.2.1
CFBL in CS7DA4S at Week 24
The first key secondary efficacy endpoint is CFBL in CS7DA4S at Week 24. The primary analysis 
population for this key secondary efficacy endpoint analysis is ITT subjects with available 
CS7DA4S data at Baseline and Week 24 visit. At each of these visits, a subject is considered as 

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having an available (NON-missing) CS7DA4S score if the daily ePRO score is available for at least 
5 of the preceding 7 days prior to the time point.
The analysis will be carried out using an ANCOVA model for change from baseline in CS7DA4S 
score at Week 24 which  includes terms for the baseline CS7DA4S score as a covariate, and fixed  
effects for  treatment group and the randomization stratification variables, presence of nasal allergy 
and presence of nasal polyps.
Additional analyses will be performed for the first key secondary endpoint of CFBL in CS7DA4S at 
Week 24, using this ANCOVA model for the following:
x
Subjects in the PP analysis set with available Baseline and Week 24 CS7DA4S score.
x
All subjects in the ITT analysis set. Missing Week 24 CS7DA4S data will be imputed by
LOCF and by multiple imputation (details of imputation of missing data are discussed in
Section 10.6.1.1).
x
Assessment of homogeneity across study regions, across nasal allergy groups and across
polyp groups will be performed in the same manner as for the primary endpoint as described
in Section 10.6.1.2.
10.6.2.2
Percentage of Subjects with Improved bilateral Zinreich score
The second key secondary endpoint is the percentage of subjects with at least 1-point decrease in 
bilateral Zinreich score in at least one pair of the anterior ethmoid, maxillary, posterior ethmoid, 
frontal, or sphenoid sinuses post treatment. Treatment groups will be compared using logistic 
regression adjusting for the baseline total Zinreich score and randomization strata. This analysis will 
be performed using subjects in the ITT analysis set with available post-treatment MRI data and 
repeated with the PP analysis set. There will be no imputation of missing data.
10.6.2.3
Time-to-Treatment Failure
The third key secondary endpoint is the time-to-treatment failure. A treatment failure is defined as, 
after subject enrollment, the subject being recommended by treating physician for oral corticosteroid 
or ESS due to worsening of CS symptoms, or the subject complaint of persistent CS symptoms with 
an average CS7DA4S score over the preceding 30 days greater than or equal to the baseline 
CS7DA4S score. Time to treatment failure will be analyzed using a Cox proportional hazards model 
with fixed effects for available baseline CS7DA4S score, treatment group and the randomization 
stratification variables. Kaplan-Meier plots of time to treatment failure will be presented for each 
treatment group. There will be no imputation of missing data; subjects without the event through 
Week 24 will be censored at the end of their follow-up period. This analysis will be performed using 
subjects in the ITT analysis set with available data and repeated using subjects in the PP set analysis 
set with available data.

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10.6.3
Non-Key Secondary Efficacy Endpoint Analysis
The non-key secondary efficacy endpoints that are continuous variables will be compared between 
treatments at each post-Day 1 in the same manner as the primary endpoint for the ITT set with 
available data and the PP set. In addition, for analyses on all ITT regardless of missing data status, 
LOCF will be used to impute missing secondary efficacy continuous endpoint data. For 
questionnaires (e.g., SNOT-22) at a given visit, if responses are missing for <50% of the questions at 
that visit then the missing responses will be imputed with the median of non-missing responses at 
that visit. Otherwise, if responses are missing for ≥50% of the questions at that visit, the entire 
questionnaire score at that visit will be considered missing and such missing questionnaire scores 
will be imputed as missing data in the same manner as for the other non-key secondary endpoints.
For non-secondary dichotomous efficacy endpoints, the number and percentage of subjects with the 
outcome will be presented for each treatment group.  The proportion of subjects will be analyzed 
using a logistic regression model with effects for baseline CS7DA4S score, treatment group and the 
randomization stratification variables, presence of nasal allergy and presence of nasal polyps. The 
analysis will be carried out on the ITT analysis set with available data and repeated using subjects in 
the PP analysis set with available data.
Secondary efficacy endpoints involving time-to-event endpoints will be analyzed as specified in 
Section 10.6.2.3.
10.6.4
Exploratory Endpoint Analysis
A one-sided 0.05 level of significance will be used to compare treatments for each exploratory 
efficacy endpoint at each visit; there will be no adjustment for multiple comparisons. These analyses 
will be performed in the ITT analysis set with available data and repeated using subjects in the PP 
analysis set. There will be no imputation of missing data for these analyses.
The exploratory efficacy endpoints that are continuous variables will be compared between 
treatments at each post-Baseline time point in the same manner as the primary endpoint.  For 
dichotomous efficacy endpoints, treatments will be compared using logistic regression adjusting for
baseline score and randomization strata.  
As further exploratory analyses on all endpoints measured longitudinally at various visits during the 
study, generalized estimating equation (GEE) linear regression (for continuous outcomes) and GEE 
logistic regression (for dichotomous outcomes) will be used to compare treatments over time; the 
assumed within-subject correlation matrix structure will be unstructured; if the unstructured model 
does not converge, then an autoregressive (1) structure will be assumed. Included as independent 
variables for each outcome variable will be treatment group, visit, treatment-by-visit and the baseline 
value of the variable being analyzed. If the treatment-by-visit interaction is not significant at the 0.10 
level of significance, it will be removed from the GEE model.  This will be carried out on ITT
subjects with available data.

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10.6.5
Pharmacokinetic Analyses 
The PK analyses will be performed based on subjects in the PK analysis set.
10.6.5.1
Pharmacokinetic Concentrations 
PK concentration will be summarized for subjects in the PK analysis set with available data by
treatment group as follows:
x
A listing by subject of all concentrations, nominal times post dose, and actual times.
Deviations from the nominal times per protocol will be given in a separate listing. In listings,
concentrations below the lower limit of quantification (LLOQ) will be reported as “<LLOQ”,
where LLOQ will be the actual value of LLOQ (to be determined).
x
A descriptive statistics summary of concentrations by dose and nominal time post dose,
including number (n), mean, standard error, standard deviation, coefficient of variation (CV),
median, minimum, maximum, geometric mean, geometric CV%, and the number of
concentrations ≥LLOQ. The “<LLOQ” values will be set to zero based on the Beal’s method
M7 [45].
10.6.5.2
Pharmacokinetic Parameters
PK parameters of MF will be estimated using a standard noncompartmental PK approach based on 
individual plasma concentration-time data as data permit (e.g. the availability of the PK study 
cohorts at Day 3, 7, 14, and 21). Actual PK sampling times will be used in the derivation of PK 
parameters. The PK parameters including Cmax and Tmax will be calculated from the plasma 
concentrations versus time profiles. Total drug exposure up to the last measured concentration 
(AUC0-last) and the 12-hour average drug exposure (AUC0-12h average) will be calculated. The AUC0-last
will be defined as the area under the concentration time curve from the time of dose until the last 
concentration above the LLOQ.  The AUC0-12h average is a value derived from AUC0-last by dividing it 
by the corresponding total dose time (in hour) and then multiplying by 12.
10.7
Sample Size
The primary endpoint is CFBL in CS7DA4S score at Week 4. The null and alternative hypotheses to 
be tested are:
H0: μL2500 = μC
H0: μL7500 = μC
vs.
vs.
H1: μL2500 < μC
H1: μL7500 < μC
where μL2500, μL7500 and μC are true mean primary endpoint for the LYR-210 (2500 μg) treatment, 
the LYR-210 (7500 μg) treatment, and the control (Sham) treatment, respectively. Each null 
hypothesis will be tested at the one-sided 0.05 level of significance. Under the assumptions that μC =
-1.30 and μL2500 and/or μL7500 = -3.00 (conservatively based on the mean of this endpoint for LYR-

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210 in Phase I study, and approximately 130% larger decrease than the assumed control mean of -
1.30) and that the true standard deviation of the primary endpoint within each treatment group is at 
most 2.4, then an evaluable sample size of 63 subjects (21 per treatment group) yields 73% power to 
reject at least one null hypothesis in favor of the alternative at a one-sided 0.05 level of significance. 
An additional 6-9 subjects will be enrolled to account for potential subject dropout.

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11.
REGULATORY OBLIGATIONS
11.1
Statements of Compliance 
This clinical investigation shall be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, the International Council for Harmonization (ICH) Good 
Clinical Practices (GCP), United States Food and Drug Administration (USFDA) Guidelines and all 
applicable regulatory requirements. The Sponsor will not commence the clinical study until all 
required approval is obtained from the relevant ECs and, if applicable, Regulatory Authorities. All 
required study documentation will be archived as required by Regulatory Authorities.
Prior to initiating the trial, the investigator will provide the Sponsor or designee all required
documents according to ICH GCP guidelines, and at a minimum:
x
A signed FDA Form 1572
x
A current (i.e. updated no more than 24 months prior) curriculum vitae for the Principal
x
Investigator and each sub-investigator listed on the FDA Form 1572. A copy of the
current medical license for the investigator and each sub-investigator
x
A letter from the IRB/EC stipulating approval of the protocol, the informed consent
document, and any other material provided to potential trial subjects with information
regarding the trial (e.g. advertisements)
x
The current IRB/EC membership list for the reviewing IRB/EC
x
A signed Investigator Protocol Agreement
x
A completed financial disclosure form for the investigator and all sub-investigators
x
A current laboratory certification for the local reference laboratory and curriculum vitae
of the laboratory director
x
A list of current laboratory normal values for the reference laboratory
11.2
Site Selection and Training 
The Sponsor will select Investigators with appropriate training and experience to participate in this 
Clinical Investigation. Sites will be selected based upon the qualifications of the Principal 
Investigator at the site as well as other parameters including proven ability and infrastructure to 
perform clinical studies. The complete list of all site Investigators and the relevant clinical sites will 
be maintained within the Sponsor’s Trial Master File. 
In addition to specific training relating to use of the investigational product, the training of the 
Investigator and appropriate clinical site personnel will be the responsibility of the Sponsor (or 
designee) and may be conducted during an Investigator Meeting, a Site Initiation Visit, or other 
appropriate venue. Training will include, but not be limited to, the Clinical Protocol and 
Investigators’ Brochure, CRF completion, GCP, and Clinical Study personnel responsibilities. All 
training will be documented prior to engaging in study-related activities.

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11.3
Ethics Committee (EC) Approval
The Clinical Protocol and Informed Consent Form (ICF) must have the approval of a properly 
constituted EC responsible for approving clinical studies prior to commencing the study at that site. 
Any additional approval requirement(s) of the EC will be followed. Any advertisements used to 
recruit subjects or any subject facing documents will also be reviewed and approved by the EC prior 
to use. 
No investigative procedures other than those defined in this Clinical Protocol will be undertaken on 
the enrolled subjects without the written agreement of the EC and Sponsor. Each site Principal 
Investigator will advise their EC of the progress of this clinical investigation on a regular basis, 
according to EC reporting requirements. Approvals for the continuation of the study at each 
investigational site must be kept current and notifications forwarded to the Sponsor. 
The Sponsor or its designee will submit reports as required by ECs and local and national 
regulations. These reports may include SAEs, withdrawal of EC or Regulatory Authority’s approval, 
annual progress reports, recall information, and final reports. 
11.4
Informed Consent
The Investigators have both an ethical and legal responsibility to ensure that each subject being 
considered for inclusion in this study is given a full explanation of the Clinical Protocol. 
All foreseeable risks and potential benefits which might occur with the use of the investigational 
product will be discussed with the subject. The subject will be informed that, should an unexpected 
adverse product- or study procedure related AE occur, which presents an unreasonable risk to 
participating subjects, he/she will be notified. The subject will be informed that his/her medical 
records are available for review by representatives of the Sponsor or designee, the EC, and the 
appropriate Regulatory Authority, as necessary. 
The subject will be informed that the information obtained during the study will be used to evaluate 
the safety and performance of the investigational product. However, his/her confidentiality will be 
maintained at all times. The subject will be told that he/she is free to refuse study participation or to 
withdraw from the study at any time without compromising future medical care.
The subject must be made aware and agree that personal information may be reviewed during an 
audit by Regulatory Authority and properly authorized persons. However, personal information will 
be treated as strictly confidential and will not be publicly available. As part of the informed consent 
process, the Investigator will obtain subjects’ permission for the Sponsor personnel or designees, 
EC, and Regulatory Authority to review, in confidence, any pertinent records relating to the subjects
in this clinical investigation. 
A sample subject ICF template with standard wording suggested for this study will be provided to 
each Investigator. A copy of the informed consent form from each site must be forwarded to the 

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Sponsor for review and approval to assure compliance with the ICH requirements prior to submitting 
it to the EC.
The EC-approved written consent form is to be reviewed with the subject by the Investigator or 
designee and will be signed by each subject prior to enrolling in the study. The Investigator or 
designee is responsible for maintaining each subject’s ICF in the study file and providing each 
subject with a copy of the ICF.
If new information becomes available that can significantly affect a subject’s future health and 
medical care, that information shall be provided to the subject affected in written form. If relevant, 
all affected subjects shall be asked to confirm their continuing informed consent in writing. 
11.5
Protocol Amendments 
The Clinical Protocol, eCRFs, ICF and other subject information, or other clinical investigation 
documents shall be amended as needed throughout the clinical investigation, and a justification 
statement shall be included with each amended section of a document. Proposed amendments to the 
Protocol shall be agreed upon between the Sponsor and Principal Investigator. The amendments to 
the Protocol and the subject’s ICF (if required) shall be provided to and approved by, the local 
Regulatory Authorities and ECs, as required. For non-substantial changes (e.g., minor logistical or 
administrative changes, change of monitor[s], telephone numbers, renewal of insurance) not 
affecting the rights, safety, and well-being of human subjects, or not related to the clinical 
investigation objectives or endpoints, a simple notification to the EC and, where appropriate, local 
Regulatory Authority can be sufficient. The version number and date of amendments shall be 
documented.
11.6
Protocol Deviations 
The Investigator agrees to conduct the study according to the Clinical Protocol and agrees that all 
persons delegated to perform study procedures will do so as well. An Investigator is not permitted to 
deviate from the Protocol without the prior written approval of the Sponsor unless there are concerns 
of subject’s safety. Under emergency circumstances, deviations from the Protocol to protect the 
rights, safety, and well-being of human subjects may proceed without prior approval of the Sponsor 
and the EC. Such deviations shall be documented and reported to the Sponsor and the EC (as 
required) as soon as possible.
A protocol deviation is a failure to comply with the requirements specified within this clinical study 
protocol. Examples of protocol deviations may include enrollment of a study subject who does not 
meet all of the inclusion/exclusion criteria specified in the protocol, visits performed outside of the 
protocol specified visit window, and missed study visits. Each site Investigator shall conduct this 
clinical study in accordance with this clinical study protocol, local regulatory authority regulations, 
GCP, and any conditions of approval imposed by their ECs. 

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The Investigator agrees to inform the EC of all protocol deviations according to Institutional 
requirements. The occurrence of protocol deviations will be monitored by the Sponsor personnel or 
designee on an ongoing basis. Deviations from the protocol include, but are not limited to, the use of 
prohibited medications or therapies and out of window visits. All protocol deviations should be 
documented and explained. Major protocol violations are defined as those that could impact the 
performance evaluation such as a subject is ineligible, missing key data, received an unauthorized 
treatment, etc. All subjects with protocol deviations will continue to be followed for safety and 
performance assessments. 
If an Investigator is found to be repeatedly non-compliant with the Clinical Trial Research 
Agreement, study Protocol or any other conditions of the Clinical Study, the Sponsor at its sole 
discretion, will either undertake remedial measures to secure compliance or terminate the 
Investigator's participation in the study.
11.7
Study Monitoring
An appropriate representative of the Sponsor or designee (Study Monitor) will verify subject data 
and ensure compliance with GCP, Clinical Protocol and other study requirements, according to the 
guidelines set forth in the monitoring SOPs and applicable regulatory requirements. The Study 
Monitor will ensure the Investigator continues to have appropriate staff and facilities to conduct the 
Clinical Study safely and effectively. Monitoring will be performed in accordance with a pre-
specified monitoring plan that is in compliance with applicable SOPs.
Completed CRFs will be verified by the monitor at the investigational sites at regular intervals 
throughout the study. The Investigator will allow the monitor and/or representative of the Sponsor, 
and any regulatory body to review and inspect the study files, subject CRFs, subject medical records 
and other related study documents as required.
All CRFs will be reviewed for completeness and clarity. Missing or unclear data will be investigated 
by the monitor and will be retrieved, clarified and completed by study personnel as necessary 
throughout the study. The Sponsor or their authorized representative may request additional 
documentation from the Investigator such as physician procedure notes or physician written 
summaries when adverse events are observed and reported. 
11.8
Data Quality Assurance
The Investigator/designees will maintain accurate source documentation as part of subject case 
histories. Electronic data capture will be utilized for collecting subject data in the clinical database.
Each site is required to have a computer and internet connection available for site entry of clinical 
data. Only authorized users will get access to the eCRF as appropriate to their study responsibilities. 
Site users must have successfully undergone EDC training prior to entering data into the eCRF. The 
Sponsor and CRO will ensure that an appropriate eCRF is developed to capture the data accurately.
The database will allow users to enter data and manage modifications documented by an audit trail.
Appropriate queries will be raised to resolve any missing or inconsistent data within the clinical 

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database. Data management will ensure that all data has been entered, cleaned, closed and signed by 
the Investigator prior to database lock. 
Data Management procedures will be completed in accordance with the CRO’s Standard Operating 
Procedures. The details will be provided in the Data Management Plan for the study.
The Sponsor will also ensure that AE data collected in the eCRF are consistent with information 
provided to the service providers Pharmacovigilance department. The coding of an AE, medical 
history and concomitant medication terms will be performed by the service provider. Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary and 
AEs/medical history terms will be coded using MedDRA.
11.9
Record Retention
Each Investigator will maintain all records pertaining to this Clinical Study as required by local 
regulations, the relevant EC and the Institution. The Investigator will maintain all study related 
documentation including all correspondence, records of financial interest, individual subject records, 
informed consent forms, all investigational product accountability records, the protocol with any/all 
amendments, all correspondence with and approval from all regulatory agencies, the budget 
agreement, the Investigator agreement, and copies of case report forms. 
Essential documents should be retained until at least 2-years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the sponsor. 
It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. No study document will be destroyed without prior written 
agreement between the Sponsor and the Investigator. In addition, in accordance with the Clinical 
Trial Agreement (CTA), the Sponsor should be contacted if the Investigator plans to leave the 
investigational site so that appropriate arrangements can be made for the transfer of the records to 
the appropriate designee at the study site.
11.10
Auditing
The Investigator will make all pertinent records available including source documentation for 
inspection by their EC or a Regulatory Authority and for auditing by the Sponsor or designee. This 
information will be considered confidential. The Sponsor’s or designee’s audit will be independent 
of and separate from routine internal monitoring or quality control function and will serve to 
evaluate the study conduct and compliance with the Protocol, SOPs, GCP, and the applicable 
regulatory requirements.
In the event that an Investigator is contacted by a Regulatory Authority or EC in relation to this 
Clinical Study, the Investigator will notify the Sponsor immediately and must provide the Sponsor 

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with copies of any associated correspondence (e.g. EC Audit Reports, warning letters). The Sponsor 
will provide any necessary support in responding to Regulatory Authority and EC audit requests.
11.11
Use and Publication of Study Results
All unpublished documentation (such as the Clinical Protocol, CRFs, IFU, and IB) given to the 
Investigator is strictly confidential. All recipients must agree not to disclose the information herein 
contained to any person without the prior written authorization of the Sponsor. The submission of 
these documents to the EC is expressly permitted. The Investigator agrees that the Sponsor maintains 
the right to use the results of this study in their original form and/or in a global report for submission 
to governmental and Regulatory Authority of any country.
The data and results from the Clinical Study are the sole property of the Sponsor. The Sponsor shall 
have the right to access and use all data and results generated during the clinical investigation. An 
Investigator may only publish data generated by this Clinical Study in accordance with the terms of 
the Clinical Trial Research Agreement. 
11.12
Confidentiality
The Investigator has a responsibility to ensure that subject anonymity is protected and maintained. 
He or she must also ensure that their identities are protected from any unauthorized parties. All study
data will be stored and archived in line with national and local laws and regulations on the protection 
of personal data. 
Subjects will be informed that the Sponsor or designee will have access to their medical records. 
Data relating to the study may be made available to third parties (e.g., in the case of an audit 
performed by a Regulatory Authority) provided the data are treated confidentially and that the 
subject’s privacy is guaranteed. Subject’s participation in the study will be treated as confidential 
and subject’s will not be referred to by name in any report of the study. Subject confidentiality will 
be maintained throughout the Clinical Study in a manner that ensures the information can always be 
tracked back to the source data. For this purpose, a unique subject identification code will be used 
that allows identification of all data reported for each subject. The identity of the subjects will not be 
disclosed in any study records and subjects’ data will be described using the unique subject
identifier. Subject data will be processed electronically to determine the outcome of this study, and 
to provide to health authorities. Subjects will be advised that all data may be transferred to other 
countries.
11.13
Early Study Discontinuation
The Sponsor reserves the right to discontinue the Clinical Study at any stage, with suitable written 
notice to the Investigator. The Investigator may also discontinue participation in the Clinical Study
with suitable written notice to the Sponsor.
Specific instances that may precipitate site termination include but are not limited to the following 
reasons:

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x
The discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in the
study
x
A decision by the Sponsor to suspend or discontinue testing, evaluation, or development
of the investigational product
x
Failure of the Investigator to enroll subjects into the study at an acceptable rate
x
Failure of the Investigator to comply with pertinent regulations of IRB/EC or appropriate
regulatory authorities
x
Failure of the Investigator to comply with the protocol
x
Submission of knowingly false information from the research facility to the Sponsor, the
study monitor, IRB/EC or regulatory authority
x
Insufficient adherence to protocol requirements consistent with the United States Code of
Federal Regulations (CFR) 21 CFR 312, [insert AUS / NZ standards], the European
Clinical Trial Directive 2001/20/EC, or other relevant national regulations, as appropriate
x
Study termination and follow-up will be performed in compliance with the conditions set
forth in International Council for Harmonization (ICH) E6(R2) on Good Clinical Practice
(GCP) as well as 21 CFR 312.56b, Australian Clinical Trial Handbook, Medsafe
guidelines on the regulations of therapeutic products in New Zealand , the European
Clinical Trial Directive 2001/20/EC, and other relevant national regulations, as
appropriate, which require a Sponsor to ensure an Investigator’s compliance with these
requirements and to promptly secure a plan for compliance or discontinue shipments of
the study drug to the Investigator and end the Investigator’s participation in the study.
If the study is discontinued for any reason, the Sponsor will provide guidelines to the institutions on 
how to safely exit subjects and appropriately close the study. Additionally, if the study is suspended, 
the Sponsor will promptly work with the Investigators/institutions to inform the local Regulatory 
Authorities of the termination or suspension and the reason(s) for the termination or suspension. The 
Investigator should also notify the EC promptly and provide the reason(s) for the termination or 
suspension by the Sponsor or by the Investigator/institution. An appropriate schedule for termination 
will be instituted.

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12.
CLINICAL RISK AND BENEFIT ANALYSIS
Despite the high prevalence of disease, there is no approved drug therapy for the treatment of CS. 
Evidence-based therapies typically involve chronic off-label use of intranasal corticosteroids 
sprays (INCS) with adjunctive use of saline irrigation, and culture directed antibiotics [9]. however,
the effect of INCS is limited by inefficient drug delivery into the deep nasal passage and/or poor 
subject compliance [10, 11].  Second line medical therapy generally used for management of flare-ups 
and worsening inflammation or severe nasal polyps includes a short course (1-3 weeks) of oral 
corticosteroids [2, 3]. While effective initially, improvements are generally not sustained for more than 
3 months [12, 13]. Additionally, oral corticosteroids can lead to systemic side effects including mood 
disturbance, gastrointestinal issues, diabetes, cataracts, glaucoma, osteoporosis and rarely avascular 
necrosis of the hip and shoulder [14, 15]
Subjects enrolled in this Phase II study will include patients who have not had functional endoscopic 
sinus surgery but their symptoms are not adequately controlled on medical management and are 
seeking further treatment. This may include patients who are considering sinus surgery or those who 
have decided against it. The anticipated benefits over existing medical therapies, for subjects in this 
trial (who have failed previous medical management and have limited treatment options) are 
increased control of and local delivery of a known effective anti-inflammatory corticosteroid drug 
(mometasone furoate) to a targeted area that is difficult to reach by intranasal sprays for an extended 
duration of time without the need for daily use compliance. Subjects are expected to experience 
decreased sino-nasal symptoms, assessed and recorded by daily ePRO and the SNOT-22 subject 
reporting instruments (see Section 8.3.1 Subject Reported Outcomes), as well as improvement of
their general physical and mental health assessed by SF-36v2 questionnaire. 
Phase I study subjects had bilateral placement of LYR-210 (2500 μg) under topical anesthesia with 
endoscopic guidance. At the week-24 visit, LYR-210 (2500 μg) was removed using standard 
instruments. No local nasal AEs, including epistaxis, nasal burning, nasal dryness, nasal irritation, 
and nasal septal perforation, were reported.  Mean changes from baseline over time in intraocular 
pressure (IOP) were minimal and not statistically significant. No subject had intraocular 
hypertension (IOP >21 mmHg) and no AEs indicative of high IOP were reported. Mean changes 
from baseline over time in morning serum cortisol levels were minimal and not statistically 
significant. No AEs indicative of adrenal insufficiency were reported. There were no adverse events 
associated with systemic levels of MF. No change in morning serum cortisol levels or intraocular 
pressures were noted (see Section 5.2 of the IB).  
The safety of the active ingredient in LYR-210, mometasone furoate, has been demonstrated across a 
range of commercially approved nasal and oral medication dosage forms including Nasonex® [46],
Asmanex® Twisthaler® [17], Sinuva™ [44] and PropelTM [47] for the treatment  of allergic rhinitis and 
nasal polyps, asthma, nasal polyps in patients who have  had ethmoid sinus surgery, or maintaining 
patency following sinus surgery, respectively.
12.
CLINICAL RISK AND BENE
NEFIT AN
ANALYSIS
Despite the high prevalence of disease, therere e is no o appr
pr
p oved drug therapy for the treatment of CS. 
Evidence-based therapies typically involve chro inic f
off-f label use of intranasal corticosteroids
sprar ys (INCS) with adjuj nctive use of saline irrigation, and
nd culture directed antibiotics [9]. however,
the effect of INCS is limited by
by ine
nefficient dru
r g de
deliliverery ininto the deep nasal passage and/or poor 
su
subject compliance [10, 11].  Sec
econ
ond line med
edical therapy generally used for management of flare-ups s 
and worsening inflammation or severe nasal polyps includes a short course (1-3 weeks) of oral 
corticosteroids [2, 3]. While effective initially, improvements are generally not sustained for more than 
3 months [12, 13]. Additionally, oral corticosteroids can lead to systemic side effects including mood 
disturbance, gastrointestinal issues, diabetes, cataracts, glaucoma, osteoporosis and rarely avascular 
necrosis of the hip and shoulder [14, 15]
Subjects enrolled in this Phase II study will include patients who have not had functional endoscopic 
sinus surgery but their symptoms are not adequately controlled on medical management and are 
seeking further treatment. This may include patients who are considering sinus surgery or those who 
have decided against it. The anticipated benefits over existing medical therapies, for subjects in this 
trial (who have failed previous medical management and have limited treatment options) are 
increased control of and local delivery of a known effective anti-inflammatory corticosteroid drug
(mometasone furoate) to a targeted area that is difficult to reach by intranasal sprays for an extended 
duration of time without the need for daily use compliance. Subjects are expected to experience 
decreased sino-nasal symptoms, assessed and recorded by daily ePRO and the SNOT-22 subject
reporting instruments (see Section 8.3.1 Subject Reported Outcomes), as well as improvement of
their general physical and mental health assessed by SF-36v2 questionnaire. 
Phase I study subjects had bilateral placement of LYR-210 (2500 μg) under topical anesthesia with
endoscopic guidance. At the week-24 visit, LYR-210 (2500 μg) was removed using standard 
instruments. No local nasal AEs, including epistaxis, nasal burning, nasal dryness, nasal irritation,
and nasal septal perforation, were reported.  Mean changes from baseline over time in intraocular 
pressure (IOP) were minimal and not statistically significant. No subject had intraocular 
hypertension (IOP >21 mmHg) and no AEs indicative of high IOP were reported. Mean changes 
from baseline over time in morning serum cortisol levels were minimal and not statistically 
significant. No AEs indicative of adrenal insufficiency were reported. There were no adverse events 
associated with systemic levels of MF. No change in morning serum cortisol levels or intraocular 
pressures were noted (see Section 5.2 of the IB).  
The safety of the active ingredient in LYR-210, mometasone furoate, has been demonstrated acros
oss s a
range of commercially approved nasal and oral medication dosage forms including Nasonex® [46],
Asmanex® Twisthaler® [17], Sinuva™ [44] and PropelTM [47] for the treatment  of allergic rhinitis and 
na
n sa
s l polyps, asthma, nasal polyps in patients who have  had ethmoid sinus surgery
r , or
or ma
m intaini ing
pa
pa
p tet ncy following sinus surgery, respectively.

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In terms of the bioabsorbable polymers; polyester families have a long history of use in 
bioabsorbable medical sutures such as Vicryl® (PLGA 10:90) and Monocryl® (PGCL 75:25) from 
Ethicon (Bridgewater, NJ, USA) and the PLCL suture from Catgut GmbH (Markneukirchen, 
Germany). These polymers are also used extensively as inactive ingredients for sustained release of 
parenteral drugs [48] (see Section 4.1 of the IB).  
Risks Analysis
Potential risks to the trial subjects are similar to those associated with endoscopy procedures and 
current therapies using local or systemic delivery of MF. More detailed information regarding 
clinical safety data can be found Section 9 (Safety Information of Study Drug Product) and in the IB 
(Section 6 Summary of Data and Guidance for the Investigator and Section 7 Reference Safety 
Information).
In clinical evaluations to date (Phase I clinical study) treatment-emergent adverse events (TEAE)
that occurred in more than 1 subject (TEAEs) have been adverse drug reaction (rash), facial pain, 
nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, headache, and nasal odor, 
and were reported in 14/20 subjects (see Section 5.2 of IB). All these events were considered to be 
non-serious, mild or moderate in severity, and anticipated risks related to endoscopic procedures. 
There were no reported AEs due to the removal procedure.
The possible risks and the highest incidence rates reported in clinical studies of similar products 
and/or LYR-210 Phase I study that are related to endoscopic procedures include procedural 
headache, epistaxis (moderate), facial pain, nasal congestion, nasal discomfort, parosmia, post 
procedural discomfort and presyncope (see Section 5.2 of IB).
Subjects will be closely monitored as part of the trial with subject safety monitored according to 
Medical Monitoring Plan (MMP) which defines in detail objectives, scope and roles and 
responsibilities of each team member involved (see Section 8.4.10 Safety Monitoring). Safety 
monitoring will be followed strictly in accordance with the study MMP.
An independent Data Monitoring Committee (DMC) will be formed by charter to assist in 
examining safety data periodically during the study (see Section 4.5 Data Monitoring Committee).
The DMC can recommend treatment discontinuation for individual subjects as well as to halt the 
entire study temporarily or permanently. Predefined stopping rules will guide the DMC review 
process. 
Extensive inclusion and exclusion criteria will also apply (see Sections 5.3 Inclusion Criterion and 
5.4 Exclusion Criterion) for which both the risks with MF and endoscopy procedures have been fully 
considered.  These include those contraindications detailed in the product literature for approved MF 
Nasal Sprays, such as excluding those subjects with localized infection, those who have experienced 
recent nasal surgery and those who are immunosuppressed (Nasonex® product literature).  
In terms of the bioabsorbable polymers; polylyes
e ter fami
mililies have a long history of use in 
bioabso
sorb
rbab
ablele medical sutures such as Vicrylyl® (P
( LGA 
A 10:90) and Monocryl® (P
(PGCL 75:25) from 
Ethicon (Bridgewater, NJ, USA)
A  and the PLC
LCL suture from Catgut GmbH (Markneukirchen, 
Germany). These polymers arere also used extensively as ininactive ingredients for sustained release of 
pa
parenteral drugs
gs [48] (s(see
ee Sec
ectition
on 4.1.1 of the IB
IB). 
Ri
Risks Analysis
Potential risks to the trial subjects are similar to those associated with endoscopy procedures and 
current therapies using local or systemic delivery of MF. More detailed information regarding 
clinical safety data can be found Section 9 (Safety Information of Study Drug Product) and in the IB
(Section 6 Summary of Data and Guidance for the Investigator and Section 7 Reference Safety 
Information).
In clinical evaluations to date (Phase I clinical study) treatment-emergent adverse events (TEAE)
that occurred in more than 1 subject (TEAEs) have been adverse drug reaction (rarash), facial pain, 
nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, headache, and nasal odor, 
and were reported in 14/20 subjects (see Section 5.2 of IB). All these events were considered to be
non-serious, mild or moderate in severity, and anticipated risks related to endoscopic procedures. 
There were no reported AEs due to the removal procedure.
The possible risks and the highest incidence rates reported in clinical studies of similar products 
and/or LYR-210 Phase I study that are related to endoscopic procedures include procedural
headache, epistaxis (moderate), facial pain, nasal congestion, nasal discomfort, parosmia, post
procedural discomfort and presyncope (see Section 5.2 of IB).
Subjects will be closely monitored as part of the trial with subject safety monitored according to
Medical Monitoring Plan (MMP) which defines in detail objectives, scope and roles and 
responsibilities of each team member involved (see Section 8.4.10 Safety Monitoring). Safety 
monitoring will be followed strictly in accordance with the study MMP.
An independent Data Monitoring Committee (DMC) will be formed by charter to assist in 
examining safety data periodically during the study (see Section 4.5 Data Monitoring Committee).
The DMC can recommend treatment discontinuation for individual subjects as well as to halt the 
entire study temporarily or permanently. Predefined stopping rules will guide the DMC review 
process. 
Extensive inclusion and exclusion criteria will also apply (see Sections 5.3 Inclusion Criterion and 
5.4 Exclusion Criterion) for which both the risks with MF and endoscopy procedures have been fully 
considered.  These include those contraindications detailed in the product literature for r ap
appr
prov
oved MF
Nasal Sprays, such as excluding those subjects with localized infection, those who have experienced 
rerecent nasal surgery and those who are immunosuppressed (Nasonex® product literatuturere).)   

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STUDY LYR-210-2018-002
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PROPRIETARY AND CONFIDENTIAL
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Following the use of intranasal corticosteroids, instances of increased intraocular pressure have been 
reported (Nasonex®). Subjects who have had past or present acute or chronic intracranial or orbital 
complications of CS (e.g., brain abscess, related problems with eyes or central nervous system) or a 
history/diagnosis (in either eye) of glaucoma or ocular hypertension (IOP > 21 mmHg) will be 
excluded from this trial. Nasonex is also not recommended in cases of nasal septum perforation; 
again, subjects with evidence of mucosal erosion and ulceration or nasal septal perforation will be 
excluded from this trial. In addition, subject who have had more than 1 episode of epistaxis bleeding 
requiring medical attention within 2 months of screening visit or more than 1 episode of epistaxis 
with frank bleeding within 1 month of screening visit, will be excluded (epistaxis is mentioned in 
Section 4.4 Special warnings and precautions of the summary of product characteristics (SmPC) of
Nasonex®).
Subjects with complete/near complete middle meatal obstruction preventing proper placement and/or 
visualization of LYR-210, will also be excluded. 
Strict subject withdrawal/discontinuation criteria will also apply (see Section 4.3 Discontinuation of 
Study Subjects) including any serious AE (SAE), clinically significant AE, severe laboratory 
abnormality, intercurrent illness, or other medical condition that indicates to the Investigator that 
continued participation is not in the best interest of the subject. Subjects will be withdrawn from the 
study if they require systemic corticosteroid medication or surgical intervention.
Prior and concomitant medications criteria is specified (see Sections 6.4.2 Prohibited Concomitant 
Medications and 6.4.3 Permitted Concomitant Medications) to avoid confounding the efficacy and 
safety assessment and LYR-210 and specific rescue medication is recommended for an acute 
exacerbation of symptoms that has lasted ≥ 7 days and resulted in the subject contacting the 
Investigator (see Section 6.4.4 Rescue Concomitant Medications).
In the Phase I study, in 5 of the 20 subjects, 1 of the bilaterally administered LYR-210 was expelled 
through the nose while sneezing or coughing between week-9 and week-21 post treatment; 4 of the 5 
dislodgements occurred after week 14. The final drug depot retention rate was 86.1% at week 24 
visit, the highest retention rate reported to date (see Section 5.3 of IB). No AEs were associated with 
these drug depot dislodgements. In the Phase II study, if spontaneous dislodgement of LYR-210
occurs before the scheduled removal visit at Week 24, subjects are required to call the study clinic 
immediately. Subject will remain in the study unless an early treatment discontinuation is 
recommended by the treating physician subject requests depot removal from the remaining side of 
the nose, or depots spontaneously dislodged from both sides of the nose (see Section 4.1.2).
Only Investigators with substantial experience in endoscopic interventions will be allowed to 
participate in the Study. Once selected, Investigators will undergo product-specific training prior to 
enrolling subjects.
Through a systematic analysis of relevant commercially approved MF drugs and based on the Phase 
Following the use of intranasal corticosteroids,s  instanc
nces
es of increased intraocular pressure have been 
reported (Nasonex®). Subjects who have had past or pr
present acute or chronic intntracranial or orbital 
complications of CS (e.g., brainin abscess, related problems with eyes or central nervous system) or a 
hihists ory/diagnosis (in either eye
ye) of glaucoma or ocular hy
hypertension (IOP > 21 mmHg) will be 
ex
excluded from ththisis tririalal. Na
Naso
sone
nex x isis alslso not t recomm
mmen
ende
d d d inin cases of nasal septum perforation;
again, subjects with evidence of mucosal ero
rosion an
and lulce
ceration or nasal septal perforation will be 
excluded from this trial. In addition, subject who have had more than 1 episode of epistaxis bleeding 
requiring medical attention within 2 months of screening visit or more than 1 episode of epistaxis 
with frank bleeding within 1 month of screening visit, will be excluded (epistaxis is mentioned in 
Section 4.4 Special warnings and precautions of the summary of product characteristics (SmPC) of
Nasonex®).
Subjects with complete/near complete middle meatal obstruction preventing proper placement and/or 
visualization of LYR-210, will also be excluded. 
Strict subject withdrawal/discontinuation criteria will also apply (see Section 4.3 Discontinuation of 
Study Subjects) including any serious AE (SAE), clinically significant AE, severe laboratory 
abnormality, intercurrent illness, or other medical condition that indicates to the Investigator that
continued participation is not in the best interest of the subject. Subjects will be withdrawn from the 
study if they require systemic corticosteroid medication or surgical intervention.
Prior and concomitant medications criteria is specified (see Sections 6.4.2 Prohibited Concomitant 
Medications and 6.4.3 Permitted Concomitant Medications) to avoid confounding the efficacy and 
safety assessment and LYR-210 and specific rescue medication is recommended for an acute 
exacerbation of symptoms that has lasted ≥ 7 days and resulted in the subject contacting the 
Investigator (see Section 6.4.4 Rescue Concomitant Medications).
In the Phase I study, in 5 of the 20 subjects, 1 of the bilaterally administered LYR-210 was expelled 
through the nose while sneezing or coughing between week-9 and week-21 post treatment; 4 of the 5 
dislodgements occurred after week 14. The final drug depot retention rate was 86.1% at week 24 
visit, the highest retention rate reported to date (see Section 5.3 of IB). No AEs were associated with 
these drug depot dislodgements. In the Phase II study, if spontaneous dislodgement of LYR-210
occurs before the scheduled removal visit at Week 24, subjects are required to call the study clinic 
immediately. Subject will remain in the study unless an early treatment discontinuation is 
recommended by the treating physician subject requests depot removal from the remaining side of 
the nose, or depots spontaneously dislodged from both sides of the nose (see Section 4.1.2).
Only Investigators with substantial experience in endoscopic interventions will be allowed to
participate in the Study. Once selected, Investigators will undergo product-specific traininining pr
prioi r to 
enrolling subjects.
Th
Th
T rough a systematic analysis of relevant commercially approved MF drugs and based d on
on the Phase
se

LYRA THERAPEUTICS, INC.
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PAGE 107 OF 129
I clinical results of LYR-210 and the safety assessments and measures implemented in the Phase II 
clinical trial, the potential benefits of LYR-210 outweigh the potential associated risks and support 
conducting the proposed Phase II clinical trial. 
I clc inical resultsts of LY
LYR-21
210 an
and ththe sa
safefetyty assessm
smen
entsts and
nd mea
easu
sureres im
implplem
emented in the Phase II 
clinical trial, the potential benefits of LYR-210 outweigh the potential associateted risks and support 
conducting the proposed Phase II clinical trial. 

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13.
LIST OF REFERENCES
1. Global Initiative for Asthma. 2018 GINA report: Global strategy for asthma management and
prevention. Availalble at: Accessed October 2, 2018.
2. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps
2012. Rhinology. 2012; 1-298.
3. Orlandi RR, Kingdom TT, Hwang PH. International consensus statement on allergy and
rhinology: Rhinosinusitis executive summary. International Forum of Allergy & Rhinology. 2016;
6:S3-S21.
4. Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe – an underestimated
disease. A GA2LEN study. Allergy. 2011; 66:1216-1223.
5. Hamilos DL. Chronic rhinosinusitis: Epidemiology and medical management. The Journal of
Allergy and Clinical Immunology. 2011; 128:693-707; quiz 708-9.
6. Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: definitions, diagnosis,
epidemiology, and pathophysiology. Otolaryngology–Head and Neck Surgery. 2003; 129:S1-S32.
7. Smith KA, Orlandi RR, Rudmik L. Cost of adult chronic rhinosinusitis: A systematic review. The
Laryngoscope. 2015; 125:1547-1556.
8. van Agthoven M, Uyl-de Groot CA, Fokkens WJ, et al. Cost analysis of regular and filgrastim
treatment in patients with refractory chronic rhinosinusitis. Rhinology. 2002; 40:69-74.
9. Rudmik L, Hoy M, Schlosser RJ, et al. Topical therapies in the management of chronic
rhinosinusitis: An evidence-based review with recommendations. International Forum of Allergy &
Rhinology. 2013; 3:281-298.
10. Moeller W, Schuschnig U, Meyer G, et al. Ventilation and aerosolized drug delivery to the
paranasal sinuses using pulsating airflow - a preliminary study. Rhinology. 2009; 47:405-12.
11. Nabi S, Rotenberg BW, Vukin I, et al. Nasal spray adherence after sinus surgery: Problems and
predictors. Journal of Otolaryngology - Head & Neck Surgery. 2012; 41:S49-55.
12. Vaidyanathan S, Barnes M, Williamson P, et al. Treatment of chronic rhinosinusitis with nasal
polyposis with oral steroids followed by topical steroids: A randomized trial. Annals of Internal
Medicine. 2011; 154:293-302.
13. Van Zele T, Gevaert P, Holtappels G, et al. Oral steroids and doxycycline: Two different
approaches to treat nasal polyps. Journal of Allergy and Clinical Immunology. 2010; 125:1069-
1076.e4.
14. Rudmik L, Soler ZM. Medical therapies for adult chronic sinusitis: A systematic review. The
Journal of the American Medical Association. 2015; 314:926-939.
15. Poetker DM, Reh DD. A comprehensive review of the adverse effects of systemic
corticosteroids. Otolaryngologic Clinics of North America. 2010; 43:753-768.
16. Young LC, Stow NW, Zhou L, et al. Efficacy of medical therapy in treatment of chronic
rhinosinusitis. Allergy Rhinol (Providence). 2012; 3:e8-e12.
17. Sanjay P, Dodds A, Miller E, et al. Cancelled elective operations: an observational study from a
district general hospital. Journal of Health Organization and Management. 2007; 21:54-58.
18. Merck & Co., Inc. NDA 20762 Drug Approval Package, NASONEX®(mometasone furoate
monohydrate) Nasal Spray, 50 mcg. Availalble at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020762_nasonex_toc.cfm. Accessed
September 29, 2018.
19. Zitt M, Kosoglou T, Hubbell J. Mometasone furoate nasal spray: A review of safety and
systemic effects. Drug Safety. 2007; 30:317-326.

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20. Walters T, Bafna S, Vold S. Efficacy and safety of sustained release dexamethasone for the
treatment of ocular pain and inflammation after cataract surgery: results from two phase 3 studies.
Journal of Clinical & Experimental Ophthalmology. 2016; 7:1-11.
21. Westphal M, Ram Z, Riddle V, et al. Gliadel® wafer in initial surgery for malignant glioma:
long-term follow-up of a multicenter controlled trial. Acta Neurochirurgica. 2006; 148:269-275.
22. Forwith KD, Chandra RK, Yun PT, et al. ADVANCE: A multisite trial of bioabsorbable steroid-
eluting sinus implants. Laryngoscope. 2011; 121:2473-2480.
23. Marple BF, Smith TL, Han JK, et al. Advance II: A prospective, randomized study assessing
safety and efficacy of bioabsorbable steroid-releasing sinus implants. Otolaryngology - Head and
Neck Surgery. 2012; 146:1004-1011.
24. Han JK, Forwith KD, Smith TL, et al. RESOLVE: A randomized, controlled, blinded study of
bioabsorbable steroid-eluting sinus implants for in-office treatment of recurrent sinonasal polyposis.
International Forum of Allergy & Rhinology. 2014; 4:861-870.
25. Kern RC, Stolovitzky JP, Silvers SL, et al. A phase 3 trial of mometasone furoate sinus implants
for chronic sinusitis with recurrent nasal polyps. International Forum of Allergy & Rhinology. 2018;
8:471-481.
26. American Rhinologic Society. ARS position statement on drug-eluting implant. Availalble at:
https://www.american-rhinologic.org/index.php?option=com_content&view=article&id=32:drug-
eluting-implants&catid=26:position-statements&Itemid=197. Accessed May 15, 2019.
27. Hopkins C, Gillett S, Slack R, et al. Psychometric validity of the 22-item Sinonasal Outcome
Test. Clinical Otolaryngology. 2009; 34:447-454.
28. Toma S, Hopkins C. Stratification of SNOT-22 scores into mild, moderate or severe and
relationship with other subjective instruments. Rhinology. 2016; 54:129-33.
29. DeConde AS, Bodner TE, Mace JC, et al. Response shift in quality of life after endoscopic sinus
surgery for chronic rhinosinusitis. JAMA Otolaryngology-- Head & Neck Surgery. 2014; 140:712-
719.
30. Scoggins JF, Patrick DL. The use of patient-reported outcomes instruments in registered clinical
trials: Evidence from ClinicalTrials.gov. Contemporary Clinical Trials. 2009; 30:289-292.
31. Optum. PSF-36v2® Health Survey Measurement Model. Availalble at:
https://www.optum.com/content/dam/optum/resources/Manual%20Excerpts/SF-36v2-Health-
Survey-Measurement-Model.pdf. Accessed June 1, 2020.
32. Likness MM, Pallanch JF, Sherris DA, et al. Computed tomography scans as an objective
measure of disease severity in chronic rhinosinusitis. Otolaryngology--Head and Neck Surgery.
2014; 150:305-311.
33. Doty RL, Shaman P, Dann M. Development of the university of pennsylvania smell
identification test: A standardized microencapsulated test of olfactory function. Physiology &
Behavior. 1984; 32:489-502.
34. Douglas RG, Psaltis AJ, Rimmer J, et al. Phase 1 clinical study to assess the safety of a novel
drug delivery system providing long-term topical steroid therapy for chronic rhinosinusitis.
International Forum of Allergy & Rhinology. 2019; 9:378-387.
35. Keck T, Leiacker R, Riechelmann H, et al. Temperature Profile in the Nasal Cavity. The
Laryngoscope. 2000; 110:651-654.
36. Crim C, Pierre LN, Daley-Yates PT. A review of the pharmacology and pharmacokinetics of
inhaled fluticasone propionate and mometasone furoate. Clinical Therapeutics. 2001; 23:1339-1354.
37. Kosoglou T, Hubbell J, Kantesaria B, et al. An evaluation of the systemic bioavailability of
mometasone furoate (MF) after oral inhalation from a MF/formoterol fumarate metered-dose inhaler

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versus an MF dry-powder inhaler in healthy subjects. Clinical Pharmacology in Drug Development. 
2014; 3:229-234.
38. Daley-Yates PT, Kunka RL, Yin Y, et al. Bioavailability of fluticasone propionate and
mometasone furoate aqueous nasal sprays. European Journal of Clinical Pharmacology. 2004;
60:265-268.
39. Merck & Co., Inc. NDA 21067 Drug Approval Package, ASMANEX® TWISTHALER® 110
mcg, 220 mcg (mometasone furoate inhalation powder). Availalble at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021067s000_AsmanexTOC.cfm.
Accessed October 8, 2018.
40. Kosoglou T, Hubbell J, Xuan F, et al. Comparison of the systemic bioavailability of mometasone
furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler
versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary
disease. International Journal of Chronic Obstructive Pulmonary Disease. 2013; 8:107-116.
41. Minshall E, Ghaffar O, Cameron L, et al. Assessment by nasal biopsy of long-term use of
mometasone furoate aqueous nasal spray (Nasonex) in the treatment of perennial rhinitis.
Otolaryngology–Head and Neck Surgery. 1998; 118:648-54.
42. Bross-Soriano D, Hanenberg-Milver C, Schimelmitz-Idi J, et al. Effects of three nasal topical
steroids in the intraocular pressure compartment. Otolaryngology–Head and Neck Surgery. 2004;
130:187-91.
43. Intersect ENT, Inc. NDA 209310 Drug Approval Package, SINUVATM (mometasone furoate)
sinus implant. Availalble at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209310Orig1s000TOC.cfm. Accessed
February 08, 2019.
44. Ozkadif S, Eken E. Three-dimensional reconstruction of multidetector computed tomography
images of paranasal sinuses of New Zealand rabbits. Turkish Journal of Veterinary and Animal
Science. 2013; 37:675-681.
45. Beal SL. Ways to Fit a PK Model with Some Data Below the Quantification Limit. Journal of
Pharmacokinetics and Pharmacodynamics. 2001; 28:481-504.
46. Young LC, Stow NW, Zhou L, et al. Efficacy of medical therapy in treatment of chronic
rhinosinusitis. Allergy & Rhinology (Providence, R.I.). 2012; 3:e8-e12.
47. Perloff JR, Palmer JN. Evidence of bacterial biofilms in a rabbit model of sinusitis. American
Journal of Rhinology & Allergy. 2005; 19:1-6.
48. Chaubal M. Polylactides/Glycolides - Excipients for injectable drug delivery & beyond. Drug
Delivery Technology. 2002; 2:34-36.

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14.
APPENDICES
14.1
Daily Electronic Subject Reported Outcome (ePRO)
Below you will find questions about 4 major symptoms of your chronic sinusitis and your daily use 
of saline irrigation. We would appreciate your answering these questions to the best of your ability. 
There are no right or wrong answers. 
Please rate your 4 major symptoms as how bad they have been within the past one hour by selecting
the severity that best describes how you feel.
1. Please rate your nasal blockage/obstruction/congestion:
0 = absent symptoms 
(no sign/symptom evident) 
1 = mild symptoms 
(sign/symptom present but minimal awareness; easily tolerated) 
2 = moderate symptoms 
(definite awareness of sign/symptom that is bothersome but tolerable) 
3 = severe symptoms 
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
2. Please rate your nasal discharge (anterior/posterior nasal drip):
0 = absent symptoms 
(no sign/symptom evident) 
1 = mild symptoms 
(sign/symptom present but minimal awareness; easily tolerated) 
2 = moderate symptoms 
(definite awareness of sign/symptom that is bothersome but tolerable) 
3 = severe symptoms 
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
3. Please rate your facial pain/pressure:
0 = absent symptoms 
(no sign/symptom evident) 
1 = mild symptoms 
14.1
Daily Electronic Subject Reported Ou
O tcome (ePRO)
Below you will find questions about 4 major symp
mptoms of your chronic sinusitis and your daily use 
ofof saline irrigation. We would appreciate yo
your ans
nswe
we
w riring
ng these questions to the best of your ability. 
Th
Ther
e e are no right or wrong answers. 
Please rate your 4 major symptoms as how bad the
hey ha
h ve
ve been within the past one hour by selecting
the severity that best describes how you feel.
1. Please rate your nasal blockage/obstruction/congestion:
0 = absent symptoms
(no sign/symptom evident) 
1 = mild symptoms
(sign/symptom present but minimal awareness; easily tolerated) 
2 = moderate symptoms
(definite awareness of sign/symptom that is bothersome but tolerable) 
3 = severe symptoms
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
2. Please rate your nasal discharge (anterior/posterior nasal drip):
0 = absent symptoms
(no sign/symptom evident) 
1 = mild symptoms
(sign/symptom present but minimal awareness; easily tolerated) 
2 = moderate symptoms 
(definite awareness of sign/symptom that is bothersome but tolerable) 
3 = severe symptoms
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
3. Please rate your facial pain/pressure:
0 = absent symptoms
(no sign/symptom evident) 
1 = mild symptoms
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